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Dopamine in Drug Abuse and Addiction: Results of Imaging Studies and Treatment Implications
Abstract
Imaging studies have provided new insights on the role of dopamine (DA) in drug abuse and addiction in the human brain. These studies have shown that the reinforcing effects of drugs of abuse in human beings are contingent not just on DA increases per se in the striatum (including the nucleus accumbens) but on the rate of DA increases. The faster the increases, the more intense the reinforcing effects. They have also shown that elevated levels of DA in the dorsal striatum are involved in the motivation to procure the drug when the addicted subject is exposed to stimuli associated with the drug (conditioned stimuli). In contrast, long-term drug use seems to be associated with decreased DA function, as evidenced by reductions in D2 DA receptors and DA release in the striatum in addicted subjects. Moreover, the reductions in D2 DA receptors in the striatum are associated with reduced activity of the orbitofrontal cortex (region involved with salience attribution and motivation and with compulsive behaviors) and of the cingulate gyrus (region involved with inhibitory control and impulsivity), which implicates deregulation of frontal regions by DA in the loss of control and compulsive drug intake that characterizes addiction. Because DA cells fire in response to salient stimuli and facilitate conditioned learning, their activation by drugs will be experienced as highly salient, driving the motivation to take the drug and further strengthening conditioned learning and producing automatic behaviors (compulsions and habits).
... However, while increased presynaptic dopamine synthesis and release is characteristic for schizophrenia, only some patients have altered postsynaptic D 2 R, pointing towards subtypes of schizophrenia (Brugger et al., 2020). Dopamine also contributes to impulsive behavior, such as aggressive outbursts and drug abuse (Schmidt et al., 2005;Schultz, 1998;Seo et al., 2008;Volkow et al., 2004). Mesolimbic dopamine pathway and upregulated striatal dopamine function is critical for aggressive behavior (Schmidt et al., 2005). ...
... Mesolimbic dopamine pathway and upregulated striatal dopamine function is critical for aggressive behavior (Schmidt et al., 2005). Hyperactive striatal dopaminergic function is also consistently linked with acute effects of drug abuse in addicted subjects, who overall show diminished dopamine and D 2 Rs in the striatum (Volkow et al., 2004). Baseline downregulation of dopamine in addictions might associate with their commonly comorbid affective symptoms (Marshall & Farrell, 2007), such as anhedonia (lack of pleasure) and dysphoria (dissatisfaction), that are coherently connected to diminished mesocorticolimbic dopamine (Bressan & Crippa, 2005). ...
... Striatal dopamine neurotransmission has a central role in motor functions that are disturbed particularly in PD (Kaasinen & Vahlberg, 2017;Kaasinen et al., 2021), and motivational processes that are impaired in many neuropsychiatric disorders (Bressan & Crippa, 2005;Knable et al., 1997;Schmidt et al., 2005;Schultz, 1998;Volkow et al., 2004). Our findings show that in PD, striatal (caudate and accumbens) and thalamic D 2 R availability is downregulated, while interregional correlation might be lowered in severe violent behavior. ...
Purpose
Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls.
Methods
Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [¹¹C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls, and subjects with Parkinson’s disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability. We also analyzed the interregional correlation in D2R availability within each group.
Results
Subjects with PD showed the clearest decline in D2R availability. Overall, the groups showed high interregional correlation in D2R availability, while this pattern was weaker in violent offenders. Subjects with schizophrenia, pathological gambling, depression, or overweight did not show clear changes in either the regional receptor availability or the interregional correlation.
Conclusion
We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also how coupled regions are across people. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region coupling might be disrupted in violence.
... Dopamin beynin ödül sisteminin birincil nörotransmitteridir. Duygu, biliş, motivasyon, zevk duyguları ve hareketi düzenlemede rol oynar (19,20). Yemek yeme gibi doğal ödüller veya eğlence amacıyla madde kullanımı dopamin salınımı yaratır ve bu, bağımlılık yapıcı uyaranların güçlendirici doğasıyla ilişkilidir (20,21). ...
... Duygu, biliş, motivasyon, zevk duyguları ve hareketi düzenlemede rol oynar (19,20). Yemek yeme gibi doğal ödüller veya eğlence amacıyla madde kullanımı dopamin salınımı yaratır ve bu, bağımlılık yapıcı uyaranların güçlendirici doğasıyla ilişkilidir (20,21). Doğrudan ya da dolaylı olarak, bağımlılık yapıcı tüm ilaçlar, dopaminerjik aktiviteyi artırmak yoluyla beynin ödül sistemini etkiler (22). ...
... Doğrudan ya da dolaylı olarak, bağımlılık yapıcı tüm ilaçlar, dopaminerjik aktiviteyi artırmak yoluyla beynin ödül sistemini etkiler (22). Birçok bağımlılık yapıcı madde aşırı alındığında, yüksek düzeyde dopaminin yineleyici şekilde salınmasına neden olur ve ödül yolaklarını artmış dopamin reseptör aktivasyonu ile etkiler (20). Ödül duyarlılığı, beyinin ödül sisteminde ödüllendirici uyarana verilen tepkide artışa neden olan bir işlemdir. ...
AMAÇ: Bu araştırmanın amacı, sigara içen doktorlarda yetişkin tip dikkat eksikliği ve hiperaktivite bozukluğu (DEHB) sıklığını değerlendirmek ve sigara bıraktırma sürecinde DEHB tanısı ve tedavisinin yerini belirlemektir. GEREÇ VE YÖNTEM: Araştırma süresi içinde (Kasım 2017 – Haziran 2018) araştırmaya İzmir Tepecik Eğitim ve Araştırma Hastanesi’nde (İTEAH) çalışan sigara kullanan doktorlar ve sigara kullanmayan kontrol grubu doktorlar dahil edilmiştir. Araştırmaya katılan 128 doktorun Dünya Sağlık Örgütü (DSÖ) Erişkin Dikkat Eksikliği ve Hiperaktivite Kendi Bildirim Ölçeği’ni (EDEHKBÖ) cevaplamaları sağlanmıştır. Sonuçta veriler SPSS 24.0 paket programı ile değerlendirilmiştir. Anlamlılık düzeyi p
... Dopamine (DA) regulates a wide range of physiological functions, including movement, cognition, reward, and addiction [13]. Dopamine is the neurotransmitter that is associated with the reinforcing effects of addictive substances and plays a significant role in initiating the neurobiological changes related to addiction [14,15]. The reuptake of DA from synaptic clefts into the presynaptic terminal is carried out by a trans-membrane protein known as dopamine transporter (DAT) [16]. ...
... Therefore, in several studies regarding drug abuse or addiction, they evaluate the distribution of DAT activity using the uptake radiolabeled substrate such as [2-[[2-[[[3-(4- [16,17]. In drug addictions such as cocaine, heroin, and methamphetamine, there are significant reductions in D 2 DA receptor availability in the striatum (14). ...
... In addition, cocaine's long-term behavioral impacts could be correlated to changes in dopamine transmission that result from DAT blockage [33]. Chronic cocaine usage is linked to a reduction in dopamine D2 receptor availability due to high levels of synaptic dopamine, which lasts three-four months after detoxification [14,33]. ...
Objective:
The study aims to elucidate the effects of kratom addiction on dopamine transporter (DAT) using [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N20,S2,S20]oxo-[1R-(exo-exo)]-[99mTc] technetium (99mTc-TRODAT-1) brain single photon emission computed tomography-computed tomography (SPECT-CT) in kratom-dependent and healthy subjects.
Materials and methods:
We recruited 12 kratom-dependent subjects and 13 healthy men to participate in this study. Addiction, craving, depression, and cognitive scores were assessed. All subjects received a single bolus injection of 99mTc-TRODAT-1 with 914.1 MBq ± 65.5 of activity (mean ± SD). The brain SPECT-CT images were reconstructed using 3D ordered subset expectation maximization (3D-OSEM) along with attenuation correction (AC), scatter correction (SC), and resolution recovery (RR) with an iteration number of four and a subset of 10. The Cohen's Kappa interrater-reliability between two raters, the standardized uptake value of body weight (SUVBW), and the asymmetrical index percentage (AI%) were evaluated.
Results:
Kappa statistics showed a fine agreement of abnormal 99mTc-TRODAT-1 uptake in the striatum region for the kratom-dependent group with the κ value of 0.69 (p = 0.0001), and the percentage of agreement for rater 1 and rater 2 was 56% and 64%, respectively. There was a reduction in average SUV in kratom-dependent subjects compared to healthy control subjects in the left caudate and left striatum (0.938 vs. 1.251, p = 0.014, and 1.055 vs. 1.29, p = 0.036, respectively). There was a significant difference in the AI% of the caudate region between the kratom-dependent group and the normal group (33% vs. 14%, p = 0.019).
Conclusion:
Our findings signify that kratom addiction, may cause a change in DAT level and the results can be confirmed using 99mTc-TRODAT-1 SPECT-CT.
