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The role of stress in addiction relapse

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Abstract

Stress is an important factor known to increase alcohol and drug relapse risk. This paper examines the stress-related processes that influence addiction relapse. First, individual patient vignettes of stress- and cue-related situations that increase drug seeking and relapse susceptibility are presented. Next, empirical findings from human laboratory and brain-imaging studies that are consistent with clinical observations and support the specific role of stress processes in the drug-craving state are reviewed. Recent findings on differences in stress responsivity in addicted versus matched community social drinkers are reviewed to demonstrate alterations in stress pathways that could explain the significant contribution of stress-related mechanisms on craving and relapse susceptibility. Finally, significant implications of these findings for clinical practice are discussed, with a specific focus on the development of novel interventions that target stress processes and drug craving to improve addiction relapse outcomes.

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... Importantly, AUD is diagnosed based on symptoms, but identifying the underlying dysfunction that maintains alcohol use is critical for precision medicine initiatives (Witkiewitz et al., 2019), and individuals with AUD likely have dysfunction across AARDoC domains. For example, craving is a construct of rewardseeking preoccupation (incentive salience domain), which can be induced by substance-related and stress-/negative affect-related cues (i.e., cue reactivity, negative emotionality; Koob & Volkow, 2010;Sinha, 2007). Negative affect and stress-related behavioral triggers are also strongly associated with alcohol craving, AUD relapse, and AUD symptomology Koob & Volkow, 2016;Seo et al., 2013;Sinha, 2007Sinha, , 2008Sinha et al., 2011). ...
... For example, craving is a construct of rewardseeking preoccupation (incentive salience domain), which can be induced by substance-related and stress-/negative affect-related cues (i.e., cue reactivity, negative emotionality; Koob & Volkow, 2010;Sinha, 2007). Negative affect and stress-related behavioral triggers are also strongly associated with alcohol craving, AUD relapse, and AUD symptomology Koob & Volkow, 2016;Seo et al., 2013;Sinha, 2007Sinha, , 2008Sinha et al., 2011). Continued research on neurobiological and behavioral phenotypes of AUD, including the AARDoC domains, is paramount to understanding its underlying etiology and toward the development of interventions that target aberrant neural mechanisms. ...
... Alcohol and drugs are chronically used in these negative affective states because alcohol and drugs are seemingly effective in providing short-term relief from discomfort. Over time, deficits in the motivational salience neural networks in response to chronic stress are then associated with addiction (Sinha, 2007(Sinha, , 2008Sinha et al., 2011). As stress-related heavy drinking induces glucocorticoid secretion and corticostriatal stimulation, acute alcohol intake in response to stress is thought to yield both reinforcement and an opponent-process mechanism of alcohol tolerance Koob, 1996;Koob et al., 2014). ...
Article
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Background The Alcohol and Addiction Research Domain Criteria (AARDoC) proposes that alcohol use disorder is associated with neural dysfunction in three primary domains: incentive salience, negative emotionality, and executive function. Prior studies in heavy drinking samples have examined brain activation changes associated with alcohol and negative affect cues, representing the incentive salience and negative emotionality domains, respectively; yet studies examining such cue‐induced changes in functional connectivity are relatively sparse. Methods Non‐treatment seeking heavy drinking adults (N=149, 56.0% male, 48.6% non‐white, average age 34.8 years (SD=10.0)) underwent functional magnetic resonance imaging during presentation of alcohol, negative, and neutral pictures. We focused on functional connectivity (FC) changes involving the nucleus accumbens and amygdala in addition to activation and FC correlations with self‐reported AUD severity. Results For alcohol cues versus neutral cues, we observed accumbens FC changes in the cerebellum and prefrontal cortex, and amygdala FC changes with occipital, parietal, and hippocampal regions. AUD severity positively correlated with activation in the cerebellum (p<0.05), accumbens FC in the cingulate gyri, somatosensory gyri, and cerebellum (p<0.05), and with amygdala FC in the prefrontal cortex and inferior parietal lobule (p<0.05) during alcohol cues. For negative cues versus neutral cues, we observed accumbens FC changes in the lateral temporal, occipital, and parietal regions, and amygdala FC changes in the fusiform and lingual gyri (p<0.05). Conclusions The present findings provide empirical support for the AARDoC domains of incentive salience and negative emotionality and indicate that AUD severity is associated with salience and response control for reward cues. When co‐varying for differences in non‐alcohol substance use and mood disorder diagnoses, AUD severity was also found to be associated with emotional reactivity for negative cues.
... In contrast, planning allows flexible decision making by assessing 20 the outcomes allowed by the environment, among the accessible courses of action. This 21 behavioural modality requires an 'internal model' of the agent-environment interactions, 22 to link candidate actions to their expected outcomes, on the grounds of previous 23 experience. A complex environment requires a substantial amount of exploration [19][20][21] 24 to be correctly represented in a useful and precise model. ...
... A complex environment requires a substantial amount of exploration [19][20][21] 24 to be correctly represented in a useful and precise model. In turn, the assessment of the 25 ramification of action-outcome represented in a complex internal model requires 26 significant cognitive resources and is negatively affected by any impairment of cognitive 27 capabilities, as for instance due to anxiety or stress [22][23][24]. 28 Despite its importance for both planning and habitual responses, the relation 29 between behaviour and environment complexity has received limited attention in 30 computational studies of addiction. It is generally accepted that environment 31 complexity hinders cognitive performance and may lead to maladaptive decisions beside 32 addictive behaviours [25][26][27][28][29][30]. ...
... A 330 dysfunctional MB component plays an important role in shaping behaviours even 331 in absence of drug related stimuli. This assumption is motivated by the 332 unlikelyhood that generalizations of drug-related sub-optimal behaviours in 333 drug-unrelated parts of the environment can be regulated by the MF omponent 334 (e.g. as in relapse[22,107]). ...
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Several decision-making vulnerabilities have been identified as underlying causes for addictive behaviours, or the repeated execution of stereotyped actions despite their adverse consequences. These vulnerabilities are mostly associated with brain alterations caused by the consumption of substances of abuse. However, addiction can also happen in the absence of a pharmacological component, such as seen in pathological gambling and videogaming. We use a new reinforcement learning model to highlight a previously neglected vulnerability that we suggest interacts with those already identified, whilst playing a prominent role in non-pharmacological forms of addiction. Specifically, we show that a duallearning system (i.e. combining model-based and model-free) can be vulnerable to highly rewarding, but suboptimal actions, that are followed by a complex ramification of stochastic adverse effects. This phenomenon is caused by the overload of the capabilities of an agent, as time and cognitive resources required for exploration, deliberation, situation recognition, and habit formation, all increase as a function of the depth and richness of detail of an environment. Furthermore, the cognitive overload can be aggravated due to alterations (e.g. caused by stress) in the bounded rationality, i.e. the limited amount of resources available for the model-based component, in turn increasing the agent’s chances to develop or maintain addictive behaviours. Our study demonstrates that, independent of drug consumption, addictive behaviours can arise in the interaction between the environmental complexity and the biologically finite resources available to explore and represent it.
... Accordingly, identifying factors that increase AUD relapse vulnerability remains an important objective. Stress-a state of mental strain and homeostatic perturbation driven by demanding circumstances and exacerbated by affective vulnerabilities (Folkman, 1986;Sinha, 2001)-has received research attention because it is known to drive maladaptive behaviors associated with lapses among individuals in AUD recovery (Eddie et al., In press;Noone et al., 1999;Sinha, 2007). ...
... Although the experience of stress is a well-known predictor of alcohol lapses among individuals overcoming AUD (Brady and Sonne, 1999;Sinha, 2007), most research has relied on retrospective self-report of stress. A limitation of this approach is that it typically requires stress to be reported as an average over some pre-determined period of time. ...
... Existing literature links stress to alcohol use among individuals seeking recovery from AUD (Brady and Sonne, 1999;Sinha, 2007). The present investigation sought to extend work that has largely relied on conventional retrospective self-report of mean-level stress by monitoring real-time perceived stress using EMA, and testing for the individual effects of meanlevel stress, stress variability, and their interactive effects on subsequent alcohol use. ...
Article
Objective: Although stress is a well-known predictor of alcohol use lapses among individuals seeking recovery from alcohol use disorder (AUD), most research has relied on retrospective self-report using conventional questionnaires that explore stress effects at the level of the mean. Ecological momentary assessment (EMA) overcomes many of the shortcomings of questionnaire-based, retrospective self-report by using real-time, in-the-environment evaluations for the acquisition of ecologically valid data that can also capture stress variability. The present investigation used EMA to disentangle stress effects on alcohol lapses among individuals in the first year of an AUD recovery attempt by exploring associations between mean-level stress, stress variability, and subsequent alcohol use. Method: Participants (N = 42) completed 6 days of EMA monitoring and were then followed up 90 days later to assess alcohol use. Putative associations were explored using hierarchical regression controlling for demographic factors and pre-baseline alcohol use, with percentage days abstinent from alcohol at follow-up as the outcome variable. Results: An interaction effect was observed such that the combination of high mean stress level and high stress variability was associated with the lowest percentage of days abstinent. For those with high mean stress levels, this relationship was attenuated as stress variability decreased. Conclusions: The findings support previous research linking stress to alcohol use lapses; however, these results indicate that the stress/alcohol use relationship is more nuanced than previously described. Our findings suggest that stress variability should also be considered in clinical contexts when assessing risk conferred by mean-level stress.
... Relapse vulnerability is a challenge for the successful treatment of ethanol (EtOH) addiction, and relapse prevention has emerged as a major problem for treatment and medication development efforts (DeJong, 1994;O'Brien and McLellan, 1996). In patients who suffer from alcohol use disorder (AUD), relapse is frequently triggered by stressful events (Breese et al., 2005;Sinha, 2007). Over recent decades, behavioral scientists have used rodent models of reinstatement to study neuronal mechanisms of stress-induced relapse to EtOH seeking (Weiss et al., 2001;Lê and Shaham, 2002;Shaham et al., 2003) and investigate brain mechanisms that regulate palatable food-seeking behavior (Ghitza et al., 2006;Nair et al., 2009). ...
... Stress is a major cause of relapse in patients who suffer from AUD (Breese et al., 2005;Sinha, 2007). The present results demonstrated the maladaptive recruitment of Orx transmission in the pPVT by EtOH dependence, reflected by changes in transcription factors in the Orx/OrxR system. ...
Article
Full-text available
Neural systems involved in processing natural rewards and drugs of abuse overlap and exposure to drugs of abuse induce neuroadaptations that can cause compulsive-like behavior. For example, the recruitment of the orexin (Orx) system by drugs of abuse has been proposed to induce neuroadaptations that in turn alter its function, reflected by maladaptive, compulsive, and addictive behavior. Orexin neurons project to the paraventricular nucleus of the thalamus (PVT)—particularly the posterior part (pPVT), a structure that plays a key role in stress regulation. This study investigated whether Orx transmission in the pPVT plays a role in stress-induced reinstatement of reward-seeking behavior toward ethanol (EtOH) and a highly palatable food reward [sweetened condensed milk (SCM)] in rats and whether this role changes with EtOH dependence. After being trained to orally self-administer EtOH or SCM, the rats were made dependent (EtOHD and SCMD) by chronic intermittent EtOH vapor exposure. The control nondependent groups (EtOHND and SCMND) were exposed to air. Following extinction, the rats were tested for stress-induced reinstatement of EtOH- and SCM-seeking behavior. Stress reinstated EtOH- and SCM-seeking behavior in all groups (EtOHD/ND and SCMD/ND). Administration of the dual Orx receptor (OrxR) antagonist TCS1102 (15 μg) in the pPVT prevented stress-induced reinstatement only in dependent rats (EtOHD and SCMD). In parallel, the qPCR analysis showed that Orx mRNA expression in the hypothalamus and OrxR1/R2 mRNA expression in the pPVT were increased at the time of testing in the EtOHD and SCMD groups. These results are the first to implicate Orx transmission in the pPVT in the stress-induced reinstatement of reward-seeking behavior in EtOH dependent rats and indicate the maladaptive recruitment of Orx transmission in the pPVT by EtOH dependence.
... The rate of drug overdose involving synthetic opioids and heroin has risen dramatically, especially in women (Scholl et al., 2018;VanHouten et al., 2019;Strang et al., 2020). Genes, environment (e.g., stress), and multi-drug use are all key factors in the opioid addiction processes in humans (Sinha, 2007;Strang et al., 2020), posing the challenge of elucidating how sex influences this complicated picture. Yet, it has been shown that women may have varying sensitivity to morphine throughout the menstrual cycle (Ribeiro-Dasilva et al., 2011), which Abbreviations: ABC, avidin-biotin complex; BSA, bovine serum albumin; CIS, chronic immobilization stress; CPP, conditioned place preference; DAB, diaminobenzidine; DG, dentate gyrus; DOR, delta opioid receptor; GABA, Gamma-amino butyric acid; GluA1, AMPA glutamate receptor subunit 1; GluN1, NMDA, glutamate receptor subunit 1; ir, immunoreactivity; LTP, long-term potentiation; MOR, mu opioid receptor; NMDA, N-methyl-D-aspartate; NPY, neuropeptide Y; Oxy, oxycodone; PARV, parvalbumin; PFA, paraformaldehyde; PB, phosphate buffer; PM, plasma membrane; ROI, region of interest; Sal, saline; SLM, stratum lacunosummoleculare; SLu, stratum lucidum; SO, stratum oriens; SOM, somatostatin; SR, stratum radiatum; TS, tris-buffered saline. ...
... Another important factor in the mechanism of addiction is stress (Saal et al., 2003;Sinha, 2007). In previous studies, stress has been shown to impact the neural mechanisms of addiction and may influence synaptic plasticity (Saal et al., 2003). ...