... Dopamine also contributes to impulsive behavior, such as aggressive outbursts and drug abuse (Schmidt, Schmidt, & Reith, 2005;Schultz, 1998;Seo, Patrick, & Kennealy, 2008;Volkow, Fowler, Wang, & Swanson, 2004). Mesolimbic dopamine pathway and upregulated striatal dopamine function is critical for aggressive behavior (Schmidt et al., 2005). ...
... Mesolimbic dopamine pathway and upregulated striatal dopamine function is critical for aggressive behavior (Schmidt et al., 2005). Hyperactive striatal dopaminergic function is also consistently linked with acute effects of drug abuse in addicted subjects, who overall show diminished dopamine and D2Rs in the striatum (Volkow et al., 2004). Baseline downregulation of dopamine in addictions might associate with their commonly comorbid affective symptoms (Marshall & Farrell, 2007), such as anhedonia (lack of pleasure) and dysphoria (dissatisfaction), that are coherently connected to diminished mesocorticolimbic dopamine (Bressan & Crippa, 2005). ...
... Striatal dopamine neurotransmission has a central role in motor function that is disturbed particularly in PD (Kaasinen & Vahlberg, 2017;Kaasinen, Vahlberg, Stoessl, Strafella, & Antonini, 2021), and motivational processes that are impaired in many neuropsychiatric disorders (Bressan & Crippa, 2005;Knable et al., 1997;Schmidt et al., 2005;Schultz, 1998;Volkow et al., 2004). Our findings show that in PD, striatal (caudate and accumbens) and thalamic D2R availability is downregulated, while interregional correlation might be lowered in antipsychotic-naïve schizophrenia, severe violent behavior, and depression. ...
PURPOSE
Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. METHODS: Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D 2 R) availability using [ ¹¹ C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls, and subjects with Parkinson’s disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D 2 R availability. We also analyzed the interregional correlation in D 2 R availability within each group. RESULTS: Subjects with PD showed the clearest decline in D 2 R availability. Overall, the groups showed high interregional correlation in D 2 R availability, while this pattern was weaker in violent offenders. Subjects with schizophrenia, pathological gambling, depression, or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. CONCLUSION: We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also the connectivity between the regions. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region connectivity might be disrupted in violence.
Highlights
We compared human striatal and thalamic type 2 dopamine receptor (D 2 R) availability between healthy controls, and subjects with Parkinson’s disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight.
We present the mean brain maps of group specific D 2 R availabilities in NeuroVault ( https://neurovault.org ; https://identifiers.org/neurovault.collection:12799 ).
Dopamine type 2 receptor availability is lowered in PD in caudate nucleus, nucleus accumbens and thalamus.
Subjects with severe violent behavior had decreased correlation between the striatal and thalamic D 2 R availability.
Altered regional D 2 R availability in the striatum and thalamus is linked with motor disorders, while lowered interregional connectivity in D 2 R might relate to violence.
KEY POINTS
QUESTION: Are there differences in the striatal (caudate nucleus, nucleus accumbens, and putamen), and thalamic D 2 R availability in a sample including healthy controls, and subjects with Parkinson’s disease, antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight?
PERTINENT FINDINGS: Based on this register-based study of a large historical sample (n=437), Parkinson’s disease links to changes in the regional receptor availability, while in severe violent behavior, the correlation between regional receptor availabilities might be lowered. No clear receptor changes were observed in overweight.
IMPLICATIONS FOR PATIENT CARE: Based on our data of striatal and thalamic type 2 dopamine receptors, region-specific changes are linked with motor disorders, while lowered between-region correlation might relate to violence.
... A more pronounced tendency to choose smaller immediate rewards (impulsive choice) is observed in individuals suffering from substance-use-disorders (SUDs) and behavioural addictions 3,4 . One prominent hypothesis assumes changes in dopamine (DA) neurotransmission as functional correlate of maladaptive changes in decision-making 5,6 . This is supported by a large body of human and animal evidence suggesting that DA plays a central role in reward valuation, prediction and decision-making [7][8][9][10] . ...
... Reinforcers act upon frontal and striatal brain regions innervated by DA and implicated in reward processing [11][12][13] . Individual differences in DA D2 receptor availability in the midbrain correlate with reward valuation 14 , whereas highly impulsive individuals and individuals suffering from SUDs tend to exhibit decreased DA function (for reviews, see 6,15 ). ...
Disorders characterised by changes in dopamine (DA) neurotransmission are often linked to changes in the temporal discounting of future rewards. Likewise, pharmacological manipulations of DA neurotransmission in healthy individuals modulates temporal discounting, but there is considerable variability in the directionality of reported pharmacological effects, as enhancements and reductions of DA signalling have been linked to both increases and reductions of temporal discounting. This may be due to meaningful individual differences in drug effects and/or false positive findings in small samples. To resolve these inconsistencies, we 1) revisited pharmacological effects of the DA precursor L-DOPA on temporal discounting in a large sample of N = 76 healthy participants (n = 44 male) and 2) examined several putative proxy measures for DA to revisit the role of individual differences in a randomised, double-blind placebo-controlled pre-registered study (https://osf.io/a4k9j/). Replicating previous findings, higher rewards were discounted less (magnitude effect). Computational modelling using hierarchical Bayesian estimation confirmed that the data in both drug conditions were best accounted for by a non-linear temporal discounting drift diffusion model. In line with recent animal and human work, L-DOPA reliably reduced the discount rate with a small effect size, challenging earlier findings in substantially smaller samples. We found no credible evidence for linear or quadratic effects of putative DA proxy measures on model parameters, calling into question the role of these measures in accounting for individual differences in DA drug effects.
... Cuanto más rápido sea el efecto de la droga, más rápidamente se establecerá la dependencia. Todas las drogas adictivas que producen refuerzo positivo, estimulan la liberación de dopamina en el núcleo accumbens, una estructura que tiene un importante papel en el refuerzo (Volkow, Fowler, Wang, & Swanson, 2004). Ejemplos de reforzadores positivos al consumo, además del placer por el efecto fisiológico del disparo de dopamina, serían los reconocimientos sociales reportados por las personas que consumen o la posibilidad de interactuar más fácilmente con otros debido al consumo. ...
... Si debido a su situación social o a factores emocionales, la persona siente malestar o ansiedad, una droga que reduzca estas sensaciones puede reforzar la conducta de consumo de droga por medio de refuerzo negativo. Asimismo, la reducción de los síntomas de abstinencia como efecto de una dosis de la droga indudablemente participa en que se mantenga la adicción a la droga, pero no es la única causa del antojo (Volkow, Fowler, Wang, & Swanson, 2004). ...
... The D2 receptor is notoriously prone to desensitization in response to pharmaceutical 21 , druginduced [22][23][24][25][26][27][28][29][30] , or experimental 31,32 increases in dopamine. Our results provide a natural function for this long-studied effect, one that is likely to generalize across animals and behaviors. ...
... doi: bioRxiv preprint lead to widespread D2R inactivation and consequent devaluation of otherwise rewarding behaviors. This is precisely the case in drug addiction, where broadly acting drugs of abuse cause widespread reduction in D2R availability in the striatum of human addicts [22][23][24][25] . This, it seems to us, is an instance of a novel finding in a model organism being effectively pre-validated in humans. ...
Goal achievement adjusts the relative importance of future behaviors. We use Drosophila to study this form of motivational control, finding that prior matings make males increasingly likely to abandon future copulations when challenged. Repetition-induced devaluation results from a reduction in dopamine reception by the Copulation Decision Neurons (CDNs), which mediate the decision to end matings. Dopamine signaling to the CDNs sustains matings in real time, but also triggers a lasting, β-arrestin-dependent desensitization of the D2R on the CDNs, leaving subsequent matings susceptible to disruption. When D2R desensitization is experimentally prevented, the male treats each mating as if it were his first. These findings provide a generalizable mechanism of motivational control and reveal a natural function for the long-studied susceptibility of the D2R to drug-induced inactivation.
... Alcoholism in humans activates the endogenous opioid system by upregulating PDYN activity on kappa-opioid receptors (KORs) [19]. This implies that long-term upregulation of PDYN expression in the amygdala and NAc potentially impacts the vulnerability of opioid addiction [20]. ...
... The upregulation of D2R and KOR expression is important to note considering their associated activity during opioid drug exposure. The upregulation of D2R expression can be due to fewer D2 receptors, a trait often seen in drug abusers that may suggest a predisposition to opioid use [20]. KOR activation in the NAc inhibits D1R-mediated activity, a key mechanism in the development and expression of locomotor sensitization, as well as localization in the striatonigral pathway that employs the opioid peptide Dynorphin [15]. ...
Drug addiction is characterized by maladaptive neural plasticity, particularly in vulnerable individuals exposed to drugs of abuse. Epigenetic factors include environmental influences, events during development, and stress adaptations, which seem to play an important role in the neuropathogenesis of drug addiction. This critical review hypothesizes that epigenetic modulation increases an individual’s susceptibility to opiate addiction in three key areas of epigenetic study: developmental, stress-related, and transgenerational effects.
The widespread use of opioids for clinical and recreational purposes raises significant societal and scientific concerns. Despite the increasing prevalence of opioid abuse, there is limited comprehensive knowledge about the impact of epigenetic factors on opiate addiction manifestation. This review hypothesizes that epigenetic modulation increases susceptibility to opiate addiction, exploring three key areas of epigenetic study: developmental, stress-related, and transgenerational effects.
Current literature reveals a correlation between epigenetic influences and vulnerability to drug addiction, specifically in the context of opioid use. Epigenetics, the modulation of genetic expression beyond genotypic predisposition, plays a crucial role in an individual’s susceptibility to drug addiction. Studies suggest that epigenetic mechanisms, once considered static in the adult brain, continue to influence synaptic plasticity and long-term memory, particularly in the endogenous opioid system.
This review examines the effects of opioids and stress on epigenetic modifications, providing evidence of increased vulnerability to opiate addiction. Animal studies demonstrate how developmental adversities and adolescent exposure to substances can induce persistent epigenetic changes, predisposing individuals to opiate addiction in adulthood. Moreover, the review explores the transgenerational effects of opioid exposure during adolescence, suggesting that functional epigenetic neuroadaptations within the nucleus accumbens can persist for multiple generations. The examination of DNA methylation patterns in opioid addicts reveals potential markers for identifying susceptibility to opiate vulnerability.
A critical analysis of research reports supports the hypothesis that developmental, transgenerational, and stress-related epigenetic mechanisms have a profound role in increasing the risk of opioid addiction susceptibility. Each study confirmed that developmental, stress-related, or transgenerational epigenetic regulations have a correlation to increased opiate sensitization and vulnerability. Unfortunately, every study reviewed was unable to elucidate an epigenetic mechanism to explain a specific neuropathogenesis of opiate drug addiction vulnerability, emphasizing our lack of knowledge in the complex pathology of epigenetics.
... Functional imaging studies during craving provocation have suggested that decreased brain activity may be associated with improvements in depressed mood or reduced drug craving Robertson et al., 2007;Volkow, Fowler, Wang, & Swanson, 2004). In an fMRI study of 10 patients with major depression, 8 weeks of bupropion extended release treatment reduced brain activation, especially, in orbital frontal cortex, cingulate, amygdala/ parahippocampal area, and caudate in response to emotionally distracting stimuli (Robertson et al., 2007). ...
... Most brain studies of patients with substance dependence suggest that brain activity will decrease in response to substance cues after bupropion treatment Robertson et al., 2007;Volkow et al., 2004). In this study, we hypothesized that brain activation of the prefrontal cortex and parahippocampal gyrus in response to video game cues in persons with Internet video game addiction (IAG) would be similar to that observed after drug cue presentation to individuals with substance dependence. ...
Bupropion has been used in the treatment of patients with substance dependence based on its weak inhibition of dopamine and norepinephrine reuptake. We hypothesized that 6 weeks of bupropion sustained release (SR) treatment would decrease craving for Internet game play as well as video game cue-induced brain activity in patients with Internet video game addiction (IAG). Eleven subjects who met criteria for IAG, playing StarCraft (>30 hr/week), and eight healthy comparison subjects (HC) who had experience playing StarCraft (<3 days/week and <1 hr/day). At baseline and at the end of 6 weeks of bupropion SR treatment, brain activity in response to StarCraft cue presentation was assessed using 1.5 Tesla functional MRI. In addition, symptoms of depression, craving for playing the game, and the severity of Internet addiction were evaluated by Beck Depression Inventory, self-report of craving on a 7-point visual analogue scale, and Young's Internet Addiction Scale, respectively. In response to game cues, IAG showed higher brain activation in left occipital lobe cuneus, left dorsolateral prefrontal cortex, and left parahippocampal gyrus than HC. After a 6 week period of bupropion SR, craving for Internet video game play, total game play time, and cue-induced brain activity in dorsolateral prefrontal cortex were decreased in the IAG. We suggest that bupropion SR may change craving and brain activity in ways that are similar to those observed in individuals with substance abuse or dependence.
... The presence of functional CB1R is different in fetal life when compared to the pattern seen in CB1R location in adults. This presence supports the vital role played by this receptor in brain development (Figure 1), which is evidenced by data showing the involvement of this receptor in the regulation of neural differentiation, axonal migration, and synaptogenesis (Grace, 2016;Volkow et al., 2004). ...
... Maternal THC exposure causes multiple molecular, cellular, and synaptic changes in juvenile male rat pups, which result in heightened dopamine function (Frau et al., 2019). The hyperdopaminergic state could explain the reduced expression of dopamine D2 receptors in the amygdala and nucleus accumbens Wang et al., 2004) of human PCE offspring as the change in receptor levels could represent an adaptive response evoked by excessive dopamine release (Volkow et al., 2004). Increased excitability of ventral tegmental area dopamine neurons leading to altered dopamine transmission is a well-known neurodevelopmental risk factor for psychological disorders, which can be apparent as aberrant associative learning and reward processing. ...
Epidemiological studies examining the influence of cannabis across the lifespan show that exposure to cannabis during gestation or during the perinatal period is associated with later-life mental health issues that manifest during childhood, adolescence, and adulthood. The risk of later-life negative outcomes following early exposure is particularly high in persons who have specific genetic variants, implying that cannabis usage interacts with genetics to heighten mental health risks. Prenatal and perinatal exposure to psychoactive components has been shown in animal research to be associated with long-term effects on neural systems relevant to psychiatric and substance use disorders. The long-term molecular, epigenetic, electrophysiological, and behavioral consequences of prenatal and perinatal exposure to cannabis are discussed in this article. Animal and human studies, as well as in vivo neuroimaging methods, are used to provide insights into the changes induced in the brain by cannabis. Here, based on the literature from both animal models and humans, it can be concluded that prenatal cannabis exposure alters the developmental route of several neuronal regions with correlated functional consequences evidenced as changes in social behavior and executive functions throughout life.
... As such, exposure to food cues increases craving for food, activates the reward circuitry in the brain that includes the basal ganglia and prefrontal cortex [75,76], and contributes to eating and weight gain [77]. Chronic opioid exposure attenuates reward sensitivity [78]. Given the higher reward potency of drugs of abuse, patients with OUD showed heightened incentive motivation towards opioids [79] and reduced interest in naturally rewarding activities [80]. ...
... Compared to healthy controls, patients with OUD demonstrated lower prefrontal neural activity in response to food cues [82,83]. Preference for opioids in lieu of food constitutes one possible mechanistic pathway underlying weight loss in OUD individuals [78]. ...
Purpose of Review
Opioid use disorder (OUD) is a chronic, relapsing condition that is epidemic in the USA. OUD is associated with serious adverse consequences, including higher incarceration rates, impaired medical and mental health, and overdose-related fatalities. Several medications with demonstrated clinical efficacy in reducing opioid use are approved to treat OUD. However, there is evidence that medications for OUD cause metabolic impairments, which raises concerns over the long-term metabolic health of individuals recovering from OUD. Here, we summarize the scientific literature on the metabolic effects of the use of opioids, including medications for treating OUD.
Recent Findings
Our findings showed lower body weight and adiposity, and better lipid profiles in individuals with OUD. In individuals with diabetes mellitus, opioid use was associated with lower blood glucose levels. In contrast, among individuals without underlying metabolic conditions, opioids promoted insulin resistance. Treatment of OUD patients with the agonists methadone or buprenorphine caused weight gain, increased liking and intake of sugar, and impaired lipid profile and glucose metabolism, whereas treatment with the antagonist naltrexone demonstrated evidence for reduced sweet preferences.
Summary
Our findings highlighted a gap in knowledge regarding the safety of medications for OUD. Further research is needed to determine how best to reduce the risk of metabolic disorder in the treatment of OUD with opioid agonists versus antagonists.
... Chronic substance abuse alters various neurotransmitter systems [54], including dopamine release. Furthermore, chronic opioid drug abuse is associated with reductions in dopamine release; D2 receptors in the brain's striatum are associated with reduced activity of the orbitofrontal cortex (region involved with motivation and compulsivity) along with the cingulate gyrus (region involved with inhibitory control and impulsivity) [55], which may exacerbate the cycle of addiction and relapse. ...
The recent identification of Piezo ion channels demonstrating a mechano-sensitive impact on neurons revealed distinct Piezo-1 and 2 types. While Piezo-1 predominates in neurons linked to non-sensory stimulation, such as pressure in blood vessels, Piezo-2 predominates in neurons linked to sensory stimulation, such as touch. Piezo-1 and 2 have a major bidirectional impact on transient receptor potential (TRP) ion channels, and TRPs also impact neurotransmitter release. Particularly existent in dorsal root ganglion (DRG) neurons, which are located in nerve endings, Piezo-2 is a key DRG activator. Subsequent Piezo findings have been vital to recent medical haptic technology developments, in tandem with breakthroughs in the emerging neurology subfield of connectomics plus AI developments. Included in this review are a historical Piezo overview, the interrelationship of Piezo channels with TRPs, inclusive of TRPV1/TRPV8, the impact on medical and rehab haptic technology, a focus on haptic technology use in stroke survivor rehab inclusive of pain mitigation, and the development of a haptic technology patch aimed at alleviating pain and/or anxiety. Neurogenic pain resulting from hyperalgesia/allodynia in stroke survivors is a potential target for drugs and haptics aimed at pain reduction; patients experiencing neuropathic or psychosomatic pain are other prime targets. Increased Piezo knowledge may promote more precisely targeted haptic therapeutic developments.