Article
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Glutamate receptors have a key role in the neurobiology of opioid addiction. Using electron microscopic immunocytochemical methods, this project elucidates how sex and chronic immobilization stress (CIS) impact the redistribution of GluN1 and GluA1 within rat hippocampal CA3 pyramidal cells following oxycodone (Oxy) conditioned place preference (CPP). Four groups of female and male Sprague-Dawley rats subjected to CPP were used: Saline- (Sal) and Oxy-injected (3 mg/kg, I.P.) naïve rats; and Sal- and Oxy-injected CIS rats. GluN1: In both naive and CIS rats, Sal-females compared to Sal-males had elevated cytoplasmic and total dendritic GluN1. Following Oxy CPP, near plasmalemmal, cytoplasmic, and total GluN1 decreased in CA3 dendrites of unstressed females suggesting reduced pools of GluN1 available for ligand binding. Following CIS, Oxy-males (which did not acquire CPP) had increased GluN1 in all compartments of dendrites and spines of CA3 neurons. GluA1: There were no differences in the distribution GluA1 in any cellular compartments of CA3 dendrites in naïve females and males following either Sal or Oxy CPP. CIS alone increased the percent of GluA1 in CA3 dendritic spines in males compared to females. CIS Oxy-males compared to CIS Sal-males had an increase in cytoplasmic and total dendritic GluA1. Thus, in CIS Oxy-males increased pools of GluN1 and GluA1 are available for ligand binding in CA3 neurons. Together with our prior experiments, these changes in GluN1 and GluA1 following CIS in males may contribute to an increased sensitivity of CA3 neurons to glutamate excitation and a reduced capacity to acquire Oxy CPP.
... Early life stress, chronic stress, and stress-related disorders, such as post-traumatic stress disorder (PTSD), increase vulnerability to substance abuse disorders , Kreek, Nielsen et al. 2005, Sinha 2007, Sinha 2008, Cousins, Teljeur et al. 2011, Phillips, Epstein et al. 2014. Additional stressors that arise during abstinence may increase vulnerability to relapse , Sinha 2007, and patients and treatment providers alike point to stress as the most common cause of relapse (Moos and Moos 2006). ...
... Early life stress, chronic stress, and stress-related disorders, such as post-traumatic stress disorder (PTSD), increase vulnerability to substance abuse disorders , Kreek, Nielsen et al. 2005, Sinha 2007, Sinha 2008, Cousins, Teljeur et al. 2011, Phillips, Epstein et al. 2014. Additional stressors that arise during abstinence may increase vulnerability to relapse , Sinha 2007, and patients and treatment providers alike point to stress as the most common cause of relapse (Moos and Moos 2006). The withdrawal/negative affect stage of the drug dependence cycle, which occurs between abstention and relapse, is characterized by chronic irritability, malaise, dysphoria, and loss of motivation for non-drug related rewards. ...
Thesis
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... Sleep has a bidirectional relationship with emotional processes known to affect OUD treatment outcomes including low positive and high negative affect (Minkel et al., 2012;Ong et al., 2017). Furthermore, there is a wellestablished link between sleep and stress, and both high chronic stress and stress reactivity are associated with negative OUD treatment outcomes (Koob, 2008;Sinha, 2007Sinha, , 2008Van Bockstaele et al., 2010). Despite these links, sleep disturbance is not a primary consideration in most OUD treatment programs, and is typically a secondary or tertiary outcome in OUD research, if it is assessed at all. ...
... There is a clear link between stress and the onset (Briand & Blendy, 2010; Koob et al., 2014;Meier et al., 2014;Mills et al., 2007;Sinha, 2008), and progression (Briand & Blendy, 2010;Goeders, 2003;Koob, 2008;Kreek et al., 2005;Sinha, 2008) of OUD, and both high tonic stress and stress reactivity contribute to relapse risk in persons in early recovery (Koob, 2008;Sinha, 2007). In animal models, acute opioid exposure reduces HPA-axis-mediated stress response (Koob, 2008), partially through inhibition of the locus coeruleus (Aghajanian & Wang, 1987;Korf et al., 1974;Van Bockstaele et al., 2010), and animal models of chronic opioid exposure demonstrate that stress reactivity is partially mediated by the HPA-axis (Covington & Miczek, 2001;Xu et al., 2004). ...
Article
Sleep health is an important factor across several physical and mental health disorders, and a growing scientific consensus has identified sleep as a critical component of opioid use disorder (OUD), both in the active disease state and during OUD recovery. The goal of this narrative review is to collate the literature on sleep, opioid use, and OUD as a means of identifying therapeutic targets to improve OUD treatment outcomes. Sleep disturbance is common and often severe in persons with OUD, especially during opioid withdrawal, but also in persons on opioid maintenance therapies. There is ample evidence that sleep disturbances including reduced total sleep time, disrupted sleep continuity, and poor sleep quality often accompany negative OUD treatment outcomes. Sleep disturbances are bidirectionally associated with several other factors related to negative treatment outcomes, including chronic stress, stress reactivity, low positive affect, high negative affect, chronic pain, and drug craving. This constellation of outcome variables represents a more comprehensive appraisal of the quality of life and quality of recovery than is typically assessed in OUD clinical trials. To date, there are very few clinical trials or experimental studies aimed at improving sleep health in OUD patients, either as a means of improving stress, affect, and craving outcomes, or as a potential mechanistic target to reduce opioid withdrawal and drug use behaviors. As such, the direct impact of sleep improvement in OUD patients is largely unknown, yet mechanistic and clinical research suggests that therapeutic interventions that target sleep are a promising avenue to improve OUD treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
... Increased stress reactivity and high tonic stress is common during SUD recovery 12,13 and has been associated with drug/alcohol use in several treatment outcome studies and clinical trials. [14][15][16] Moreover, persons with SUDs often have co-occurring mood and anxiety disorders or experience symptoms of anxiety as part of recovery, which has also been associated with drug/alcohol use. [17][18][19] Stress and anxiety have common psychopathology and behavioral manifestations, 20,21 including sleep disturbance, which has itself been shown to further exacerbate negative outcomes in persons with SUDs. ...
... Persons in recovery from SUDs often experience high levels of stress, anxiety, and sleep disturbance, which have been associated with negative treatment outcomes in previous studies. 11,12,15,24,35 Perhaps the most clinically-relevant finding from this study is that thresholds for high stress, clinically-significant levels of anxiety symptoms, and clinical insomnia on the PSS, BAI, and ISI, respectively, were associated with significantly higher odds of drug/alcohol use. Thus, these instruments may provide a relatively quick and clinically-relevant means for providers to assess the risk of drug/alcohol use among persons being treated for SUDs during the COVID-19 crisis. ...
Article
Objectives: The novel 2019 coronavirus (COVID-19) crisis has caused considerable upheaval in the U.S. healthcare system. The current study examined patient-reported experiences in substance use disorder (SUD) treatment during the early stages of the COVID-19 crisis. Methods: Participants in SUD treatment were recruited via online crowdsourcing from April 14, 2020 to May 26, 2020, during the early stages of the COVID-19 crisis. Participants reported disruptions in SUD treatment, stress and anxiety caused by these disruptions on a 0-100 point visual analogue scale (VAS), stress associated with childcare responsibilities on a 0-100 VAS, current stress on the Perceived Stress Scale (PSS), anxiety symptoms on the Beck Anxiety Inventory (BAI), sleep disturbances on the Insomnia Severity Index (ISI), and whether they used drugs or alcohol during the COVID-19 crisis. Results: Participants (N = 240) endorsed that at least 1 SUD treatment was switched to telemedicine (63.7%), had some appointments cancelled (37.5%), or was discontinued due to COVID-19 (29.6%). Participants who did versus did not endorse drug/alcohol use reported difficulty obtaining medications to treat their SUD (OR = 2.47, 95% CI, 1.17-5.22, χ2 = 5.98, P = .016), greater scores on VAS treatment-related stress (F1,197 = 5.70, P = .018) and anxiety (F1,197 = 4.07, P = .045), greater VAS stress related to childcare (F1,107 = 10.24, P = .002), and greater scores on the PSS (F1,235 = 19.27, P < .001), BAI (F1,235 = 28.59, P < .001), and ISI (F1,235 = 14.41, P < .001). Conclusions: Providers and public health officials should work to improve continuity and quality of care during the COVID-19 crisis, with special attention on addressing childcare difficulties and providing remote methods to improve stress, anxiety, and sleep for persons in SUD treatment.
... Stressors and psychiatric illnesses, such as depression, anxiety, and bipolar disorder, can contribute to the development of AUD, as people believe they can solve their problems by drinking alcohol [16][17][18][19] . Indeed, different types of stressful factors like exposure to early life stress, acute stress, chronic stress, and posttraumatic stress disorders are responsible for the development of alcohol dependence 20 . In addition to psychological factors, alcohol addiction is caused by environmental factors, social factors, and biological factors, such as genetic predisposition 21 . ...
... Stressful events during childhood and other chronic stressors have a great effect on health leading to the development of mental disorders (figure 1). Alcohol consumption reduces stress, but at the same time its prolonged use alters the activity of the hypothalamus-pituitary-adrenal cortex causing neuroadaptive changes 20,65 . Sometimes even abstinence can lead to anxiety and dysphoria which stimulate a high use of substances 19 . ...
Article
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Patients with alcohol use disorder (AUD) do not manifest homogeneous clinical symptoms. Various studies described both cognitive impairments and psy- chiatric disorders among people with AUD. This disorder is one of the most frequent mental disorders in devel- oped countries, due to excessive alcohol consumption. Alcohol is toxic as it increases the production of reactive oxygen species (ROS) and can cause dependence. This causes negative effects on brain development and cog- nitive functions that affect the individual’s work, health, and social life. Current pharmacology treatment for al- cohol addiction is based on direct action against the neurotransmitters involved in alcohol dependence. AUD patients without comorbid psychiatric disorders or se- vere cognitive deficits are defined as “pure alcoholics”. To date, poor is known about effective treatments for this typology of AUD patients. Psychotherapy is largely used in resolving many psychiatric disorders, including substance use disorders. Motivational enhancement therapy (MET) and cognitive-behavioral therapy (CBT) are two psychotherapies used to achieve and maintain abstinence in patients affected by substance use disorders. This short review aims to describe CBT and MET and to present the advantages and disadvantages of these two psychotherapies in the treatment of AUD.
... Job loss is a demonstrated risk factor for cannabis use, and unemployed young adults in particular have higher rates of developing a CUD [7,8]. CUD is also highly comorbid with anxiety and depression [9,10], and stress is an important factor in the escalation of use, development of addiction and relapse [11,12]. Particularly in regular cannabis users, stress and tension reduction are commonly reported motives for use [13], correlating with CUD severity [14]. ...
Article
Full-text available
Background and aims Lockdown measures aimed at limiting the number of infections and deaths from the coronavirus disease 2019 (COVID‐19) have introduced substantial psychosocial stressors in everyday life. We aimed to investigate the influence of the Dutch lockdown on cannabis use and cannabis use disorder (CUD) and investigate relations with change in mental wellbeing and experienced psychosocial stressors during the lockdown. Design Explorative longitudinal baseline‐, pre‐ and during lockdown survey study. Setting The Netherlands, online between January 2019 and May 2020. Participants Community sample of 120 monthly to daily cannabis users and reference group of 63 non‐using controls. Measurements Change in cannabis use and CUD symptom severity from baseline to pre‐lockdown to post‐lockdown. Change in cannabis use motives, mental health, quality of social relationships and job status from pre‐lockdown to post‐lockdown. Findings In cannabis users, lockdown related to increased cannabis use (B = 1.92, 95% CI 0.23‐3.61, p = 0.027), but not CUD symptom severity. Cannabis users experienced 30% job loss and increased loneliness (p < 0.001, BF10 > 100), while contact with partners (p = 0.005, BF10= 8.21) and families improved (p < 0.001, BF10 = 19.73), with no differences between cannabis users and control. Generally, mental health problems (all p's > 0.277, all BF10< 0.139) did not change but individual differences were significant and severity of cannabis use pre‐lockdown, COVID‐19 related worries, change in anxiety, expansion motives, social motives and family contact all uniquely related to variance in change in cannabis use or CUD. Conclusions While cannabis use among daily cannabis users in The Netherlands increased at the group level during the period of COVID‐19 lockdown, the effect of the first months of lockdown on cannabis use disorder severity and mental wellbeing varied significantly among individual daily cannabis users.
... Determining how to prevent relapse following a quit attempt is key to successful long-term tobacco abstinence. When considering predictors of relapse, the experience of stress, or negative affect, is strongly associated with the risk of relapse [2,3], and high stress is related to an increased likelihood of lapse during a smoking quit attempt [4]. Developing smoking cessation interventions that target stress are needed and may be particularly useful for individuals with low socioeconomic status (SES), given increased exposure to chronic stressors and other negative life events (eg, discrimination and violence) [5][6][7][8]. ...
Article
Background Cigarette smoking has numerous health consequences and is the leading cause of morbidity and mortality in the United States. Mindfulness has the ability to enhance resilience to stressors and can strengthen an individual’s ability to deal with discomfort, which may be particularly useful when managing withdrawal and craving to smoke. Objective This study aims to evaluate feasibility results from an intervention that provides real-time, real-world mindfulness strategies to a sample of racially and ethnically diverse smokers making a quit attempt. Methods This study uses a microrandomized trial design to deliver mindfulness-based strategies in real time to individuals attempting to quit smoking. Data will be collected via wearable sensors, a study smartphone, and questionnaires filled out during the in-person study visits. Results Recruitment is complete, and data management is ongoing. Conclusions The data collected during this feasibility trial will provide preliminary findings about whether mindfulness strategies delivered in real time are a useful quit smoking aid that warrants additional investigation. Trial Registration Clinicaltrials.gov NCT03404596; https://clinicaltrials.gov/ct2/show/NCT03404596 International Registered Report Identifier (IRRID) DERR1-10.2196/22877
... Sex differences in neuroendocrine adaptations to stress and reward systems may mediate women's susceptibility to drug abuse and relapse [53]. Several studies have examined sex differences in stress response (e.g., subjective, autonomic) and relapse [53,54]. ...
Article
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Purpose of Review Substance use disorders (SUD) affect differentially women and men. Although the prevalence has been reported higher in men, those women with addictive disorders present a more vulnerable profile and are less likely to enter treatment than men. The aim of this paper is to present an overview of how sex and gender may influence epidemiology, clinical manifestations, social impact, and the neurobiological basis of these differences of women with SUD, based on human research. Recent Findings The differences in prevalence rates between genders are getting narrower; also, women tend to increase the amount of consumption more rapidly than men, showing an accelerated onset of the SUD (telescoping effect). In respect to clinical features, the most important differences are related to the risk of experience psychiatric comorbidity, the exposure to intimate partner violence, and the associated high risks in sexual and reproductive health; and those who are mothers and addicted to substances are at risk of losing the custody of children accumulating more adverse life events. Some of these differences can be based on neurobiological differences: pharmacokinetic response to substances, sensitivity to gonadal hormones, differences in neurobiological systems as glutamate, endocannabinoids, and genetic differences. Summary Specific research in women who use drugs is very scarce and treatments are not gender-sensitive oriented. For these reasons, it is important to guarantee access to the appropriate treatment of women who use drugs and a need for a gender perspective in the treatment and research of substance use disorders.
... As mentioned above, FDS was induced immediately after injection of the antagonist for 24 h should also be considered. It should also be mentioned that stress modulates many neuronal pathways in common with neuronal circuits involved in drug abuse, both of which enhance the activity of the mesolimbic dopamine system [33]. The effect of stress on the activation and expression of the CREB-ERK signaling pathway depends on several factors such as stress protocol, stress induction period and the brain regions studied [34,35]. ...
Article
Reinstatement to drug abuse is the most challenging issue in the treatment of addiction. Thus, knowledge of the involved neurobiological mechanisms of reinstatement is a fundamental necessity. There is substantial and crucial evidence that dopamine is implicated in motivational processes such as relapse. Our behavioral results reported that the administration of dopamine receptor antagonists inhibited reinstatement of morphine in food-deprived rats. Previous studies have indicated that the ERK pathway plays a critical role in the cellular responses to stress and reward. Therefore, the purpose of the current study was to evaluate the effect of intra-dentate gyrus administration of dopamine receptor antagonists on the phosphorylation of hippocampal ERK in the reinstatement phase of morphine reward in food-deprived rats. All groups of animals passed conditioned place preference and were bilaterally given different doses of D1- or D2-like dopamine compounds (0.25, 1 and 4 μg/0.5 μl) into the dentate gyrus. Immediately after the reinstatement phase, each animal was euthanized, and the hippocampi were immediately dissected. Then, the p-ERK/ERK ratio was evaluated using Western blot analysis. The principal findings in this study demonstrated that intra-dentate gyrus administration of the highest dose of the D1-like receptor antagonist could enhance the hippocampal p-ERK/ERK ratio in food-deprived rats while the D2-Like receptor antagonist failed to change this ratio.
... On the other side, we found the opposite effect of cortisol administration on craving in patients with only one previous detoxification. Even though there is extensive evidence that stress increases alcohol craving and the vulnerability for relapse [47][48][49][50][51] , findings from animal and human studies are heterogeneous regarding the involvement of cortisol in mediating these stress effects [52][53][54] . Another explanation for the differential effects may come from the adaptation in the hypothalamic-pituitary-adrenal (HPA) axis function through chronic alcohol use and AUD 47,55-58 . ...
Article
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Alcohol-associated memories and craving play a crucial role in the development and maintenance of alcohol use disorder (AUD). As treatment options are limited in AUD, novel treatment strategies focus on the manipulation of alcohol-associated memories. The stress hormone cortisol affects various memory processes, and first clinical studies have shown that it inhibits the retrieval of disorder-specific memories and enhances extinction memory. This study aimed to investigate the effects of a single oral administration of cortisol on craving in patients with AUD during repeated in vivo exposure to alcohol pictures and the preferred alcoholic drink. In a double-blind, block-randomized, placebo-controlled cross-over design, 46 patients with AUD were treated with two sessions of in vivo exposure to alcohol. Cortisol (20 mg) or placebo was orally administered 1 h before each test day. Craving, stress, and cortisol were repeatedly measured during exposure sessions. Results show, that cortisol administration had distinct effects on craving depending on the severity of AUD and test day. While cortisol administration significantly enhanced craving during exposure on the first test day in patients with less severe AUD, it reduced craving in patients with more severe AUD. Independent of the cortisol administration, repeated in vivo exposure reduced craving from test day 1 to test day 2. In conclusion, adding cortisol to in vivo exposure might be a promising approach for reducing the strength of alcohol-associated memories and might promote the consolidation of extinction memory in patients with severe AUD. However, the differential effect of cortisol on craving depending on AUD severity cannot be conclusively explained and highlights the need for future studies elucidating the underlying mechanism.
... Stress plays critical roles in drug addiction. For instance, stress could be a risk factor for not only urges of symptoms but also subsequent relapse after treatments (21,22). Impulse behavior has been shown to develop in response to stress due to deficits in regulatory control over emotional and motor-related behaviors (22,23). ...
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Although studies have demonstrated that negative affects are critical attributes of drug addiction, this has remained less clear in behavioral addiction. In this preliminary study with a relatively small number of samples, we investigated negative affects in patients diagnosed with behavioral addiction, particularly paraphilia and kleptomania. Negative affects were examined using self-rating questionnaire and further evaluated by objective assessments in behavioral addicts and normal subjects. Explicit, self-referential negative affects, such as anxiety, stress, and depression, were higher in behavioral addicts than control subjects. Such self-referential negative affects were, although not entirely, consistent with objective evaluations by others and blood stress hormone concentrations. Further investigation of personality traits in behavioral addicts unveiled that heightened negative affects were associated with stronger neurotic personality in behavioral addicts than normal subjects. These results suggest that behavioral addiction, such as paraphilia and kleptomania, may be characterized by heightened negative affects attributable to stronger neurotic personality.
... These effects can be attributed, at least in part, to KOR decreasing dopamine system function in mesocorticolimbic areas involved in reinforcement circuitry (Margolis and Karkhanis 2019 for review). Substance use after stress exposure, as well as stress related to drug withdrawal, plays a role in drug craving and relapse (Sinha 2007). One theoretical framework proposed that the effects of KOR activation on drug self-administration is dependent on the hedonic state of the animal, which changes based on stress history (see Bruchas et al. 2010 for review). ...
Chapter
Drug addiction is a complex, persistent, and chronically relapsing neurological disorder exacerbated by acute and chronic stress. It is well known that the dynorphin/kappa opioid receptor (KOR) system regulates stress perception and responsivity, while the mesolimbic dopamine system plays a role in reward and reinforcement associated with alcohol and substance use disorders. Interestingly, the dopamine and dynorphin/KOR systems are highly integrated in mesolimbic areas, with KOR activation leading to inhibition of dopamine release, further altering the perception of reinforcing and aversive stimuli. Chronic or repeated exposure to stress or drugs potentiates KOR function ultimately contributing to a hypodopaminergic state. This hypodopaminergic state is one of the hallmarks of hyperkatifeia, defined as the hypersensitivity to emotional distress that is exacerbated during drug withdrawal and abstinence. The relationship between stress and drug addiction is bidirectional; repeated/chronic stress promotes pro-addictive behaviors, and repeated cycles of drug exposure and withdrawal, across various drug classes, produces stress. Neuroadaptations driven by this bidirectional relationship ultimately influence the perception of the reinforcing value of rewarding stimuli. In this chapter, we address the involvement of the dopamine and dynorphin/KOR systems and their interactions in shaping reinforcement value processing after drug and stress exposure, as well as a combinatorial impact of both drugs and stress.
... This measure was used as the outcome for our predictive modeling analyses as it captures cognitive processes underlying persistent pursuit of a goal despite setbacks that are likely disrupted in clinical addiction disorders, and are likely prognostically relevant (e.g. capturing unwillingness to persist on a rehabilitation program after experiencing a relapse; Sinha, 2007). In the Results, we confirm the clinical relevance of this behavioral measure by contrasting it across the POUD and control groups via 2-sample ttest. ...
Article
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Prescription opioid use disorder (POUD) has reached epidemic proportions in the United States, raising an urgent need for diagnostic biological tools that can improve predictions of disease characteristics. The use of neuroimaging methods to develop such biomarkers have yielded promising results when applied to neurodegenerative and psychiatric disorders, yet have not been extended to prescription opioid addiction. With this long-term goal in mind, we conducted a preliminary study in this understudied clinical group. Univariate and multivariate approaches to distinguishing between POUD (n=26) and healthy controls (n=21) were investigated, on the basis of structural MRI (sMRI) and resting-state functional connectivity (restFC) features. Univariate approaches revealed reduced structural integrity in the subcortical extent of a previously reported addiction-related network in POUD subjects. No reliable univariate between-group differences in cortical structure or edgewise restFC were observed. Contrasting these mixed univariate results, multivariate machine learning classification approaches recovered more statistically reliable group differences, especially when sMRI and restFC features were combined in a multi-modal model (classification accuracy=66.7%, p<.001). The same multivariate multi-modal approach also yielded reliable prediction of individual differences in a clinically relevant behavioral measure (persistence behavior; predicted-to-actual overlap r=.42, p=.009). Our findings suggest that sMRI and restFC measures can be used to reliably distinguish the neural effects of long-term opioid use, and that this endeavor numerically benefits from multivariate predictive approaches and multi-modal feature sets. This can serve as theoretical proof-of-concept for future longitudinal modeling of prognostic POUD characteristics from neuroimaging features, which would have clearer clinical utility.
... As described below, stress exposure weakens PFC function, and severe stressors that cause PTSD can cause atrophy of PFC (Kühn & Gallinat, 2013;Meng & iang, Jin, Liu, Zhao, Wang, Gong, 2016). Stress exposure is also often a cause of substance abuse, which in turn further weakens PFC abilities, creating a vicious cycle (Sinha, 2007). Finally, aging causes weakening and removal of dlPFC synapses on spines (Morrison & Baxter, 2012), a process which is worsened by Alzheimer's Disease (AD), where tau pathology often begins in the medial and ventral areas and moves to dlPFC as the disease progresses, correlating with the rise in dementia (Bussière et al., 2003). ...
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The selective norepinephrine (NE) α2A-adrenoceptor (α2A-AR) agonist, guanfacine (Intuniv™), is FDA-approved for treating Attention Deficit Hyperactivity Disorder (ADHD) based on research in animals, a translational success story. Guanfacine is also widely used off-label in additional mental disorders that involve impaired functioning of the prefrontal cortex (PFC), including stress-related disorders such as substance abuse, schizotypic cognitive deficits, and traumatic brain injury. The PFC subserves high order cognitive and executive functions including working memory, abstract reasoning, insight and judgment, and top-down control of attention, action and emotion. These abilities arise from PFC microcircuits with extensive recurrent excitation through NMDAR synapses. There is powerful modulation of these synapses, where cAMP-PKA opening of nearby potassium (K⁺) channels can rapidly and dynamically alter synaptic strength to coordinate arousal state with cognitive state, e.g. to take PFC “offline” during uncontrollable stress. A variety of evidence shows that guanfacine acts within the PFC via post-synaptic α2A-AR on dendritic spines to inhibit cAMP-PKA-K⁺ channel signaling, thus strengthening network connectivity, enhancing PFC neuronal firing, and improving PFC cognitive functions. Although guanfacine’s beneficial effects are present in rodent, they are especially evident in primates, where the PFC greatly expands and differentiates. In addition to therapeutic actions in PFC, stress-related disorders may also benefit from additional α2-AR actions, such as weakening plasticity in the amygdala, reducing NE release, and anti-inflammatory actions by deactivating microglia. Altogether, these NE α2-AR actions optimize top-down control by PFC networks, which may explain guanfacine’s benefits in a variety of mental disorders.
... Epidemiological data demonstrate that psychiatric disorders account for about 14% of the global burden of disease (Vigo et al., 2016). Although the pathophysiology of psychiatric disorders remains largely unknown, a growing body of literature suggests an association between prenatal maternal stress and a variety of adverse offspring outcomes, including neurodevelopmental disorders like anxiety, depression, schizophrenia, bipolar disorders, personal disorders, autism spectrum disorders, attention deficit hyperactivity disorder and alcohol use disorder (Becker et al., 2011;Gordon, 2002;Sinha, 2007Sinha, , 2008Uhart & Wand, 2009;Charil et al., 2010;Fine et al., 2014;Markham & Koenig, 2011;Mulder et al., 2002;Fumagalli et al., 2007;Weinstock et al, 2008;Maccari et al., 1995, Ramborger et al., 2018, McGowan & Szyf., 2010. This evidence implies the notion that an aberrant prenatal biological programming driven by epigenetic mechanisms may be an important contributing factor of psychiatric disorders. ...
Chapter
New insights into the pathophysiology of psychiatric disorders suggest the existence of a complex interplay between genetics and environment. This notion is supported by evidence suggesting that exposure to stress during pregnancy exerts profound effects on the neurodevelopment and behavior of the offspring and predisposes them to psychiatric disorders later in life. Accumulated evidence suggests that vulnerability to psychiatric disorders may result from permanent negative effects of long-term changes in synaptic plasticity due to altered epigenetic mechanisms (histone modifications and DNA methylation) that lead to condensed chromatin architecture, thereby decreasing the expression of candidate genes during early brain development. In this chapter, we have summarized the literature of clinical studies on psychiatric disorders induced by maternal stress during pregnancy. We also discussed the epigenetic alterations of gene regulations induced by prenatal stress. Because the clinical manifestations of psychiatric disorders are complex, it is obvious that the biological progression of these diseases cannot be studied only in postmortem brains of patients and the use of animal models is required. Therefore, in this chapter, we have introduced a well-established mouse model of prenatal stress (PRS) generated in restrained pregnant dams. The behavioral phenotypes of the offspring (PRS mice) born to the stressed dam and underlying epigenetic changes in key molecules related to synaptic activity were described and highlighted. PRS mice may serve as a useful model for investigating the pathogenesis of psychiatric disorders and may be a useful tool for screening for the potential compounds that may normalize aberrant epigenetic mechanisms induced by prenatal stress.