... Dopamine neurons provide a teaching signal that resembles reward prediction errors and modulates cue-reward associations [10][11][12][13] . A leading hypothesis of cue reactivity is that addictive drugs, all of which increase dopamine signaling due to their direct pharmacological effects even when the cue-drug association is fully learned 14 , result in enhanced maladaptive learning by causing a persistently positive reward prediction error every time the drug is taken 5,6,15 . Over time, this leads to a runaway enhancement of dopamine firing response to drug cues that approaches a maximum, resulting in overvaluation and triggering intense craving and relapse. ...
Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. A widely accepted assumption is that drugs of abuse result in disparate dopamine responses to cues that predict drug vs. natural rewards. The leading hypothesis is that drug-induced dopamine release represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation. However, this hypothesis has not been directly tested. Here, we develop Pavlovian and operant procedures in male rats to measure firing responses within the same dopamine neurons to drug versus natural reward cues, which we find to be similarly enhanced compared to cues predicting natural rewards in drug-naive controls. This enhancement is associated with increased behavioral reactivity to the drug cue, suggesting that dopamine neuronal activity may still be relevant to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting revised models of dopaminergic function in opioid addiction, and provide insights into the neurobiology of cue reactivity with potential implications for relapse prevention.
... Its psychoactive action is due to the presence of Myristicin and elemicin which have been reported to have antidepressant action (5, 6). Addictive Substances have been reported to increase dopamine levels in the brain (7), on the contrary, long-term exposure to addictive substances can lead to a decrease in dopamine levels (8). Dopaminergic neurons arising from the compacta part of the substantia nigra, send their projections to the striatum (9,10), in that way, they are involved in motor coordination, associative learning, and reward recognition. ...
... The effect of CBD on alcohol cue-induced NAc activation was tested using a validated alcohol cue-reactivity functional magnetic resonance imaging (fMRI) paradigm [14,15]. We focused on the NAc as region of interest, because it was identified as a key neurobiological substrate of the addiction circuit [16,17], and because neuroimaging studies demonstrated robust effects of alcohol cue presentation on NAc activation [18] and significant associations of NAc activation, alcohol craving [18] and relapse risk in AUD [19]. In addition, it was demonstrated, that higher activation in the ventral striatum is associated with the efficacy of naltrexone, supporting the potential of cue-induced brain response as a marker for individual efficacy of pharmacotherapeutic approaches [20]. ...
Although alcohol use disorder (AUD) is highly prevalent, only a few medications are approved for its treatment leaving much room for improvement. Cannabidiol (CBD) might be a particularly promising candidate, with preclinical data suggesting that CBD is effective in targeting AUD symptoms and disease processes that drive alcohol use and relapse, due to its anti-craving, stress-reducing, and anti-compulsive effects. Here we report data from the double-blind randomized controlled ICONIC trial that compared the effects of a single dose of 800 mg cannabidiol against placebo (PLC) in N = 28 individuals with AUD. Cue-induced nucleus accumbens (NAc) activation, alcohol craving during a combined stress- and alcohol cue exposure session, as well as craving during an fMRI alcohol cue-reactivity task and CBD plasma levels served as outcomes. Individuals receiving CBD showed lower bilateral cue-induced NAc activation (tleft_NAc(23) = 4.906, p < 0.001, d = 1.15; tright_NAc (23) = 4.873, p < 0.001, d = 1.13) and reported significantly lower alcohol craving after a combined stress- and alcohol cue exposure session (Fgroup(1,26) = 4.516, p = 0.043, eta² = 0.15) and during the fMRI cue-reactivity task (Fgroup(1,24) = 6.665, p = 0.015, eta² = 0.23). CBD levels were significantly higher in the CBD group (t(25) = 3.808, p < 0.001, d = 1.47) and showed a significant negative association with alcohol craving during the cue exposure experiment (r = −0.394, pFDR = 0.030) and during fMRI (r = −0.389, pFDR = 0.030), and with left and right NAc activation (rleft_NAc = −0.459, pFDR = 0.030; rright_NAc = −0.405, pFDR = 0.030). CBD’s capacity to reduce stress- and cue-induced alcohol craving and to normalize NAc activation – a region critical to the pathophysiology of AUD – contribute to understanding the neurobiological basis of its clinical effects and support its potential as a treatment option for AUD. Clinical Trials Registry: DRKS00029993.
... The mechanism by which alcohol activates mesolimbic DA transmission has been the subject of intense research for decades, as this pathway is critical in mediating the reinforcing effects of alcohol, as well as other drugs of abuse [28,29]. Even in humans, positron emission tomography studies have shown that alcohol induces a release of DA in the ventral striatum [30], and that this fast release of DA is associated with alcohol-induced reinforcing effects and acquisition of conditioned responses [31]. In this regard, the metabolic conversion of alcohol into acetaldehyde has been recognized as critically involved [32,33], and this suggestion was further extended by the observation that another molecule, 1methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), obtainable by Pictet-Spengler condensation of acetaldehyde and DA, could be responsible for the reinforcing properties of alcohol and for its addictive potential [34,35]. ...
The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.
... They also play a proximal role in the transition from controlled to compulsive drug seeking in humans Volkow 2010, 2016). For example, nearly all drug intoxication is accompanied by the release of dopamine and opioid peptides into the ventral striatum (Mitchell et al. 2012;Volkow et al. 2007;Koob 2015). This serves to elicit appetitive, positive affective emotions (Baldo and Kelley 2007;Burgdorf and Panksepp 2006), high incentive salience (Berridge and Robinson 1998) and to reinforce drug consumption via stimulus-response and conditioned learning processes (Delgado 2007;Daniel and Pollmann 2014). ...
... Imaging studies have shown that the reinforcing effects of drugs are dependent not only on dopamine increases in the striatum but also on the rate at which these increases occur. However, long-term drug use seems to be linked to diminished dopamine function as the brain of addicted subjects presents reductions in D2 DA receptors and DA release in the striatum [32]. Second, serotonin also plays a crucial role in the development and maintenance of addiction as it is involved in the modulation of impulsivity [33], which is a risk factor for addiction [34]. ...
Substance use/abuse and suicide are two closely related phenomena, mostly due to neuro-biological, psychological, and social impairments. In the present narrative review, the relationship between suicidal behavior (SB) and the use and abuse of common recreational drugs, such as alcohol, cannabis, cocaine, methamphetamine, heroin, nicotine, ketamine, psilocybin, MDMA, and LSD, has been explored. Furthermore, potential mechanisms linking the two have also been examined. According to current research, all substances appear to have a deleterious effect on SB except for ketamine and psilocybin, which could potentially confer a protective effect. Further studies are needed to understand the relationship between MDMA, LSD, and suicide.
... The mechanism by which alcohol activates mesolimbic DA transmission has been the subject of intense research for decades, as this pathway is critical in mediating the reinforcing effects of alcohol, as well as other drugs of abuse (28,29). Even in humans, positron emission tomography studies have shown that alcohol induces a release of DA in the ventral striatum (30), and that this fast release of DA is associated with alcohol-induced reinforcing effects and acquisition of conditioned responses (31). In this regard, the metabolic conversion of alcohol into acetaldehyde has been recognized as critically involved (32,33), and this suggestion was further extended by the observation that another molecule, 1-methyl-6,7dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), obtainable by Pictet-Spengler condensation of acetaldehyde and DA, could be responsible for the reinforcing properties of alcohol and for its addictive potential (34,35). ...
The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.
... Animal models have shown that both ethanol intake and anticipation prompt dopamine release in the NAc, impacting the mesocorticolimbic system associated with craving, reward, and behavioral control [111]. The NAc is a crucial region in AUD models [112]. Neuroimaging studies consistently demonstrate that exposure to alcohol cues increases activation in the NAc and striatum, which is correlated with subjective alcohol craving [113]. ...
Alcohol use disorder (AUD) is a significant contributor to morbidity and mortality in the United States. It contributes to over 140,000 annual deaths, to over 200 related diseases and health conditions globally, and accounts for 5.1% of the global disease burden. Despite its substantial impact, AUD remains undertreated, marked by a scarcity of approved medications. This paper explores the current treatment landscape and novel strategies for both alcohol withdrawal syndrome and AUD. Promising results, including the use of psychedelics alongside psychotherapy, noninvasive neural-circuit-based interventions, phosphodiesterase-4 inhibitors, and GLP-1 receptor agonists, have emerged from recent studies. While these advancements show potential, further research is crucial for a comprehensive understanding of their effectiveness. The clear shortage of approved medications and other treatment modalities underscores the pressing need for ongoing research.
... For example,Holton and Berridge (2013), Robinson (2011, 2016),Schroeder (2004),Volkow (2007). 2 For example,Levy (2006), Holton (2009), Heather (2017,Yaffe (2013),West (2006),Ainslie (2001),Wallace (1999). ...