... Mutationen im ALDH2-Gen, welche besonders innerhalb der asiatischen Bevölkerung zu beobachten sind, können die Verstoffwechselung von Acetaldehyd, einem Zwischenabbauprodukt von Ethanol, derart beeinträchtigen, so dass es zu einer schockähnlichen Symptomatik kommt, wobei homozygote ALDH2*2-Träger stärker betroffen sind als heterozygote, die nur einen Flush entwickeln (Li 2000;Wall et al. 1999). Ebenfalls zu höheren Acetaldehydspiegeln kommt es durch eine schnellere Metabolisierung von Ethanol durch Varianten der Alkoholdehydrogenase, die bei Veränderungen im ADH1B-und ADH1C-Gen zu beobachten sind (Duranceaux et al. 2006 (Kendler et al. 1999) oder eine andauernde Substanzabhängigkeit (Sinha 2007), sondern auch körperliche wie Immunerkrankungen oder kardiovaskuläre Ereignisse (Cohen et al. 2007 (Sarnyai et al. 2001), wie sie bei alkoholabhängigen Patienten während und nach eines Entzuges festzustellen war (Bardeleben et al. 1989). (Davies et al. 2002;Wochnik et al. 2005). ...
Thesis
Die Alkoholabhängigkeit gilt als eine häufige und schwere psychiatrische Erkrankung, für welche bislang keine effektive Pharmakotherapie zur Verfügung steht. Sie entsteht oft aus einem Zusammenspiel aus Phasen des Alkoholabusus und einer zunehmenden Instrumentalisierung des Alkohols zum besseren Umgang mit Stress. Ein wichtiger Schlüsselpunkt für protektive als auch für Risikofaktoren gegenüber der Anfälligkeit für Stress stellt die Hypothalamus-Hypophysen-Nebennierenrinden-Achse (HPA-Achse) dar. Mit der Identifikation des HPA-Achsen-Regulators FK506-bindenden Proteins 51 (FKBP51), dessen Disinhibition mit stressinduzierten psychiatrischen und weiteren Erkrankungen assoziiert wird, ist ein neuer therapeutischer Angriffspunkt gefunden worden. Erst kürzlich gelang die Entwicklung des ersten selektiven FKBP51-Inhibitors SAFit2, der antidepressive Eigenschaften aufweist. Vor diesem Hintergrund untersucht die folgende Arbeit die Effekte von SAFit2 auf den Alkoholkonsum im Mausmodell in unterschiedlichen Trinkparadigmen in verschiedenen Stadien der Alkoholabhängigkeit. Im ersten Experiment wurde der Alkoholkonsum von 40 männlichen C57/BL6 Mäusen anhand eines Zwei-Flaschen-Wahlparadigmas bei kontinuierlichem, uneingeschränktem Zugang zu Alkohol untersucht. Die Tiere waren separat in einem Käfig untergebracht und erhielten Wasser ad libitum sowie Alkohol in langsam ansteigender Konzentration (2 Vol. % bis 16 Vol. %). Nach 6-wöchiger Alkoholtrinketablierung wurden die Tiere mit entweder 20mg/kg SAFit2 oder einem Vehikel intraperitoneal (i.p.) zweimal am Tag für 3 Tage während des akuten Trinkens ohne Entzugserfahrungen, im Entzug vor dem Wiedereinsetzen des Trinkens sowie während eines Rückfalls behandelt, um festzustellen, ob SAFit2 den Alkoholkonsum in den jeweiligen Paradigmen reduzieren kann. Im zweiten Experiment wurde der Alkoholkonsum von 12 männlichen C57/BL6 Mäusen bei intermittierendem, eingeschränktem Zugang zu 20%igem Alkohol an drei zufälligen Tagen in der Woche untersucht bei ansonsten gleichen Versuchsbedingungen. Nach 6-wöchiger Alkoholtrinketablierung wurden drei Tiergruppen mit entweder SAFit2 (10 oder 20 mg/kg) oder einem Vehikel i.p. zweimal am Tag für jeweils 3 Tage während des akuten Trinkens ohne Entzugserfahrungen und im Entzug vor dem Wiedereinsetzen des Trinkens behandelt, um die Auswirkungen von SAFit2 auf das Binge-Drinking zu analysieren. Während aller Behandlungen wurden der Alkoholkonsum [g/kg], der Wasserkonsum [ml/kg] sowie die Alkoholpräferenz gegenüber Wasser [%] der Tiere pro Tag gemessen und ausgewertet. Die Resultate des ersten Experiments zeigen, dass der Alkoholkonsum der SAFit2-Gruppe im akuten Trinken ohne Entzugserfahrungen signifikant geringer war als in der Kontrollgruppe, wohingegen sich die Alkoholpräferenz sowie der Wasserkonsum nicht unterschieden, was auf einen trinkmengenreduzierenden Effekt von SAFit2 hinweist. Nach der Behandlung während des Entzugs tranken und präferierten die SAFit2-Tiere signifikant weniger Alkohol als die Kontrollgruppe bei nicht signifikant unterschiedlichem Wasserkonsum, wobei rückfallpräventive Eigenschaften von SAFit2 ursächlich sein könnten. Kein signifikanter Unterschied im Alkoholkonsum und in der Alkoholpräferenz war während des Rückfalls feststellbar, jedoch trank die SAFit2-Gruppe signifikant weniger Wasser. Die Ergebnisse des zweiten Experiments blieben ohne jeglichen signifikanten Unterschied in allen getesteten Paradigmen, weshalb SAFit2 wahrscheinlich keinen Einfluss auf das Binge-Drinking hat. Die Beobachtungen dieser Studie bekräftigen die Hypothese, dass SAFit2 den Alkoholkonsum in unterschiedlichen, aber nicht allen Stadien der Alkoholabhängigkeit im Mausmodell reduzieren kann. Ein therapeutischer Einsatz bei Patienten ohne Entzugserfahrungen sowie ein rückfallprophylaktischer, unterstützender während eines Entzugs wären demnach denkbar. Darüber hinaus könnten sich auch depressive Patienten, die ein erhöhtes Risiko für die Entwicklung einer Substanzabhängigkeit aufweisen, sowie Patienten mit einer dysregulierten HPA-Achse für eine individuelle Therapie eignen, die zukünftig mit Hilfe einer Identifikation von Risikoendophänotypen möglich sein könnte. Zuvor bedarf es jedoch noch einiger tierexperimenteller und klinischer Studien, um bleibende offene Fragen über den genauen Wirkmechanismus von SAFit2 auf die HPA-Achse und deren Effektorhormone oder andere Stoffwechselwege zu beantworten.
... Stressors and mental disorders, such as depression, can contribute to the development of AUD as people are driven to drink alcohol with the aim of alleviating stress and negative symptoms [194][195][196]. Indeed, different kinds of stressful factors like exposure to early life stress, acute stress, chronic stress and posttraumatic stress disorders contribute to the development of AUD or can aggravate it [197][198][199]. Furthermore, alcohol itself is a stressor as acute alcohol exposure, chronic alcohol consumption and periods of abstinence can alter the HPA axis activity and the normal homeostasis equilibrium [194,[200][201][202][203]. ...
Article
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Stress is a constant threat for homeostasis and is represented by different extrinsic and intrinsic stimuli (stressors, Hans Selye's "noxious agents"), such as aggressive behavior, fear, diseases, physical activity, drugs, surgical injury, and environmental and physiological changes. Our organism responds to stress activating the adaptive stress system to activate compensatory responses for restoring homeostasis. Nerve Growth Factor (NGF) was discovered as a signaling molecule involved in survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons. NGF mediates stress with an important role in translating environmental stimuli into physiological and pathological feedbacks since NGF levels undergo important variations after exposure to stressful events. Psychological stress, lifestyle stress, and oxidative stress are well known to increase the risk of mental disorders such as schizophrenia, major depressive disorders, bipolar disorder, alcohol use disorders and metabolic disorders such as metabolic syndrome. This review reports recent works describing the activity of NGF in mental and metabolic disorders related to stress.
... 33 Evidence from animal models suggests that prolonged nicotine exposure may also induce epigenetic changes 33 and increase vulnerability to stress sensitivity. 38,39 These biological changes may, in part, underlie associations between adolescent nicotine use and subsequent development of mood disorders, 39,40 schizophrenia, 41 and substance use disorders. 33 Furthermore, reliance on nicotine to overcome challenges interferes with the development of adaptive coping skills. ...
Article
Background: The prevalence of electronic cigarette (EC) use has risen dramatically among adolescents and young adults (AYA, ages 12-26) over the past decade. Despite extensive established relationships between combustible cigarette (CC) use and mental health problems, the mental health comorbidities of EC use remain unclear. Objective: To provide a systematic review of existing literature on mental health co-morbidities of EC use among AYA. Methods: Database searches using search terms related to EC, AYA, and mental health identified 1168 unique articles, 87 of which prompted full-text screening. Multiple authors extracted data, applied the Effective Public Health Practice Project Quality Assessment Tool to evaluate the evidence, and synthesized findings. Results: Forty articles met eligibility criteria (n=24 predominantly adolescent and 16 predominantly young adult). Analyses yielded three main categories of focus: internalizing disorders (including depression, anxiety, suicidality, eating disorders, PTSD), externalizing disorders (ADHD and conduct disorder), and transdiagnostic concepts (impulsivity and perceived stress). Significant methodological limitations were noted. Conclusions: Youth EC use is associated with greater mental health problems (compared to non-use) across several domains, particularly among adolescents. Since many existing studies are cross-sectional, directionality remains uncertain. Well-designed longitudinal studies to investigate long-term mental health sequalae of EC use remain needed.
... During adolescence, brain regions that underlie executive functions undergo significant reorganization [36,37], regulated in part by nicotinic acetylcholine receptors [33]. Evidence from animal models suggests that prolonged nicotine exposure may also induce epigenetic changes [33] and increase vulnerability to stress sensitivity [38,39]. These biological changes may, in part, underlie associations A c c e p t e d M a n u s c r i p t 5 between adolescent nicotine use and subsequent development of mood disorders [39,40], schizophrenia [41], and substance use disorders [33]. ...
Article
Background The prevalence of electronic cigarette (EC) use has risen dramatically among adolescents and young adults (AYA, ages 12-26) over the past decade. Despite extensive established relationships between combustible cigarette (CC) use and mental health problems, the mental health comorbidities of EC use remain unclear. Objective To provide a systematic review of existing literature on mental health co-morbidities of EC use among AYA. Methods Database searches using search terms related to EC, AYA, and mental health identified 1168 unique articles, 87 of which prompted full-text screening. Multiple authors extracted data, applied the Effective Public Health Practice Project Quality Assessment Tool to evaluate the evidence, and synthesized findings. Results Forty articles met eligibility criteria (n=24 predominantly adolescent and 16 predominantly young adult). Analyses yielded three main categories of focus: internalizing disorders (including depression, anxiety, suicidality, eating disorders, PTSD), externalizing disorders (ADHD and conduct disorder), and transdiagnostic concepts (impulsivity and perceived stress). Significant methodological limitations were noted. Conclusions Youth EC use is associated with greater mental health problems (compared to non-use) across several domains, particularly among adolescents. Since many existing studies are cross-sectional, directionality remains uncertain. Well-designed longitudinal studies to investigate long-term mental health sequalae of EC use remain needed.
... The issue is complicated even further by the fact that the genesis of substance abuse and addiction varies from person to person and there is not one explanation or cause for why people become addicted to drugs or alcohol [5,6,7,8]. In fact, there are multiple risk factors associated with substance abuse and addiction including: an individual's psychological state (using the substance to relieve stress, anxiety or tension) [9,10,11,12], psychopathology [10,13,14,15], family history, biology, and genetics [10,16,17], social and cultural influences [13,18,19], and medical conditions [20,21]. ...
Article
The purpose of this study was to evaluate the effectiveness of the Bonny Method of Guided Imagery and Music (GIM) on interpersonal problems, coping measures and immune function in 19 adults in chemical dependency treatment for an average of 43 days. Psychological measures included the Inventory of Interpersonal Problems Short Circumplex Form (IIP-SC), the Sense of Coherence Scale (SOC) and physiological measure included salivary immunoglobulin A. Pre-test measures were collected at the initial interview session and post-tests at the final BMGIM session. Experimental subjects received one GIM session a week during their treatment. Results show significant decrease on the domineering, cold, and non-assertive subscales of the IIP-SC and on the manageability subscale of the SOC scale. The physiological measure of sIgA did not show a significant increase. The BMGIM appears to be effective in addressing issues underlying substance abuse, in addition showing a positive impact on physical health.
... Bien que l'inverse ait été moins souvent démontré, il existe des preuves qu'une sesibilisation à l'amphétamine induit une réponse comportementale plus importante face à un stress (Antelman et al., 1980;Hamamura et Fibiger, 1993;Robinson et al., 1987;Uban et al., 2015). Cette sensibilisation croisée particulière donne du crédit au modèle de sensibilisation comportementale dans la mesure où le stress est largement impliqué dans la transition vers l'addiction ainsi que dans la rechute (Koob et Kreek, 2007;Sinha, 2007 Les recherches sur la plasticité neuronale associée à la sensibilisation comportementale se sont essentiellement concentrées sur le système dopaminergique mésolimbique. Des études sur des rongeurs ont en effet révélé que les neurones dopaminergiques de l'ATV présentent une excitabilité augmentée suite à une sensibilisation comportementale à l'amphétamine (White et Wang, 1984), à la cocaïne (Henry et al., 1989) ou encore à l'éthanol (Brodie, 2002;Didone et al., 2014). ...