Research in the philosophy of addiction commonly explores how agency is impacted in addiction by focusing on moments of apparent loss of control over addictive behavior and seeking to explain how such moments result from the effects of psychoactive substance use on cognition and volition. Recently, Glackin et al. (2021) have suggested that agency in addiction can be helpfully analyzed using the concept of affordances. They argue that addicted agents experience addiction-related affordances, such as action possibilities relating to drugs, drug paraphernalia, and drug-related activities, as aberrantly salient motivations for action. Building on this approach, we present a novel two-tiered affordance model of addiction. In doing so, we suggest that what is significant about the addicted person's world is not simply what affordances are experienced as salient, but also the way in which the addicted person's world is shaped by a dominant concern. It is not only that addiction-related affordances become more prominent as addiction progresses but that one's plurality of concerns become monopolized by and funneled through addiction. Our model endorses Glackin et al.'s idea that addiction-related affordances become aberrantly salient, while proposing why they become and remain so. This way of viewing agency in addiction also brings to light important implications for recovery and treatment. For, if an addicted person adopts a new, even "socially approved", dominant concern, there is a risk that the shape of addiction is preserved, even though the content changes, leaving an individual at the risk of addiction substitution or relapse.
... After chronic use of the drug, dopamine response toward other non-drug stimuli is reduced, reducing the motivation for different types of healthier rewarding behaviors (social interaction, etc.). 168 Addiction could thus be seen as a limbic trap because of multiple effects on self-control, including acute impacts of the drug, reduced reward of other behaviors, and, with substances like alcohol; damage to the frontal lobes that decreases the ability to self-control. ...
... Dopamine (DA) has a catechol ring. Dopaminergic neural system dysfunction is associated with various CNS disorders, such as paranoia, schizophrenia, autism, and Parkinson's disease [1,2]. In the evaluation of the effectiveness of drugs designed to treat and control DA-related disorders, determining changes in the baseline level of DA in the brain is significant. ...
... Chronic opioid use is associated with a decrease in binding of the Dopamine Transporter (DAT) [75] and D-2 receptor binding measured with PET and the radiolig and [C-11] raclopride [40, 69,76]. This may reflect a decrease in endogenous dopamine release following chronic overstimulation with opioids and/or decreased transporter and/or receptor binding [40]. ...
... Latterly, we consume large doses of DA abnormally through various platforms such as Internet addiction, consumption of nicotine, 3 alcohol, 4 drugs, and junk food. 1 All these stimulants and additives significantly enhance the level of DA in our body and could lead to numerous diseases and disorders. 5 Recently, electrochemical techniques have received great attention 6 for sensing DA because of their simple operational modes, fast response, with high accessibility, and low cost-effectivity. However, the problem arises during the measurement of DA in our brain cells and bodily fluids because DA often coexists with ascorbic acid (AA) and uric acid (UA). ...
... Addiction and dopamine (DA) intertwine at a synaptic level, as the dopaminergic pathways are heavily implicated with substance abuse [1][2][3]. Key neurotransmitters modulate these pathways, regulating both behavioral and perceptual actions. While many neurochemicals play regulatory roles in addiction mechanisms, DA is unique in its function [4,5]. ...
Dopamine (DA)’s relationship with addiction is complex, and the related pathways in the mesocorticolimbic system are used to deliver DA, regulating both behavioral and perceptual actions. Specifically, the mesolimbic pathway connecting the ventral tegmental area (VTA) and the nucleus accumbens (NAc) is crucial in regulating memory, emotion, motivation, and behavior due to its responsibility to modulate dopamine. To better investigate the relationship between DA and addiction, more advanced mapping methods are necessary to monitor its production and propagation accurately and efficiently. In this study, we incorporate dLight1.2 adeno-associated virus (AAV) into our latest CMOS (complementary metal-oxide semiconductor) imaging platform to investigate the effects of two pharmacological substances, morphine and cocaine, in the NAc using adult mice. By implanting our self-fabricated CMOS imaging device into the deep brain, fluorescence imaging of the NAc using the dLight1.2 AAV allows for the visualization of DA molecules delivered from the VTA in real time. Our results suggest that changes in extracellular DA can be observed with this adapted system, showing potential for new applications and methods for approaching addiction studies. Additionally, we can identify the unique characteristic trend of DA release for both morphine and cocaine, further validating the underlying biochemical mechanisms used to modulate dopaminergic activation.
... Thr75-DARPP-32 phosphorylation has been proposed to be a marker of chronic drug exposure (Bibb et al., 2001). The altered dopaminergic state postulated to occur following drug exposure (Volkow et al., 2007(Volkow et al., , 2009) and activation of the D1-D2 heteromer signaling pathway leads to accumulation of pThr75-DARPP32 (Hasbi et al., 2018), which may contribute to observed THC-induced negative effects, as it has been linked to depressive-like behaviour (Brito et al., 2019;Yger and Girault, 2011). DARPP32 phosphorylation at Thr75 is mediated by protein kinase Cdk5 (Bibb et al., 2001) and inhibition of Cdk5 has been shown to directly block the aversive effects of D1-D2 activation (Hasbi et al., 2018). ...
Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects.
... Nicotine is a potent agonist at the eponymous nicotinic acetylcholine receptors (nAChR) [69]. In the brain, these receptors excite neurons and elicit the release of multiple neurotransmitters; importantly here, this includes the release of dopamine which mediates the mild sense of pleasure experienced by smokers by activating the mesocorticolimbic reward pathway [70] (Figure 4). This reward pathway is a critical neuronal underpinning of drug addiction, and its relationship with nicotine has been studied intensely for decades (reviewed in [71]). ...
The endocannabinoid system is found throughout the CNS and the body where it impacts many important physiological processes. Expectations were high that targeting cannabinoid receptors would prove therapeutically beneficial; pharmaceutical companies quickly seized on the appetitive and metabolic effects of cannabinoids to develop a drug for the treatment of weight loss. Alas, the experience with first-in-class cannabinoid type-1 receptor (CB1R) antagonist rimonabant is a now-classic cautionary tale of the perils of drug development and the outcome of rimonabant’s fall from grace dealt a blow to those pursuing therapies involving CB1R antagonists. And this most commercially compelling application of rimonabant has now been partially eclipsed by drugs with different mechanisms of action and greater effect. Still, blocking CB1 receptors causes intriguing metabolic effects, some of which appear to occur outside the CNS. Moreover, recent years have seen a startling change in the legal status of cannabis, accompanied by a popular embrace of ‘all things cannabis’. These changes combined with new pharmacological strategies and diligent medicinal chemistry may yet see the field to some measure of fulfillment of its early promise. Here, we review the story of rimonabant and some of the therapeutic niches and strategies that still hold promise after the fall.
... Cocaine blocks the action of the transporter, preventing the DA absorption in the CNS and thus allowing its accumulation at the synapse. Initially, the pharmacological effect it exerted was DAT blockade, followed by an increase in DA concentration and dopamine receptors activation [31,32]. Through a synaptic mechanism, the drug directly amplifies the mesolimbic dopaminergic signal at the DA receptor, increasing synaptic dopaminergic concentrations and thus mediating certain behavioral effects [33]. ...
... These functions are supported by complex and dynamic interactions with a wide range of cortical and subcortical structures (8,9,10,11) . Dysregulation between the St and other regions might contribute to clinical or psychiatric disorders, including substance abuse, pathological gambling, schizophrenia, Parkinson's disease and depression (12,13,14,15,16,17,18) . ...
The description refers to what caudate nucleus is a huge, subcortical grey mass in the forebrain known for its role in motor function and involved in a number of clinical syndromes. During ontogenesis, the caudate nucleus follows the curvature of the telencephalic vesicle, hence its curved shape. Its rostral portion referred to as the head, is far more voluminous than the body.
Aims: This study was built to describe the different types and characteristics of neurons in the caudate nucleus of the brain of camel and human and compare these neurons with their counterparts in other species.
Method: 4mm thick blocks containing caudate nucleus was cut, dry and processed according to the rapid Golgi and or the Golgi-Kopsch methods. Well impregnated neurons studied under light microscope.
Results: According to the presence, density and distribution of the spines we classify neurons in this study to three main types in the caudate nucleus of camel and human. According to the somal size each group includes one or more of the following cell size: large, medium and small. Rich-spiny neurons (Type I): include medium and small subtypes. Hairy-like, mushroom-like and stubby spines were present in the secondary dendrite and their branching. Sparsely-spiny neurons (Type II): they have relatively larger cell bodies and thicker primary dendrites than (Type I).Characterized by their very low density of spines and poorer branching of their dendrites. Aspiny-neurons (Type III): are large, medium and small size. May have varicose, appendages with various types and short axon which gives collaterals mostly within the dendritic domain.
Conclusion: The neuronal structure of the caudate nucleus in the camel is differ from that of the human. The human neurons appear slightly larger than those of the camel and they have more dendritic trunks that break up more often than the neurons of the camel. Although the types of spines are similar in both species, the density of spines appears to be greater in the camel than in the human. The more complex structure of the caudate in the human may result from the fact that this species belongs to a phylogenetically younger order (Anthropoidea) than the camel (Artiodactyla). Which support the fact that the number and diversity of the types of neurons go to increase throughout phylogenesis.
... This system is a primary target of drug abuse to change synaptic plasticity in an addicted brain, which suffers from cognitive impairment. In light of this cognitive functionality in the corticolimbic system, modern imaging has outlined evident brain networks involved in memory loss due to drug abuse (Volkow et al., 2004). Classical neurotransmitter systems, including dopamine, glutamate, Ach, and GABA, are critically involved in mesocorticolimbic memory establishment. ...
Drug abuse changes neurophysiological functions at multiple cellular and molecular levels in the addicted brain. Well-supported scientific evidence suggests that drugs negatively affect memory formation, decision-making and inhibition, and emotional and cognitive behaviors. The mesocorticolimbic brain regions are involved in reward-related learning and habitual drug-seeking/taking behaviors to develop physiological and psychological dependence on the drugs. This review highlights the importance of specific drug-induced chemical imbalances resulting in memory impairment through various neurotransmitter receptor-mediated signaling pathways. The mesocorticolimbic modifications in the expression levels of brain-derived neurotrophic factor (BDNF) and the cAMP-response element binding protein (CREB) impair reward-related memory formation following drug abuse. The contributions of protein kinases and microRNAs (miRNAs), along with the transcriptional and epigenetic regulation have also been considered in memory impairment underlying drug addiction. Overall, we integrate the research on various types of drug-induced memory impairment in distinguished brain regions and provide a comprehensive review with clinical implications addressing the upcoming studies.
... There is an extensive literature documenting lower measures of D2/ D3R availability using PET in human subjects (e.g. [19,[40][41][42]) and in animal models (e.g. [11]). ...
Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.
At cellular and circuit levels, drug addiction is considered a dysregulation of synaptic plasticity. In addition, dysfunction of the glutamate transporter 1 (GLT‐1) in the nucleus accumbens (NAc) has also been proposed as a mechanism underlying drug addiction. However, the cellular and synaptic impact of GLT‐1 alterations in the NAc remain unclear. Here we show in the NAc that 10 days withdraw after 5 days treatment with cocaine or amphetamine decreases GLT‐1 expression in astrocytes, which results in the prolongation of the excitatory postsynaptic potential (EPSP) decay kinetics in D1 receptor‐containing medium spiny neurons (D1R‐MSNs). Using the spike timing dependent plasticity (STDP) paradigm, we found that enlargement of EPSP duration results in switching the LTP elicited in control animals to LTD in psychostimulant‐treated mice. In contrast to D1‐MSNs, D2‐MSNs did not display changes in EPSP kinetics and synaptic plasticity. Notably, the psychostimulant‐induced synaptic transmission and synaptic plasticity effects were absent in IP3R2 −/− mice, which lack astrocyte calcium signal, but were mimicked by the selective astrocytes stimulation with DREADDs. Finally, ceftriaxone, which upregulates GLT‐1, restored normal GLT‐1 function, EPSP kinetics, and synaptic plasticity in psychostimulant‐treated mice. Therefore, we propose that cocaine and amphetamine increase dopaminergic levels in the NAc, which stimulates astrocytes and downregulates the GLT‐1. The decreased GLT‐1 function prolonged the EPSP kinetics, leading to the modulation of the STDP, transforming the LTP observed in control animals into LTD in psychostimulant‐treated mice. Present work reveals a novel mechanism underlying the synaptic plasticity changes induced by these drugs of abuse.
Plasma levels of sublingual buprenorphine utilized in the therapy of opioid use disorder, has been demonstrated to undergo gestation-associated decline in vivo, to an extent influenced by upheavals physiologically across gestational trimesters. However, based on extant literature, a dearth of knowledge exists in the optimization of buprenorphine therapeutic modalities, pharmacokinetic interactions and posological scrutiny, necessary for successful regimen adherence. A physiologically-based pharmacokinetic modelling methodology in a virtual clinical trial premise was utilized to investigate gestational upheavals in peak plasma buprenorphine concentrations, followed by a pharmacokinetic drug-drug interaction investigation and dose optimization strategy, to maintain buprenorphine levels above proposed thresholds of 1ng/ml and below 22.2ng/ml adjudicated as a fatality limit. A fold decline (> 1.3fold) in buprenorphine mean peak plasma concentration (92% - 74%) was evident for the model predicted buprenorphine metrics across selected gestational weeks to term in line with the model predicted increases in physiological upheavals occurring across gestation which may influence the changes. The rifampicin mediated drug-drug interaction on buprenorphine levels initially resulted in fold decreases (>1.5 fold) over a twenty-four hour duration, in concert with escalating physiological metrics across gestational trimesters. The interaction perpetrated with Clarithromycin dosing resulted in fold increases (> 2-fold) in the plasma concentration as well as an increase in other metrics associated with buprenorphine kinetics. The dose optimization approach maintained majority of subjects (>90%) with the extensive metabolizer (EM) phenotype above 1ng/ml and below 22.2ng/ml in the 8mg – 24mg dose ranges albeit with 1% and 3% in the 28mg and 32mg doses above the fatality limit respectively. This study demonstrates the utility of physiologically based pharmacokinetic methods to predict the time course of administered buprenorphine in plasma during gestation which could aid clinician decisions in a translational manner, in order to optimize therapeutic modalities in the therapy of opioid use disorder.
Adult attention-deficit/hyperactivity disorder (ADHD) is a common precursor and comorbidity in those seeking treatment for substance use disorders (SUDs). Up to one in four patients with SUD may have comorbid ADHD. ADHD and SUD have common neurobiological features. Both ADHD and SUD have a chronic course, with severe functional impairments in educational, employment, interpersonal, and quality-of-life outcomes. Untreated childhood ADHD may lead to younger patient presentation with comorbid SUD+ADHD. The presence of ADHD increases the duration, severity, chronicity, and complexity of SUDs.
Because treatment of comorbid ADHD can improve the ultimate outcomes for patients with SUD+ADHD, prompt screening and diagnosis of ADHD is important. Therefore, it is now recommended that SUD treatment programs: (1) include routine screening for ADHD in every initial SUD evaluation; and (2) perform a full diagnostic evaluation of ADHD, for those screening positive for ADHD.
SUD treatment programs can increase their effectiveness by enhancing traditional care with 1) pharmacological treatment for ADHD, added to the SUD treatments already in use; and 2) cognitive-behavioral psychotherapy (CBT) specifically adapted to include ADHD-specific skills training (“integrated CBT”). Treatment for both conditions in those with SUD+ADHD is strongly recommended, with ADHD treatment starting as soon as the patient’s SUD is stabilized. Many excellent ADHD treatment options have demonstrated benefit to patients with SUD+ADHD. Abuse-resistant, extended-release stimulant medications demonstrate the best outcomes, and nonstimulant options have also shown success. Prescribers can do much to prevent stimulant medication misuse and diversion, while still offering first-line pharmacological treatment for ADHD. Recognition and treatment of comorbid SUD+ADHD ultimately improves SUD treatment retention and outcomes.
The nucleus accumbens (NAc), a central component of the brain’s reward circuitry, has been implicated in a wide range of behaviors and emotional states. Emerging evidence, primarily drawing from recent rodent studies, suggests that the function of the NAc in reward and aversion processing is multifaceted. Prolonged stress or drug use induces maladaptive neuronal function in the NAc circuitry, which results in pathological conditions. This review aims to provide comprehensive and up-to-date insights on the role of the NAc in motivated behavior regulation and highlights areas that demand further in-depth analysis. It synthesizes the latest findings on how distinct NAc neuronal populations and pathways contribute to the processing of opposite valences. The review examines how a range of neuromodulators, especially monoamines, influence the NAc’s control over various motivational states. Furthermore, it delves into the complex underlying mechanisms of psychiatric disorders such as addiction and depression and evaluates prospective interventions to restore NAc functionality.
Caudate nucleus (CN) neurons in camels and humans were examined using modified Golgi impregnation methods. Neurons were classified based on soma morphology, dendritic characteristics, and spine distribution. Three primary neuron types were identified in both species: rich‐spiny (Type I), sparsely‐spiny (Type II), and aspiny (Type III), each comprising subtypes with specific features. Comparative analysis revealed significant differences in soma size, dendritic morphology, and spine distribution between camels and humans. The study contributes to our understanding of structural diversity in CN neurons and provides insights into evolutionary neural adaptations.
Sparse principal component analysis (SPCA) is designed to enhance the interpretability of traditional principal component analysis by optimally selecting a subset of features that comprise the first principal component. Given the NP-hard nature of SPCA, most current approaches resort to approximate solutions, typically achieved through tractable semidefinite programs or heuristic methods. To solve SPCA to optimality, we propose two exact mixed-integer semidefinite programs (MISDPs) and an arbitrarily equivalent mixed-integer linear program. The MISDPs allow us to design an effective branch-and-cut algorithm with closed-form cuts that do not need to solve dual problems. For the proposed mixed-integer formulations, we further derive the theoretical optimality gaps of their continuous relaxations. Besides, we apply the greedy and local search algorithms to solving SPCA and derive their first-known approximation ratios. Our numerical experiments reveal that the exact methods we developed can efficiently find optimal solutions for data sets containing hundreds of features. Furthermore, our approximation algorithms demonstrate both scalability and near-optimal performance when benchmarked on larger data sets, specifically those with thousands of features.