Thesis
La sensibilisation comportementale aux effets stimulants moteurs de l’alcool jouerait un rôle important dans l’escalade de la consommation et la rechute après abstinence. Cependant son implication dans le développement de l’addiction et notamment dans la perte de contrôle de la consommation et dans la prise compulsive n’a pas encore été clairement démontrée. C’est pourquoi l’objectif principal de cette thèse est d’étudier chez la souris le rôle de la sensibilisation selon différentes modalités d’auto-administration d’alcool. Nous avons tout d’abord démontré qu’il existe un phénotype vulnérable, certains individus développent une sensibilisation avec les injections répétées d’alcool alors que d’autres sont résistants. Dans une situation de libre choix classique, ce sont les souris résistantes qui augmentent le plus leur consommation mais cette augmentation est plus sensible à l’ajout d’agent aversif. Dans une procédure d’auto-administration opérante, ce sont les souris vulnérables qui sont les plus motivées à consommer l’alcool avec une acquisition plus rapide de la tâche. Les conclusions de ce travail sont majeures car c’est à notre connaissance la première démonstration de l’influence du phénomène de sensibilisation dans la vulnérabilité à consommer l’alcool associée à une plus forte motivation
... Stress is a critical risk factor affecting both the development of addictive disorders, by promoting drug seeking and excessive drug intake, and the relapse to addictive behaviors, when drug withdrawal can increase stress response, which increases reward-seeking behavior [3][4][5][6]. Stress exposure, as well as drugs of abuse, activate the hypothalamuspituitary-adrenal axis causing the release of both corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus paraventricular nucleus [7]. CRH and AVP are subsequently transported to the anterior pituitary, where they stimulate adrenocorticotrophic hormone (ACTH) release, which in turn stimulates synthesis and release of glucocorticoids from the adrenal cortex. ...
Article
Aim: Heroin addiction is a chronic, relapsing disease that has genetic and environmental, including drug-induced, contributions. Stress influences the development of addictions. This study was conducted to determine if variants in stress-related genes are associated with opioid dependence (OD). Patients & methods: One hundred and twenty variants in 26 genes were analyzed in 597 Dutch subjects. Patients included 281 OD in methadone maintenance with or without heroin-assisted treatment and 316 controls. Results: Twelve SNPs in seven genes showed a nominally significant association with OD. Experiment-wise significant associations (p < 0.05) were found for three SNP pairs, through an interaction effect: NPY1R/ GAL rs4691910/rs1893679, NPY1R/ GAL rs4691910/rs3136541 and GALR1/GAL rs9807208/rs3136541. Conclusion: This study lends more evidence to previous reports of association of stress-related variants with heroin dependence.
... Dorota Klus-Stańska (2017) nazwała to obrazowo "walką o testo-maniakalne przetrwanie". Jedną z dobrze udokumentowanych konsekwencji funkcjonowania w niestabilnym środowisku pełnym presji i zagrożeń przekraczających możliwości adaptacyjne człowieka jest rozwój uzależnień od substancji i zachowań jako formy radzenia sobie z nadmiernym stresem (Goeders 2003;Sinha 2007;Tavolacci et al. 2013). ...
Article
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W artykule przedstawione zostały związki łączące presję na osiągnięcia szkolne i akademickie, odczuwaną przez uczniów i studentów, z rozwojem uzależnienia od uczenia się, uzależnienia od pracy oraz innych zaburzeń psychicznych i wzrostu częstotliwości występowania zjawisk z obszaru psychopatologii (takich, jak np. samobójstwa). Dokonana została analiza aktualnego stanu wiedzy na temat uzależnienia od pracy oraz uzależnienia od uczenia się, a także omówione zostały podobieństwa i różnice między zaangażowaniem w daną aktywność (pracę lub naukę) a uzależnieniem od tej aktywności. W szczególności przedstawiono teoretyczne i praktyczne znaczenie konceptualizacji problemów pogarszającego się stanu zdrowia psychicznego młodego pokolenia w kategoriach uzależnienia od pracy i uczenia się, a także ich związku z obsesją sukcesu socjoekonomicznego.
... Schmidt ve arkadaşlarının yaptığı prospektif çalışmada anksiyete duyarlılığının alkol kullanım bozukluğu ile yüksek derecede ilişkili olduğu tespit edilmiştir (10). Depresyon ve anksiyete bağımlılığın oluşmasında rol oynayabileceği gibi bağımlılığın devam etmesinde de önemli bir faktör olarak karşımıza çıkar (11). ...
... (Barocas, Morgan, et al., 2020;Greiner et al., 2021;Kimmel et al., 2020; National Academies of Sciences, Engineering, and Medicine et al., 2019;Sordo et al., 2017;Suzuki et al., 2020;Wakeman et al., 2020). Important contributing factors to failure to initiate and treatment interruption include stress, drug cravings, and emotional dysregulation (Kreek & Koob, 1998;Sinha, 2007). ...
... Moreover, access to healthy foods may not always be available or easy at work, especially when exposed to difficult working conditions, making it thus harder to optimize food intake. Finally, our findings are overall in accordance with the propensity to use substance and to overconsume sugar and fat to cope with stressful life events 28,29,[35][36][37][38] . When stratified by age and sex, we did not find any differences across age categories. ...
Article
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We examined the prospective association of physical exertion at work with subsequent tobacco, cannabis, alcohol use, and sugar and fat consumption. Volunteers of the French population-based CONSTANCES cohort currently employed were included from 2012 to 2017 for tobacco and cannabis outcomes (n = 100,612), and from 2012 to 2016 for alcohol and sugar and fat outcomes (n = 75,414). High level of physical exertion at work was defined as a score ≥ 12 at the Rating Perceived Exertion Borg scale. Substance use was self-reported and diet rich in sugar and fat was obtained from principal component analysis and analyzed as quartiles. Generalized linear models computed odds of substance use and sugar and fat consumption at follow-up according to baseline physical exertion at work, while adjusting for sociodemographic factors, depressive symptoms and baseline level of consumption. High physical exertion was associated with tobacco use with dose-dependent relationships. It was also associated with increased odds of cannabis use at least once per month compared to no use in the past and with increased odds of diet rich in sugar and fat. Hence, the role of physical exertion at work on tobacco and cannabis use and diet rich in sugar and fat should be tackled for information and prevention strategies.
... According to the literature, stable accommodations (16), effective financial assistance from the family (35) and psychological and emotional counseling (36,37) can effectively reduce the occurrence of relapse among drug abstainers. Regarding the professional service follow-up provided to those in the experimental group, it was necessary to combine these services with available detoxification resources and the existing efforts of the subdistricts. ...
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Background and Aims: There are no accurate statistical data on the relapse rate of drug abstainers after compulsory detoxification in China. This study aimed to collect relapse data for drug abstainers through follow-up visits, verify the effectiveness of professional social worker services and explore significant factors affecting relapse. Design and Setting: The drug abstainers released from Guangzhou T Compulsory Isolated Detoxification Center were randomly divided into two groups. The difference between the experimental group and the control group is that assistance services were provided by social workers to the former. Participants: The study included 510 drug abstainers released from T Center, including 153 in the experimental group and 357 in the control group. Measurements: Demographic information, history of drug abuse, and motivation for drug rehabilitation (SOCRATES) were collected one month prior to drug abstainer release from compulsory detoxification. Then, the relapse situation after their release was tracked according to fixed time points. Findings: The overall relapse rate of 510 drug abstainers after their release from compulsory detoxification was 47.6%. The average survival time to relapse based on survival analysis was 220 days (N = 486), as calculated with Bayesian estimation by the MCMC method. The average survival times to relapse of the experimental group and control group were 393 and 175 days, respectively. By taking the specific survival time as the dependent variable and the group as the control variable (OR = 25.362), logistic regression analysis showed that marital status (OR = 2.666), previous compulsory detoxification experience (OR = 2.329) and location of household registration (OR= 1.557) had a significant impact on the survival time to relapse. Conclusions: The occurrence of relapse among drug patients released from compulsory detoxification can be delayed effectively through the intervention of professional social worker services. Regardless of whether patients receive aftercare after compulsory detoxification, drug-using patients who are single, have multiple detoxification experiences and whose households are registered in other provinces deserve special attention. Relevant suggestions to avoid relapse are provided.
... For example, it is estimated that stressrelated disorders, such as depression, anxiety disorders, and alcohol and drug use disorders, affect more than one in six people across European Union countries, and that the total costs of mental health have surpassed €600 billionor more than 4% of gross domestic productacross the 28 European Union countries (OECD & European Union, 2018). Given that stress has been strongly associated with a broad range of psychopathology (Bogdan and Pizzagalli, 2006;Koob and Volkow, 2016;Mkrtchian et al., 2017;Pizzagalli, 2014;Saal et al., 2003;Sinha, 2007), investigating the mechanisms by which acute stress influences cognition and behaviour is critical not only for understanding the effects of acute stress on day-to-day life, but may also offer important insights into the design of prevention and treatment strategies for individuals with stress-related clinical disorders. ...
Article
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Acute stress is pervasive in everyday modern life and is thought to affect how people make choices and learn from them. Reinforcement learning, which implicates learning from the unexpected rewarding and punishing outcomes of our choices (i.e., prediction errors), is critical for adjusted behaviour and seems to be affected by acute stress. However, the neural mechanisms by which acute stress disrupts this type of learning are still poorly understood. Here, we investigate whether and how acute stress blunts neural signalling of prediction errors during reinforcement learning using model-based functional magnetic resonance imaging. Male participants completed a well-established reinforcement learning task involving monetary gains and losses whilst under stress and control conditions. Acute stress impaired participants’ (n = 23) behavioural performance towards obtaining monetary gains (p < 0.001), but not towards avoiding losses (p = 0.57). Importantly, acute stress blunted signalling of prediction errors during gain and loss trials in the dorsal striatum (p = 0.040) — with subsidiary analyses suggesting that acute stress preferentially blunted signalling of positive prediction errors. Our results thus reveal a neurocomputational mechanism by which acute stress may impair reward learning.
... Stress effects also vary by sex, with pronounced and multi-faceted sex differences in stress reactivity in the central nervous system that span neurochemical, behavioral, and cognitive responsiveness (Bowman et al., 2003;Kajantie & Phillips, 2006;Luine, 2009;Merz & Wolf, 2016). Stress is an important factor known to increase alcohol relapse risk (Brown et al., 1995;Noone et al., 1999;Sinha, 2007Sinha, , 2011Sinha, , 2012, but stress is also a major public health concern on its own: one third of adults report increasing stress over the past year with an increasing proportion reporting extreme stress (Babor, 2002;Babor & Higgins-Biddle, 2000). This increase in stress is additionally concerning due to the relationship between stress, motivation to drink, and dysfunctional drinking behaviors (Breese et al., 2006;Miller et al., 1974;Seo et al., 2011;Uhart & Wand, 2008). ...
Preprint
Objective Stress is a motivator to consume alcohol, a well-documented relapse risk, and is known to differentially affect biological and psychological processes as people age. Because alcohol consumption is known to decrease stress and increase affect, this study examined differences in ratings of stress and affect across the day in middle-aged versus younger adults who regularly consumed alcohol. Methods A sample of males and females including younger (n=17) and middle-aged (n=18) drinkers was studied across two experimental periods: a 3-day period of usual drinking and a 3-day period of abstinence from alcohol. We also measured resting levels of respiratory sinus arrhythmia (RSA rest ), since it is a well-documented biomarker of stress and known to decrease with age. Ecological momentary assessment (EMA) ratings across periods of normal drinking and abstinence were modeled using hierarchical regression to assess differences in stress and affect throughout days of abstinence and normal drinking between the two age groups. Results As anticipated, middle-aged participants had lower RSA rest than those who were younger. Our analyses showed that middle-aged adults experienced a significant reduction in stress following drinking while no such effect was observed in the younger adults. Although the middle-aged adults showed overall lower stress, generally they also expressed higher affect than younger adults. Conclusions Despite the mitigating role of alcohol on stress in the middle-aged group and the fact that they had higher affect than the younger adults, their lower levels of RSA rest and higher daily reports of stress could pose a risk for chronic alcohol consumption.
... Overall, most of the research has looked at symbolicexpressive and physiological drug craving in a laboratory or otherwise controlled settings (Rohsenow et al., 1994;Carter and Tiffany, 1999;Conklin and Tiffany, 2002;Sinha, 2007;Carpenter et al., 2009;Verdejo-Garcia et al., 2012;Witteman et al., 2015). Recently, some behavioral research has aimed to bridge the gap between the lab and the field. ...
Article
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Neuroanthropology is the integration of neuroscience into anthropology and aims to understand “brains in the wild.” This interdisciplinary field examines patterns of human variation in field settings and provides empirical research that complements work done in clinical and laboratory settings. Neuroanthropology often uses ethnography in combination with theories and methods from cognitive science as a way to capture how culture, mind, and brain interact. This article describes nine elements that outline how to do neuroanthropology research: (1) integrating biology and culture through neuroscience and biocultural anthropology; (2) extending focus of anthropology on what people say and do to include what people process; (3) sizing culture appropriately, from broad patterns of culture to culture in small-scale settings; (4) understanding patterns of cultural variation, in particular how culture produces patterns of shared variation; (5) considering individuals in interaction with culture, with levels of analysis that can go from biology to social structures; (6) focusing on interactive elements that bring together biological and cultural processes; (7) conceptual triangulation, which draws on anthropology, psychology, and neuroscience in conjunction with field, clinic, and laboratory; (8) critical complementarity as a way to integrate the strengths of critical scholarship with interdisciplinary work; and (9) using methodological triangulation as a way to advance interdisciplinary research. These elements are illustrated through three case studies: research on US combat veterans and how they use Brazilian Jiu Jitsu as a way to manage the transition to becoming civilians, work on human-raptor interactions to understand how and why these interactions can prove beneficial for human handlers, and adapting cue reactivity research on addiction to a field-based approach to understand how people interact with cues in naturalistic settings.
... Specifically, a dysregulated HPA axis can enhance a drug's positive reinforcing effects, thus promoting continued use that is necessary for the development of dependence [25]. A dysregulated HPA axis can also strengthen the negative effects associated with abstinence and withdrawal, thus contributing to relapse and the maintenance of substance use through negative reinforcement [26,27]. Glucocorticoids, in particular, interact with various neurotransmitter and neuropeptide systems implicated in substance use disorders and are thought to play a critical role in addiction, partly by modulating the formation of drug-related memories [28,29]. ...
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Early life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13–14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.
... In a review of prospective studies examining remission from SUD in the United States, results showed the highest remission rate among those using amphetamine (0.45) . Additionally, approximately 24% of people relapse back to weekly cocaine use and 61% of individuals using methamphetamine relapse within a year following treatment (Brect and Herbeck, 2014;Sinha, 2007). ...
Technical Report
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The version of California Senate Bill 888 analyzed by CHBRP would, as law, regulation, and funding allow, require the Department of Health Care Services (DHCS) to cover contingency management (CM) as an aspect of substance use disorder (SUD) treatment for approximately 10.9 million Medi-Cal beneficiaries.
... An interesting open question is whether mGluR5 in D1-expressing neurons mediate stress-induced responses by influencing the eCB system. Given the tight relationship between stress and relapse to drug addiction, in which stress is often cited as a reason to relapse to drug use [73], these studies further support our findings describing the role of a specific subgroup of neurons expressing both D1 and mGluR5 as crucial mediators of behavioral stress coping. ...
Article
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The metabotropic glutamate receptor type 5 (mGluR5) has been proposed to play a crucial role in the selection and regulation of cognitive, affective, and emotional behaviors. However, the mechanisms by which these receptors mediate these effects remain largely unexplored. Here, we studied the role of mGluR5 located in D1 receptor-expressing (D1) neurons in the manifestation of different behavioral expressions. Mice with conditional knockout (cKO) of mGluR5 in D1 neurons (mGluR5D1 cKO) and littermate controls displayed similar phenotypical profiles in relation to memory expression, anxiety, and social behaviors. However, mGluR5D1 cKO mice presented different coping mechanisms in response to acute escapable or inescapable stress. mGluR5D1 cKO mice adopted an enhanced active stress coping strategy upon exposure to escapable stress in the two-way active avoidance (TWA) task and a greater passive strategy upon exposure to inescapable stress in the forced swim test (FST). In summary, this work provides evidence for a functional integration of the dopaminergic and glutamatergic system to mediate control over internal states upon stress exposure and directly implicates D1 neurons and mGluR5 as crucial mediators of behavioral stress responses.
... Such increased regulatory control has been shown to affect the processing of emotional stimuli (Salemink & Wiers, 2012) and could result in less anxiety and depressive symptoms. Given the role of negative emotions and stress in relapse (Sinha, 2007), the increased cognitive control and reduced emotions might be an additional mechanism through which ApBM reduces relapse rates, specifically in AUD patients with ANX-DEP comorbidity. By including measures of cognitive control and emotional symptoms, future research could test the latter explanation of ApBM's increased effectiveness in AUD patients with comorbid ANX-DEP. ...
Article
Objective: Approach bias modification (ApBM) is a promising new add-on training intervention for patients with alcohol use disorder (AUD). Given that comorbid anxiety and major depressive disorders are very common in AUD, and that such comorbidity affects psychological treatments negatively, the primary aim of the present study was investigating whether ApBM training is moderated by anxiety/major depressive disorder comorbidity. The secondary aim was to examine whether ApBM's relapse-preventive effect can be replicated. Method: We conducted a large-scale randomized controlled trial (RCT) in a clinical sample of AUD inpatients (n = 729) with a follow-up assessment after 1 year. All patients received 12 weeks of inpatient treatment as usual (TAU). On top of that, patients were randomized to a 12-session ApBM (TAU + ApBM), and a no-training control condition (TAU-only). Treatment success was defined as either no relapse or a single lapse shorter than 3 days in duration, ended by the patient and followed by at least 4 weeks of abstinence. Failure was defined as relapse, passed away, no contact, or refusal to provide information. Results: We found that TAU + ApBM had significantly higher success rates than TAU-only at 1-year follow-up. Importantly, anxiety/depressive comorbidity moderated ApBM's effects: Adding ApBM to TAU increased success rates more for patients with a comorbid anxiety and/or depressive disorder than for patients without such comorbidity. Conclusions: Our data suggest that adding ApBM to TAU works better in patients with a comorbid anxiety and/or depressive disorder; a promising finding gave the high rates of comorbidity in clinical practice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
... Stress plays a powerful role in the initiation, escalation, and relapse to drug abuse (Garcia-Keller et al, 2016, 2019aKim et al., 2009;Shaham et al., 2000;Sinha, 2007Sinha, , 2009). Here, we show that cofilin, has a crucial role in the vulnerability to develop SUDs. ...
Article
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Actin dynamics in dendritic spines can be associated with the neurobiological mechanisms supporting the comorbidity between stress exposure and cocaine increase rewards. The actin cytoskeleton remodeling in the nucleus accumbens (NA) has been implicated in the expression of stress-induced cross-sensitization with cocaine. The present study evaluates the involvement of cofilin, a direct regulator of actin dynamics, in the impact of stress on vulnerability to cocaine addiction. We assess whether the neurobiological mechanisms that modulate repeated-cocaine administration also occur in a chronic restraint stress-induced cocaine self-administration model. We also determine if chronic stress induces alterations in dendritic spines through dysregulation of cofilin activity in the NA core. Here, we show that the inhibition of cofilin expression in the NA core using viral short-hairpin RNA is sufficient to prevent the cocaine sensitization induced by chronic stress. The reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor surface expression enhancement and promote the reduction of head diameter in animals pre-exposed to stress after a cocaine challenge in the NA core. Moreover, downregulation of cofilin expression prevents facilitation of the acquisition of cocaine self-administration (SA) in male rats pre-exposed to chronic stress without modifying performance in sucrose SA. These findings reveal a novel, crucial role for cofilin in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction-related disorders.
Article
Background and Objectives A growing body of literature demonstrates that the human microbiota plays a crucial role in health and disease states, as well as in the body's response to stress. In addition, the microbiome plays a role in psychological well-being and regulating negative affect. Regulation of negative affect is a factor in psychostimulant abuse disorders. We propose a risk chain in which stress leads to negative affect that places an individual at risk to develop or relapse to psychostimulant abuse disorder. Stress, negative affect, and psychostimulant use all alter the gut microbiome. Methods This review brings together the literature on affective disorders, stress, and psychostimulant abuse disorders to assess possible modulatory actions of the gut–brain axis to regulate these conditions. Results Studies reviewed across the various disciplines suggest that the dysbiosis resulting from drug use, drug withdrawal, or stress may cause an individual to be more susceptible to addiction and relapse. Probiotics and prebiotics reduce stress and negative affect. Scientific Significance Treatment during the withdrawal phase of psychostimulant abuse disorder, when the microbiome is altered, may ameliorate the symptoms of stress and negative affect leading to a reduced risk of relapse to psychostimulant use.
Article
Personalized recovery technologies may enable individuals with Substance Use Disorder (SUD) to monitor and manage acute craving and drug use urges in ways that improve drug-seeking decisions in real-time. Direct and indirect regulation of the autonomic nervous system through sensory input monitoring and modulation may enhance control over behavioral decisions and prevent relapse. A personalized sensory support system that monitors neurophysiological reactivity and offers non-pharmacological point-in-time personalized digital interventions may increase awareness of and control over craving reactivity. It is critical to be able to detect these warning signs and intervene early and effectively. The use of wearable technologies that assess point-in-time neurophysiological escalation and shape behavioral responses through personalized interventions could be transformative in allowing individuals to better manage their recovery as they transition out of institutions and move back into community settings.
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We examined the prospective association of physical exertion at work with subsequent tobacco, cannabis, alcohol use, and sugar and fat consumption. Volunteers of the French population-based CONSTANCES cohort currently employed were included from 2012–2017 for tobacco and cannabis outcomes (n = 100,612), and from 2012–2016 for alcohol and sugar and fat outcomes (n = 75,414). High level of physical exertion at work was defined as a score ≥ 12 at the Rating Perceived Exertion Borg scale. Substance use was self-reported and diet rich in sugar and fat was obtained from principal component analysis and analyzed as quartiles. Generalized linear models computed odds of substance use and sugar and fat consumption at follow-up according to baseline physical exertion at work, while adjusting for sociodemographic factors, depressive symptoms and baseline level of consumption. High physical exertion was associated with tobacco use with dose-dependent relationships. It was also associated with increased odds of cannabis use at least once per month compared to no use in the past and with increased odds of diet rich in sugar and fat. Hence, the role of physical exertion at work on tobacco and cannabis use and diet rich in sugar and fat should be tackled for information and prevention strategies.
Article
Exposure to adversity during early childhood and adolescence increases an individual's vulnerability to developing substance use disorder. Despite the knowledge of this vulnerability, the mechanisms underlying it are still poorly understood. Excitatory afferents to the nucleus accumbens (NAc) mediate responses to both stressful and rewarding stimuli. Understanding how adolescent social isolation alters these afferents could inform the development of targeted interventions both before and after drug use. Here, we used social isolation rearing as a model of early life adversity which we have previously demonstrated increases vulnerability to cocaine addiction-like behaviour. The current study examined the effect of social isolation rearing on presynaptic glutamatergic transmission in NAc medium spiny neurons in both male and female mice. We show that social isolation rearing alters presynaptic plasticity in the NAc by decreasing the paired-pulse ratio and the size of the readily releasable pool of glutamate. Optogenetically activating the glutamatergic input from the ventral hippocampus to the NAc is sufficient to recapitulate the decreases in paired-pulse ratio and readily releasable pool size seen following electrical stimulation of all NAc afferents. Further, optogenetically inhibiting the ventral hippocampal afferent during electrical stimulation eliminates the effect of early life adversity on the paired-pulse ratio or readily releasable pool size. In summary, we demonstrate that social isolation rearing leads to alterations in glutamate transmission driven by projections from the ventral hippocampus. These data suggest that targeting the circuit from the ventral hippocampus to the nucleus accumbens could provide a means to reverse stress-induced plasticity.
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Neurons containing neuropeptide S (NPS) and orexins are activated during stress. Previously, we reported that orexins released during stress, via orexin OX1 receptors (OX1Rs), contribute to the reinstatement of cocaine seeking through endocannabinoid/CB1 receptor (CB1R)‐mediated dopaminergic disinhibition in the ventral tegmental area (VTA). Here, we further demonstrated that NPS released during stress is an up‐stream activator of this orexin‐endocannabinoid cascade in the VTA, leading to the reinstatement of cocaine seeking. Mice were trained to acquire cocaine conditioned place preference (CPP) by context‐pairing cocaine injections followed by the extinction training with context‐pairing saline injections. Interestingly, the extinguished cocaine CPP in mice was significantly reinstated by intracerebroventricular injection (i.c.v.) of NPS (1 nmol) in a manner prevented by intraperitoneal injection (i.p.) of SHA68 (50 mg/kg), an NPS receptor antagonist. This NPS‐induced cocaine reinstatement was prevented by either i.p. or intra‐VTA microinjection (i.vta.) of SB‐334867 (15 mg/kg, i.p. or 15 nmol, i.vta.) and AM 251 (1.1 mg/kg, i.p. or 30 nmol, i.vta.), antagonists of OX1Rs and CB1Rs, respectively. Besides, NPS (1 nmol, i.c.v.) increased the number of c‐Fos‐containing orexin neurons in the lateral hypothalamus (LH) and increased orexin‐A level in the VTA. The latter effect was blocked by SHA68. Furthermore, a 30‐min restraint stress in mice reinstated extinguished cocaine CPP and was prevented by SHA68. These results suggest that NPS is released upon stress and subsequently activates LH orexin neurons to release orexins in the VTA. The released orexins then reinstate extinguished cocaine CPP via an OX1R‐ and endocannabinoid‐CB1R‐mediated signaling in the VTA.