History: Accepted by Andrea Lodi, Area Editor for Design & Analysis of Algorithms—Discrete.
Funding: This research was supported in part by the Division of Civil, Mechanical and Manufacturing Innovation [Grant 224614], the Division of Computing and Communication Foundations [Grant 2246417], and the Office of Naval Research [Grant N00014-24-1-2066].
Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0372 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0372 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
Background:
Psychostimulant use and engagement with probabilistic schedules of reward both sensitize the mesocorticolimbic dopamine system. Such behaviours may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation.
Methods:
To probe these interactions, we sensitized ventral tegmental area (VTA) dopamine neurons via chronic chemogenetic stimulation while rats (n = 134) learned the rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine, and potentiated phasic excitability of VTA dopamine neurons through in vivo electrophysiological recordings.
Results:
In the absence of cues, sensitization promoted risk-taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males, while attenuating cue-induced risk-taking in females.
Conclusions:
While these results provide further confirmation that VTA dopamine neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact which dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision-making on the cued rGT increased as both males and females learned to self-administer cocaine. The combination of dopamine sensitization and win-paired cues while gambling lead to significantly greater cocaine-taking, but these rats did not show any increase in risky choice as a result. Cocaine and heavily-cued gambles may therefore partially substitute for each other once the dopamine system is rendered labile through sensitization, compounding addiction risk across modalities.
Objective:
The objectives of this report were to characterize the regional and state differences in prescription methamphetamine and amphetamine distribution in the US.
Methods:
Prescription methamphetamine and amphetamine distribution was obtained from the Drug Enforcement Administration for 2019.
Results:
Total per capita drug weight distribution of amphetamine was 4,000 times higher than methamphetamine. Regionally, total per capita drug weight for methamphetamine was highest in the West (32.2% of total distribution) and lowest in the Northeast (17.4%). The total per capita drug weight for amphetamine was highest in the South (37.0% of total distribution) and lowest in the Northeast (19.4%). Distribution of methamphetamine was 16.1% while amphetamine was 54.0% of its production quota.
Conclusion:
Overall, prescription amphetamine distribution was common while prescription methamphetamine distribution was rare. The patterns observed in distribution are likely the result of stigmatization, differences in accessibility, and the efforts of initiatives such as the Montana Meth Project.
Psychostimulant use and engagement with probabilistic schedules of reward both sensitize the mesocorticolimbic dopamine system. Such behaviours may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. To probe these interactions, we sensitized ventral tegmental area (VTA) dopamine neurons via chronic chemogenetic stimulation while rats learned the rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort, we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine, and potentiated phasic excitability of VTA dopamine neurons through in vivo electrophysiological recordings. In the absence of cues, sensitization promoted risk-taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males, while attenuating cue-induced risk-taking in females. While these results provide further confirmation that VTA dopamine neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact which dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision-making on the cued rGT increased as both males and females learned to self-administer cocaine. The combination of dopamine sensitization and win-paired cues while gambling lead to significantly greater cocaine-taking, but these rats did not show any increase in risky choice as a result. Cocaine and heavily-cued gambles may therefore partially substitute for each other once the dopamine system is rendered labile through sensitization, compounding addiction risk across modalities.
The neurochemistry of catecholamines plays a crucial and complex role in human memory, behavior, and cognition, while affecting other organs such as the lungs, heart, liver, and skin. Dopamine, norepinephrine, and epinephrine are three closely-related catecholamines that have been widely studied over the last seven decades for development of medications for life-threatening diseases. Other studies have also suggested a link between drug abuse and catecholamine levels. The determination of catecholamine levels in different parts of the human body has also been a hot topic for research in these years. HPLC, spectrophotometry, fluorescence, electrochemistry and other techniques have been used to quantify catecholamines in mostly in biological samples like serum and urine, although in vivo studies are also possible. This article attempts to present the research on catecholamines from the perspectives of their bodily functions, development of medications for diseases related to these, and the techniques used for their detection and quantification.
The purposes of this study were to investigate the pharmacokinetics of methylphenidate hydrochloride (Ritalin) in the human brain, to compare them with those of cocaine, and to evaluate whether cocaine and methylphenidate compete for the same binding sites.
We used positron emission tomography to measure the temporal and spatial distribution of carbon 11 (11C)-labeled methylphenidate. These results were compared with those obtained previously for [11C]cocaine. Eight healthy male subjects, 20 to 51 years of age, were scanned with [11C]methylphenidate. Three were tested twice to assess test-retest variability, four were tested at baseline and after administration of methylphenidate, and one was tested with [11C]methylphenidate and [11C]cocaine. Two baboons were scanned to evaluate whether there was competition between cocaine and methylphenidate for the same binding sites in the brain.
The uptake of [11C]methylphenidate in the brain was high (mean +/- SD, 7.5% +/- 1.5%), and the maximal concentration occurred in striatum. Pretreatment with methylphenidate decreased binding only in striatum (40%). Although the regional distribution of [11C]methylphenidate, was identical to that of [11C]cocaine and they competed with each other for the same binding sites, these two drugs differed markedly in their pharmacokinetics. Clearance of [11C]methylphenidate from striatum (90 minutes) was significantly slower than that of [11C]cocaine (20 minutes). For both drugs, their fast uptake in striatum paralleled the experience of the "high." For methylphenidate, the high decreased very rapidly despite significant binding of the drug in the brain. In contrast, for cocaine, the decline in the high paralleled its fast rate of clearance from the brain.
We speculate that because the experience of the high is associated with the fast uptake of cocaine and methylphenidate in the brain, the slow clearance of methylphenidate from the brain may serve as a limiting factor in promoting its frequent self-administration.
Cocaine blocks the reuptake of dopamine, a neurotransmitter involved in the control of movement, cognition, motivation and reward. This leads to an increase in extracellular dopamine; the reinforcing effect of cocaine is associated with elevated dopamine levels in the nucleus accumbens. But addiction to cocaine involves other effects, such as craving, loss of control and compulsive drug intake; the role of the dopamine system in these effects is less well-understood. We therefore used positron emission tomography (PET) to compare the responses of cocaine addicts and normal controls to intravenous methylphenidate, a drug that, like cocaine, causes an increase in synaptic dopamine. Addicts showed reduced dopamine release in the striatum, the brain region where the nucleus accumbens is located, and also had a reduced 'high' relative to controls. In contrast, addicts showed an increased response to methylphenidate in the thalamus (a region that conveys sensory input to the cortex). This thalamic response was associated with cocaine craving and was not seen in control subjects. Thus, our findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria. Moreover, they suggest a participation of thalamic dopamine pathways in cocaine addiction, a possibility that merits further investigation.
The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.
Alcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.
To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.
Randomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.
Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.
Percent days abstinent from alcohol and time to first heavy drinking day.
All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone x behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.
Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.
clinicaltrials.gov Identifier: NCT00006206.
The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and [11C]raclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of [11C]raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [11C]raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.
The majority of cigarette smokers who achieve abstinence relapse within the first year and require many attempts before achieving permanent abstinence. Evidence to support pharmacological treatment for relapse prevention is insufficient.
To determine whether smokers who quit after 12 weeks of treatment with varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, maintain greater continuous abstinence rates (defined as not a single "puff" of a cigarette) than placebo controls during an additional 12 weeks of treatment and until 52 weeks after treatment initiation.
Randomized controlled trial conducted at multiple medical clinics in 7 countries with follow-up to 52 weeks after study baseline. Of 1927 cigarette smokers recruited between April 2003 and February 2004 and treated for 12 weeks with open-label varenicline titrated to 1 mg twice per day, 1236 (64.1%) did not smoke, use tobacco, or use nicotine replacement therapy during the last week of treatment and 62.8% (n = 1210) were randomized to additional treatment or placebo.
Participants were randomly assigned to receive either double-blind varenicline, 1 mg twice per day (n = 603), or placebo (n = 607) for an additional 12 weeks.
Carbon monoxide-confirmed continued abstinence during weeks 13 to 24 and weeks 13 to 52 of the study.
The carbon monoxide-confirmed continuous abstinence rate was significantly higher for the varenicline group than for the placebo group for weeks 13 to 24 (70.5% vs 49.6%; odds ratio [OR], 2.48; 95% confidence interval [CI], 1.95-3.16; P<.001) as well as for weeks 13 to 52 (43.6% vs 36.9%; OR, 1.34; 95% CI, 1.06-1.69; P = .02). Adverse events reported in the open-label period were mostly mild; no difference in adverse events between varenicline and placebo was observed during the double-blind period.