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Opioid Use Disorders (OUDs) and drug overdose deaths are increasing at alarmingly high rates in the United States. Stress and dysregulation in biologic stress response systems such as the hypothalamic-pituitary-adrenal axis and noradrenergic system appear to play an important role in the pathophysiology of substance use disorders and relapse to drug use, particularly for women. Alpha-2 adrenergic agonist medications effectively decrease noradrenergic activity and have demonstrated benefit in preventing relapse to substance use and decreasing stress-reactivity and craving in cocaine- and nicotine-dependent women, compared to men. Alpha-2 adrenergic agonists may help decrease stress reactivity in individuals with OUDs and prevent relapse to drug use, but gender differences have yet to be systematically explored. We describe the rationale, study design and methodology of a randomized, double-blind, placebo-controlled clinical trial examining gender differences in stress, craving and drug use among adult men and women with OUD taking methadone or buprenorphine and randomly assigned to an alpha-2 adrenergic agonist, lofexidine, compared to placebo. In addition, we describe methods for measuring daily stress, craving and drug use in participant's natural environment as well as participant's physiological (i.e., heart rate, cortisol) and psychological (i.e., stress, craving) response to laboratory social and drug cue stressors. Lastly, we detail methods adopted to sustain research activity while following guidelines for the COVID-19 pandemic. ClinicalTrials.gov Registration Number: NCT03718065
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Social support (SS), or having people to depend on during times of stress, may offer an emotional and neurological buffer to problem drinking. Specifically, SS may modulate reward and stress-related brain responses to mitigate perceptions of alcohol reward and stress. There is limited evidence, however, on this topic and specifically on brain networks that may modulate SS effects on stress and alcohol reward. Here we present a review of the current literature on this topic as well as data from a large community sample of 115 social drinkers. Findings from a novel fMRI task viewing alcohol cue, stress, and neutral images, in separate blocks, while providing ratings on subjective feelings of alcohol craving, stress, and arousal are included. Lower SS significantly predicted greater alcohol craving during alcohol cue and stress conditions, higher baseline levels of stress, and greater arousal in the alcohol cue, relative to neutral condition. Remarkably, individuals with low SS showed greater reward activation (ventral medial prefrontal cortex (VmPFC) and ventral striatum) during alcohol cue exposure, while those with high SS showed no such activation (p < 0.001, family wise error corrected at 0.05). Furthermore, individuals with lower SS showed greater stress circuit (VmPFC, dorsal striatum, and periaqueductal gray) activation not observed in the high SS groups. Both groups showed increased amygdala activation under stress condition. The findings support the notion that SS is a powerful modulator of stress response and reward motivation. High SS buffers neural and subjective stress responses, while low SS potentiates greater reward seeking with higher alcohol craving and greater brain activation during alcohol cue exposure. Previous research and current results suggest the need to further explore the role of SS in those at risk of developing alcohol use disorder and assess novel prevention strategies to boost SS in at-risk drinkers.
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Stress and low mood are powerful triggers for compulsive overeating, a maladaptive form of eating leading to negative physical and mental health consequences. Stress-vulnerable individuals, such as people with obesity, are particularly prone to overconsumption of high energy foods and may use it as a coping mechanism for general life stressors. Recent advances in the treatment of obesity and related co-morbidities have focused on the therapeutic potential of anorexigenic gut hormones, such as glucagon-like peptide 1 (GLP-1), which acts both peripherally and centrally to reduce energy intake. Besides its appetite suppressing effect, GLP-1 acts on areas of the brain involved in stress response and emotion regulation. However, the role of GLP-1 in emotion and stress regulation, and whether it is a viable treatment for stress-induced compulsive overeating, has yet to be established. A thorough review of the pre-clinical literature measuring markers of stress, anxiety and mood after GLP-1 exposure points to potential divergent effects based on temporality. Specifically, acute GLP-1 injection consistently stimulates the physiological stress response in rodents whereas long-term exposure indicates anxiolytic and anti-depressive benefits. However, the limited clinical evidence is not as clear cut. While prolonged GLP-1 analogue treatment in people with type 2 diabetes improved measures of mood and general psychological wellbeing, the mechanisms underlying this may be confounded by associated weight loss and improved blood glucose control. There is a paucity of longitudinal clinical literature on mechanistic pathways by which stress influences eating behavior and how centrally-acting gut hormones such as GLP-1, can modify these. (250)
Article
Background: Negative emotion is associated with substance craving and use in individuals recovering from substance use disorders, including prescription opioid use disorder (POUD). Decisions to abandon or persist towards a goal after negative emotion-eliciting events, and neural responses that shape such decisions, may be important in maintaining recovery from POUD. Objectives: We examined differences in neural responses to negative events and subsequent persistence decisions in individuals recovering from POUD without a history of a substance use disorder. Methods: 20 individuals with POUD (POUD group: 4 females, abstinent 2–3 weeks after admission to an inpatient treatment facility post-detoxification, no other substance use disorder), and 20 individuals with no substance use history (control group: 6 females) completed a persistence-after-setbacks task during functional magnetic resonance imaging. Participants advanced along a path toward a reward; after encountering each negative event (i.e., progress-erasing setback), participants made decisions to persist or abandon the path. Persistence decision rates were compared between groups and blood-oxygen-level-dependent signal to negative events was analyzed within a striatum region of interest (ROI) as well as whole-brain. Results: The POUD group persisted less (t(38) = 2.293, p = .028, d = .725) and showed lower striatum (left ventral putamen) signal to negative events compared to the control group (p < .05, corrected for striatum ROI). Conclusions: In POUD, neural and behavioral responses to negative events differ from controls. These differences are a target for research to address whether POUD treatment increases persistence and striatum responses to negative events and improves recovery outcomes.
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Opioid use disorder (OUD) is a chronic and relapsing brain disease characterized by loss of control over opioid use and impairments in cognitive function, mood, pain perception, and autonomic activity. Sleep deficiency, a term that encompasses insufficient or disrupted sleep due to multiple potential causes, including sleep disorders (eg, insomnia, sleep apnea), circadian disruption (eg, delayed sleep phase and social jet lag), and poor sleep quality (eg, sleep fragmentation, impaired sleep architecture), is present in greater than 75% of patients with OUD. This article focuses on highlighting bidirectional mechanisms between OUD and sleep deficiency and points toward promising therapeutic targets.
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— Aims: to investigate a possible association of cortisol stress response during early abstention with relapse. Methods: Thirty-six alcohol-dependent males, half of them with a comorbid anxiety disorder, and 15 healthy controls were exposed to a standardized psychosocial stress test. Thirty-one of the patients were assessed for relapse 6 weeks after discharge. Results: The relapsers showed almost no cortisol responses in the stress test. Comorbid anxiety disorder influenced neither stress response nor relapse. Conclusions: During early abstention from alcohol, reduced stress-responsivity of the hypothalamo–pituitary–adrenocortical axis seems to be connected to early relapse.
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Background: This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM-IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic-pituitary-adrenocortical (HPA) reactivity in recovering alcoholics. Methods: Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20-min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days. Results: The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics. Conclusions: The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.
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Contemporary urge models assume that urges are necessary but not sufficient for the production of drug use in ongoing addicts, are responsible for the initiation of relapse in abstinent addicts, and can be indexed across 3 classes of behavior: verbal report, overt behavior, and somatovisceral response. A review of available data does not provide strong support for these assumptions. An alternative cognitive model of drug use and drug urges is proposed that hypothesizes that drug use in the addict is controlled by automatized action schemata. Urges are conceptualized as responses supported by nonautomatic cognitive processes activated in parallel with drug-use action schemata either in support of the schema or in support of attempts to block the execution of the schema. The implications of this model for the assessment of urge responding and drug-use behavior are presented.
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Reviews recent behavioral and neuropharmacological findings, which suggest that opiate and stimulant drugs act on common neurochemical systems of the brain to generate positive appetitive states that maintain drug-taking behavior. CSs associated with these drugs arouse neural states that mimic features of those produced by the drugs themselves and thereby serve to increase the effectiveness of drug-related stimuli and to increase the probability of drug-related thoughts and actions. This positive incentive account of compulsive drug use contrasts with the drive-reduction view that continued drug use depends primarily on efforts to reduce or to avoid symptoms of withdrawal, and that conditioned stimuli initiate and maintain drug-taking behavior through the elicitation of withdrawal-like, drug-opposing CRs. (4 p ref)
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Evidence accumulated over more than 45 years has indicated that environmental stimuli can induce craving for drugs of abuse in individuals who have addictive disorders. However, the brain mechanisms that subserve such craving have not been elucidated. Here a positron emission tomographic study shows increased glucose metabolism in cortical and limbic regions implicated in several forms of memory when human volunteers who abuse cocaine are exposed to drug-related stimuli. Correlations of metabolic increases in the dorsolateral prefrontal cortex, medial temporal lobe (amygdala), and cerebellum with self-reports of craving suggest that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving.
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There is a good deal of clinical evidence suggesting that compulsion to resume drug taking is an important part of the addiction syndrome. The symptoms comprising motivation to resume drug use, namely craving and compulsion, have been studied experimentally in human subjects. While much work remains to be done, there is evidence showing that these symptoms are influenced by learning. The research has been guided by animal studies demonstrating that drug effects can be conditioned. Much attention has been directed toward demonstrating the existence of drug conditioning in human addicts and exploring the neurological structures that may underlie such learned responses. We do not yet know the relative importance of learning in the overall phenomenon of relapse, and treatments based on conditioning principles are still under investigation.
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Since signals for cocaine induce limbic brain activation in animals and cocaine craving in humans, the objective of this study was to test whether limbic activation occurs during cue-induced craving in humans. Using positron emission tomography, the researchers measured relative regional cerebral blood flow (CBF) in limbic and comparison brain regions of 14 detoxified male cocaine users and six cocaine-naive comparison subjects during exposure to both non-drug-related and cocaine-related videos and during resting baseline conditions. During the cocaine video, the cocaine users experienced craving and showed a pattern of increases in limbic (amygdala and anterior cingulate) CBF and decreases in basal ganglia CBF relative to their responses to the non-drug video. This pattern did not occur in the cocaine-naive comparison subjects, and the two groups did not differ in their responses in the comparison regions (i.e., the dorsolateral prefrontal cortex, cerebellum, thalamus, and visual cortex). These findings indicate that limbic activation is one component of cue-induced cocaine craving. Limbic activation may be similarly involved in appetitive craving for other drugs and for natural rewards.
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This paper presents a review of the current status of empirical research in the area of alcohol craving. After an introduction on the origins of the construct of craving, we first present clinical studies that have examined craving as a hallmark symptom of alcohol dependence and demonstrated its sensitivity as an outcome measure in assessing change in pharmacotherapy trials of alcohol dependence. There is also discussion regarding new multifactorial self-report instruments of alcohol craving with good reliability and predictive validity, that may be sensitive to detecting alcohol craving and assessing change in craving as it relates to relapse during treatment. Next, we examine the experimental paradigms that have been used to induce alcohol craving in the laboratory. Further, the methodological issues affecting laboratory-based paradigms are presented, while also elucidating the potential use of effective laboratory-based craving induction paradigms, both in clinical studies as well as in laboratory studies that examine the brain mechanisms associated with the concept of craving. Finally, directions for future research on craving in the laboratory and the clinic are presented in the context of developing more effective treatments for different phases of recovery from alcohol dependence.
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Cognitive-Behavioral approach to treating insomnia Cognitive behavioral therapy (CBT) for insomnia is a brief and structured therapeutic intervention aimed at changing maladaptive sleep habits and unhelpful sleep-related beliefs and attitudes that perpetuate insomnia. The main therapeutic components include restriction of time spent in bed, stimulus control procedures, cognitive restructuring of beliefs and perceptions related to insomnia and its perceived consequences, and sleep hygiene education. Based upon a solid conceptual framework and supported by strong empirical evidence, CBT is now recognized and endorsed in clinical practice guidelines of medical and sleep societies as the first-line treatment for adults with chronic insomnia. Although it requires more time both from patients and clinicians, CBT produces clinically meaningful and more durable changes in sleep and associated insomnia symptoms than those obtained with medication treatment used singly.
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This paper presents a biopsychological theory of drug addiction, the 'Incentive-Sensitization Theory'. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether 'wanting' drugs (drug craving) is attributable to 'liking' drugs (to the subjective pleasurable effects of drugs)? The theory posits the following. (1) Addictive drugs share the ability to enhance mesotelencephalic dopamine neurotransmission. (2) One psychological function of this neural system is to attribute 'incentive salience' to the perception and mental representation of events associated with activation of the system. Incentive salience is a psychological process that transforms the perception of stimuli, imbuing them with salience, making them attractive, 'wanted', incentive stimuli. (3) In some individuals the repeated use of addictive drugs produces incremental neuroadaptations in this neural system, rendering it increasingly and perhaps permanently, hypersensitive ('sensitized') to drugs and drug-associated stimuli. The sensitization of dopamine systems is gated by associative learning, which causes excessive incentive salience to be attributed to the act of drug taking and to stimuli associated with drug taking. It is specifically the sensitization of incentive salience, therefore, that transforms ordinary 'wanting' into excessive drug craving. (4) It is further proposed that sensitization of the neural systems responsible for incentive salience ('for wanting') can occur independently of changes in neural systems that mediate the subjective pleasurable effects of drugs (drug 'liking') and of neural systems that mediate withdrawal. Thus, sensitization of incentive salience can produce addictive behavior (compulsive drug seeking and drug taking) even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family. We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.
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• Male alcoholics (n=460) and drug addicts (n=282) were evaluated at six-month follow-up after treatment in six rehabilitation programs. Initial analyses of the unstratified samples showed significant patient improvement, but no evidence of differential effectiveness from different treatments or from "matching" patients to treatments. The two samples were then divided into groups based on the number, duration, and intensity of their psychiatric symptoms at admission, ie, their overall "psychiatric severity." Patients with low psychiatric severity improved in every treatment program. Patients with high psychiatric severity showed virtually no improvement in any treatment. Patients with midrange psychiatric severity (60% of the samples) showed outcome differences from different treatments and especially from specific patient-program matches. These findings support the effectiveness and specificity of different substance abuse treatments, suggest methodologic reasons for the lack of similar findings in previous studies, and demonstrate the importance of psychiatric factors in substance abuse treatment.(Arch Gen Psychiatry 1983;40:620-625)
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Self-reported and observer-rated signs and symptoms of nicotine withdrawal were assessed precessation and 2, 7,14, 30, 90, and 180 days postcessation in smokers who quit on their own for 30 days. Anxiety, difficulty concentrating, hunger, irritability, restlessness, and weight gain increased, and heart rate decreased, postcessation (p <.001). Except for hunger and weight gain, these symptoms returned to precessation levels by 30 days postcessation. Craving, depression, and alcohol or caffeine intake did not reliably increase. Postcessation depression, but not withdrawal symptoms, craving, or weight gain, predicted relapse. These results are consistent with prior studies.
Article
Background: The primary objective of the study was to prospectively determine possible noradrenergic dysregulation in cocaine addicts by assessing biochemical, behavioral, and cardiovascular responses to intravenous yohimbine hydrochloride during early and late discontinuation of cocaine use. Methods: Twelve male and two female hospitalized cocaine-dependent subjects (mean±SD age, 30.9±7.3 years) who were not seeking primary treatment for addiction participated voluntarily for monetary remuneration. Following an initial test dose of intranasal cocaine, 2 mg/kg, cocaine addicts received single-blind, monitored cocaine insufflation, 2 mg/kg three times each day, for 3 consecutive days. One to two days (early discontinuation) and 15 to 16 days (late discontinuation) after the last dose of cocaine, subjects received double-blind, randomized intravenous infusions of yohimbine hydrochloride, 0.4 mg/kg, or placebo. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and plasma cortisol levels, anxiety-related symptoms on clinician- and subject-rated scales, blood pressure, and heart rate were measured throughout each test day. Ten of 14 subjects completed the entire study. Results: Subjects had a significantly greater placebocorrected MHPG response to yohimbine during early compared with late discontinuation. Subjects rated themselves significantly more nervous following yohimbine administration during early compared with late discontinuation. Seventy-one percent of subjects experienced a yohimbine-induced panic attack during early discontinuation compared with none during late discontinuation. Conclusions: The results of this study provide evidence of an underlying dysregulation in noradrenergic function and a vulnerability to panic anxiety during early discontinuation of cocaine use in addicts. Additional investigations of noradrenergic function appear warranted to further clarify derangements associated with cocaine addiction.
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Most major theories and models of addiction identify stress as an important factor in increasing drug use and in relapse. The basis for this association comes from epidemiological studies, clinical observations and survey data and some human laboratory studies. While substantial preclinical data support the notion that stress exposure enhances drug self-administration and that stress reinstates drug-seeking behavior, there is little direct evidence in humans on the interactions between stress and addictive processes, such as drug use, craving, tolerance, sensitization, withdrawal, and relapse. The purpose of this chapter is to examine the role of stress in addictive processes with a specific focus on human studies. The role of stress on additive processes is broken down into two categories: first, how stress may increase the vulnerability to drug abuse is examined, and second, the effects of chronic drug abuse on the stress response, stress-related coping and relapse are assessed. Unanswered questions and areas of future research on the association between stress and drug abuse in humans are identified. By examining the proposed mechanisms underlying the association between stress and drug abuse and the supporting empirical evidence, the goal is to expand the current knowledge base on how stress may perpetuate drug abuse. A greater understanding of this association will facilitate future research in this area, which in turn can have a significant impact on both prevention and treatment development in the field of addiction.
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Background: The International Conference on Applications of Neuroimaging to Alcoholism was convened at Yale University in New Haven, Connecticut. One session featured six speakers who discussed magnetic resonance spectroscopy (MRS) applications in alcoholism, with topics ranging from multimodality imaging to measurements of neurotransmitter synthesis in the human brain in vivo.MethodS: This session covered methodological topics related to 1H and 13C MRS, both theory and examples. The primary features of the 1H MR spectra were described, including resonances from creatine- and choline-choline–containing compounds, N-acetylaspartate, myo-inositol, glutamate, glutamine, GABA, and macromolecules. Methods reviewed also included MRS imaging, in which numerous MRS voxels are observed simultaneously. Other methods described J-editing of GABA and 13C MRS detection of oxidative metabolism and neurotransmitter synthesis.Results: Across studies, region-specific neurochemical changes were associated with alcohol dependence. With sobriety, many of the neurochemical alterations associated with alcohol dependence partially or fully abated, in association with partial recovery of brain structure and cognitive functions. The utility of 1H MRS to measure brain ethanol was discussed. This work highlighted the need to consider method- and analysis-dependent mechanisms that can affect the quantification of ethanol using 1H MRS. The utility of MRS as a tool to study alcohol dependence–related neurotoxicity was reviewed. In particular, the possibility that MRS may provide a noninvasive tool for studying glutamatergic activation associated with acute alcohol withdrawal may prove to be an important approach for mechanistic human studies related to neuropsychiatric complications of ethanol dependence and withdrawal, including dementia and hepatic encephalopathy.Conclusions: The International Conference on Applications of Neuroimaging to Alcoholism provided one of the first opportunities to convene a large group of investigators who used MRS techniques in the study of alcohol dependence. The range of data presented highlighted the growing range of insights related to the acute and chronic effects of ethanol on human brain chemistry. The ability to measure directly glutamate-glutamine cycling using 13C-MRS presents new and exciting opportunities to probe excitatory neurotransmission.
Article
This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stress-responses of the HPA axis in abstinent alcohol-dependent subjects, therefore, may influence their affective and behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review of HPA axis dysfunction in alcohol-dependent subjects, including recent studies from his lab demonstrating an attenuated glucocorticoid response to both endogenous and exogenous stimulation in one-month abstinent men. Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors (social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined the interaction between naltrexone and HPA responsiveness in alcohol-dependent or at-risk subjects, as naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased over the course of the study in the medication groups, but not the placebo group. Lower basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only. Suchitra Krishnan-Sarin described her preliminary work, in which family-history positive (FH+) and family history negative (FH-) subjects were administered naltrexone, followed by an assessment of alcohol-induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH-, subjects. Alterations in HPA axis responsivity may therefore have a negative impact upon clinical outcome in alcohol-dependent subjects, and disinhibition of the axis with medication may have therapeutic potential.
Article
The question of addiction specifically concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the “incentivesensitization theory of addiction”, which we first proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive (“sensitized”) to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug “liking”), but instead they mediate a subcomponent of reward we have termed incentive salience (drug “wanting”). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.
Article
This paper presents a biopsychological theory of drug addiction, the ‘Incentive-Sensitization Theory’. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether ‘wanting’ drugs (drug craving) is attributable to ‘liking’ drugs (to the subjective pleasurable effects of drugs)? The theory posits the following.
Article
Self-reported and observer-rated signs and symptoms of nicotine withdrawal were assessed precessation and 2, 7, 14, 30, 90, and 180 days postcessation in smokers who quit on their own for 30 days. Anxiety, difficulty concentrating, hunger, irritability, restlessness, and weight gain increased, and heart rate decreased, postcessation (p less than .001). Except for hunger and weight gain, these symptoms returned to precessation levels by 30 days postcessation. Craving, depression, and alcohol or caffeine intake did not reliably increase. Postcessation depression, but not withdrawal symptoms, craving, or weight gain, predicted relapse. These results are consistent with prior studies.
Article
Adrenal gland metabolism is markedly altered in heroin addicts. During daytime hours, the addict may suffer corticoid deficiency of the addisonian type, and in the evening, an excess of the cushingoid type. The high plasma levels of cortisol that are found in the evening in addicts antagonize endogenous opioids in a manner similar to naloxone. In the present study, 72% of the heroin addicts who sought treatment demonstrated reduced adrenal cortisol reserve. Effective immune and stress responses are dependent on adrenal cortisol reserve. This finding provides an explanation for the heroin addict's vulnerability to AIDS and other infectious diseases. One of methadone's greatest attributes is that it helps normalize adrenal metabolism. Clinical methods to at least partially correct adrenal metabolism may enhance current opioid addiction treatment modalities.
Article
Several learning theory based models propose that substance users may have conditioned reactions to stimuli (cues) associated with substance use and that these reactions may increase the probability of relapse. The conditioned withdrawal, conditioned compensatory response, and appetitive motivational models were evaluated in light of empirical evidence from cue reactivity studies with alcoholics, smokers, opiate users, and cocaine users. The nature of the stimuli that elicit reactivity and the nature of the responses elicited are most consistent with an appetitive motivational model and do not appear to support the other two models. A few studies have been conducted or are underway that investigate the use of cue exposure with response prevention as a treatment to decrease cue reactivity. Preliminary work with alcoholics, opiate users and cocaine users is promising but insufficient evidence exists to evaluate this approach. The implications for theory and treatment are discussed.
Article
Euphoric properties of cocaine lead to the development of chronic abuse, and appear to involve the acute activation of central DA neuronal systems. This is based upon known effects of cocaine on DA neurons, and the role played by DA in reward states and self-stimulation behavior. With chronic cocaine use, neurotransmitter and neuroendocrine alterations occur. DA depletion is hypothesized to result from overstimulation of these neurons and excessive synaptic metabolism of the neurotransmitter. DA depletion may underlie dysphoric aspects of cocaine abstinence, and cocaine urges. Neurochemical disruptions caused by cocaine are consistent with the concept of "physical" rather than "psychological" addiction. Possible pharmacological interventions in cocaine addiction are outlined and the psychological approach to these patients is discussed.
Article
Clonidine, an alpha-2-adrenergic agonist, significantly reduces opiate withdrawal. Fifteen heavy smokers abstained from cigarettes on three separate occasions and received instead clonidine, placebo, or the benzodiazepine alprazolam. Clonidine and alprazolam diminished withdrawal symptoms. The two drugs suppressed anxiety, tension, irritability, and restlessness equally but clonidine had a greater effect than alprazolam on cigarette craving. These observations suggest that noradrenergic activity is a common feature in the pathophysiology of withdrawal and that a special relationship exists between central noradrenergic activity and craving.
Article
Male alcoholics (n = 460) and drug addicts (n = 282) were evaluated at six-month follow-up after treatment in six rehabilitation programs. Initial analyses of the unstratified samples showed significant patient improvement, but no evidence of differential effectiveness from different treatments or from "matching" patients to treatments. The two samples were then divided into groups based on the number, duration, and intensity of their psychiatric symptoms at admission, ie, their overall "psychiatric severity." Patients with low psychiatric severity improved in every treatment program. Patients with high psychiatric severity showed virtually no improvement in any treatment. Patients with midrange psychiatric severity (60% of the samples) showed outcome differences from different treatments and especially from specific patient-program matches. These findings support the effectiveness and specificity of different substance abuse treatments, suggest methodologic reasons for the lack of similar findings in previous studies, and demonstrate the importance of psychiatric factors in substance abuse treatment.
Article
The urges to smoke reported by 215 former smokers were measured 1 day, 7 days, 14 days and 30 days after they quit to examine: (a) the time course of smoking urges, (b) the relationship of urges to relapse, and (c) predictors of urges to smoke. Urges to smoke were strongest 1 day after quitting, and decreased at each subsequent measurement point. Urges were a powerful predictor of relapse. At each of the four assessment points, abstinent subjects who reported stronger urges to smoke were more likely to relapse by the next measurement point. Urges to smoke at a given day (e.g., day 1) were consistently the best predictors of the persistence of urges at the next assessment (e.g., day 7). Greater negative emotion (e.g., anxiety, sadness, anger, and confusion) and psychosocial stress also predicted stronger urges to smoke. Nicotine gum significantly reduced urges during week 1 post-cessation. Clinical implications of the findings are discussed.
Article
Cocaine mediates its powerful reinforcement by binding to recognition sites on the dopamine (DA) transporter. The pharmacological identity of cocaine recognition sites and their relevance to dopamine transport function has remained unclear. Ligand binding studies with transport inhibitors and cocaine congeners have provided evidence for multiple sites or "states" of the DA transporter. The potent cocaine congener [3H]WIN 35,428 ((CFT), 2B-carbomethoxy-3 beta-(4-fluorophenyl)-tropane) has been shown to recognize high and low affinity binding sites on the DA transporter. We have used [3H]WIN 35,428 to map and quantify the high affinity cocaine recognition site on the DA transporter in victims of fatal cocaine overdose. Region-of-interest densitometric analysis of the autoradiograms demonstrated a 2- to 3-fold elevation in the apparent density of [3H]WIN 35,428 binding in particular sectors of the striatum from victims of cocaine overdose as compared to age-matched and drug-free control subjects. The most marked increase in [3H]WIN 35,428 binding was seen in the nucleus accumbens. The apparent increase in the density of high affinity sites was confirmed by saturation binding analysis of [3H]WIN 35,428 to putamen membranes. Saturation analysis revealed high and low affinity binding components with affinities (KD values) of 4.3 +/- 1.2 and 84.7 +/- 19.7 nM (mean +/- S.E.) and densities of 9.9 +/- 4.0 and 193.0 +/- 28.6 pmol/g of tissue, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The primary objective of the study was to prospectively determine possible noradrenergic dysregulation in cocaine addicts by assessing biochemical, behavioral, and cardiovascular responses to intravenous yohimbine hydrochloride during early and late discontinuation of cocaine use. Twelve male and two female hospitalized cocaine-dependent subjects (mean +/- SD age, 30.9 +/- 7.3 years) who were not seeking primary treatment for addiction participated voluntarily for monetary remuneration. Following an initial test dose of intranasal cocaine, 2 mg/kg, cocaine addicts received single-blind, monitored cocaine insufflation, 2 mg/kg three times each day, for 3 consecutive days. One to two days (early discontinuation) and 15 to 16 days (late discontinuation) after the last dose of cocaine, subjects received double-blind, randomized intravenous infusions of yohimbine hydrochloride, 0.4 mg/kg, or placebo. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and plasma cortisol levels, anxiety-related symptoms on clinician- and subject-rated scales, blood pressure, and heart rate were measured throughout each test day. Ten of 14 subjects completed the entire study. Subjects had a significantly greater placebo-corrected MHPG response to yohimbine during early compared with late discontinuation. Subjects rated themselves significantly more nervous following yohimbine administration during early compared with late discontinuation. Seventy-one percent of subjects experienced a yohimbine-induced panic attack during early discontinuation compared with none during late discontinuation. The results of this study provide evidence of an underlying dysregulation in noradrenergic function and a vulnerability to panic anxiety during early discontinuation of cocaine use in addicts. Additional investigations of noradrenergic function appear warranted to further clarify derangements associated with cocaine addiction.