Smokers who achieved abstinence for at least 7 days at the end of 12 weeks of open-label varenicline treatment and were randomized to receive an additional 12 weeks of varenicline treatment showed significantly greater continuous abstinence in weeks 13 to 24 compared with placebo. This advantage was maintained through the nontreatment follow-up to week 52. Varenicline may be an efficacious, safe, and well-tolerated agent for maintaining abstinence from smoking.
clinicaltrials.gov Identifier: NCT00143286.
This double-blinded, placebo-controlled trial evaluated the efficacy of naltrexone as an adjunct to standard smoking cessation treatment. Participants (N = 110) were adult male and female nicotine-dependent smokers who expressed interest in quitting smoking. All subjects received six sessions of behavioral counseling (1 hr/session for 6 weeks), and 1 month of the nicotine patch (21 mg for the first 2 weeks, 14 mg the third week, 7 mg the fourth week). Subjects were randomly assigned to the naltrexone or placebo group. The naltrexone group started at 25 mg daily for 3 days prior to the quit date, and increased to 50 mg/day on the quit date and following 8 weeks. At the end of medication treatment, the naltrexone group had better quit rates versus the placebo group (48% quit on naltrexone vs. 41% on placebo), but this difference was not statistically significant. However, men and women differed on several measures: in the placebo group, women had significantly lower quit rates than men (39% vs. 67%, p<.05), but in the naltrexone group, women had quit rates comparable with those of men (58% vs. 62%, p = ns). Further examination revealed that naltrexone significantly reduced men's and women's cessation-related weight gain and selectively reduced women's urge to smoke to relieve negative affect and withdrawal. The results suggest continued examination of naltrexone as an adjunct in smoking cessation, particularly in female smokers, who have historically shown worse outcomes with traditional treatment methods.
Rhesus monkeys were trained on a fixed-interval 9-min limited-hold 3-min schedule of intravenous cocaine reinforcement. A 15-min timeout followed each reinforcement or limited-hold expiration. An identical schedule of food reinforcement was interspersed in the session to assess rate-modifying effects of the drug infusions not specific to drug reinforcement. In one experiment, response rate for cocaine reinforcement was shown to be a positive function of reinforcement magnitude for a dose range from 0 to 800 ug/kg/inj. At these doses, there was little effect on food reinforced responding except at the highest dose, where responding decreased. Results of the second experiment indicated that increasing the duration of the cocaine infusion produced a change in response rate similar to decreasing unit dose. The response rate change for a given increase in infustion duration was less at a unit dose of 400 ug/kg than at 200 ug/kg.
About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that acamprosate may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence.
In this multicentre, double-blind, placebo-controlled study, we recruited 455 patients, aged 18-65 years, with chronic or episodic alcohol dependence. Patients were randomly allocated treatment with acamprosate (1998 mg daily for bodyweight > 60 kg; 1332 mg daily for < or = kg) or placebo for 360 days. Patients were assessed on the day treatment started and on days 30, 90, 180, 270, and 360 by interview, self-report, questionnaire, and laboratory screening. Patients were classified as abstinent, relapsing, or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure.
Seven patients were excluded from the intention-to-treat analysis because they did not attend on the first treatment day and therefore received no medication. The acamprosate (n = 224) and placebo (n = 224) groups were well matched in terms of baseline demographic and alcohol-related variables. 94 acamprosate-treated and 85 placebo-treated patients completed the treatment phase: of those withdrawn, 104 (52 in each group) relapsed, 69 (33 vs 36, respectively) were lost to follow-up, 63 (31 vs 32) refused to continue treatment, 16 (15 vs 11) had concurrent illness, three (two vs one) died, ten (six vs four) had adverse side-effects, one (acamprosate treated) received the wrong medication, and three (placebo treated) were non-compliant. The proportion without treatment failure was higher in the acamprosate than in the placebo group throughout the treatment period (p < 0.001, Mantel-Cox). At the end of treatment, 41 (18.3%) acamprosate-treated and 16 (7.1%) placebo-treated patients had been continuously abstinent (p = 0.007). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (138.8 [SD 137.5] vs 103.8 [119.0] days; p = 0.012). 148 patients (79 acamprosate, 69 placebo) completed 27 months follow-up: 27 (11.9%) acamprosate-treated and 11 (4.9%) placebo-treated patients remained continuously abstinent, and the mean cumulative abstinence duration was 230.8 days (259.1) and 183.0 days (235.2), respectively. Apart from occasional diarrhoea, there was no difference in side-effects between groups.
Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of alcohol-dependent patients.
Understanding the changes in the brain which occur in the transition from normal to addictive behavior has major implications in public health. Here we postulate that while reward circuits (nucleus accumbens, amygdala), which have been central to theories of drug addiction, may be crucial to initiate drug self-administration, the addictive state also involves disruption of circuits involved with compulsive behaviors and with drive. We postulate that intermittent dopaminergic activation of reward circuits secondary to drug self-administration leads to dysfunction of the orbitofrontal cortex via the striato-thalamo-orbitofrontal circuit. This is supported by imaging studies showing that in drug abusers studied during protracted withdrawal, the orbitofrontal cortex is hypoactive in proportion to the levels of dopamine D2 receptors in the striatum. In contrast, when drug abusers are tested shortly after last cocaine use or during drug-induced craving, the orbitofrontal cortex is hypermetabolic in proportion to the intensity of the craving. Because the orbitofrontal cortex is involved with drive and with compulsive repetitive behaviors, its abnormal activation in the addicted subject could explain why compulsive drug self-administration occurs even with tolerance to the pleasurable drug effects and in the presence of adverse reactions. This model implies that pleasure per se is not enough to maintain compulsive drug administration in the drugaddicted subject and that drugs that could interfere with the activation of the striato-thalamo-orbitofrontal circuit could be beneficial in the treatment of drug addiction.
Our understanding of alcohol craving, both as a cause for chronic abuse and relapse and as a target for intervention, has been refined significantly in recent years. For example, craving experienced during alcohol withdrawal may be mediated by gamma-aminobutyric acid (GABA) and glutamate receptor mechanisms, whereas the memory of the rewarding aspects of alcohol may be mediated by dopamine, opiate, and glutamate systems. Therefore, pharmacologic treatments for alcohol dependence may be targeted to numerous pathways. This article will discuss animal and clinical studies of the opioid antagonists (primarily naltrexone), acamprosate, and disulfiram. The side effects and treatment recommendations for each drug will also be reviewed.
Recent neurophysiological studies reveal that neurons in certain brain structures carry specific signals about past and future rewards. Dopamine neurons display a short-latency, phasic reward signal indicating the difference between actual and predicted rewards. The signal is useful for enhancing neuronal processing and learning behavioral reactions. It is distinctly different from dopamine's tonic enabling of numerous behavioral processes. Neurons in the striatum, frontal cortex, and amygdala also process reward information but provide more differentiated information for identifying and anticipating rewards and organizing goal-directed behavior. The different reward signals have complementary functions, and the optimal use of rewards in voluntary behavior would benefit from interactions between the signals. Addictive psychostimulant drugs may exert their action by amplifying the dopamine reward signal.
The natural incentives that shape behavior reach the central circuitry of motivation trans-synaptically, via the five senses, whereas the laboratory rewards of intracranial stimulation or drug injections activate reward circuitry directly, bypassing peripheral sensory pathways. The unsensed incentives of brain stimulation and intracranial drug injections thus give us tools to identify reward circuit elements within the associational portions of the CNS. Such studies have implicated the mesolimbic dopamine system and several of its afferents and efferents in motivational function. Comparisons of natural and laboratory incentives suggest hypotheses as to why some habits become compulsive and give insights into the roles of reinforcement and of prediction of reinforcement in habit formation.
Since dopaminergic mechanisms appear to be involved in nicotine dependence, we studied the safety and efficacy of the monoamine oxidase B inhibitor selegiline hydrochloride compared with placebo for smoking cessation in nicotine-dependent cigarette smokers.
Forty subjects with DSM-IV nicotine dependence were randomized to: 1) selegiline hydrochloride (5 mg p.o. twice daily) or 2) placebo in an 8-week trial. Outcome measures included smoking cessation rates, treatment retention, and medication side effects.
Selegiline hydrochloride increased trial end point (week 8) 7-day point prevalence smoking cessation rates (selegiline hydrochloride, 9/20 [45.0%]; placebo, 3/20 [15.0%], odds ratio = 4.64, 95% CI, 1.02-21.00, p <.05), and smoking cessation rates during the last 4 weeks of the trial (selegiline hydrochloride, 6/20 [30.0%]; placebo, 1/20 [5.0%], odds ratio = 8.14, 95% CI, 0.88-75.48, p =.07) in comparison with placebo. Six-month follow-up 7-day point prevalence smoking cessation rates were reduced compared with trial end point (selegiline hydrochloride, 4/20 [20.0%]; placebo, 1/20 [5.0%], odds ratio = 4.75, 95% CI, 0.48-46.91, p =.18). Treatment retention was similar between drug and placebo groups (p =.13), and selegiline hydrochloride was well tolerated in cigarette smokers.
This preliminary study suggests that selegiline (10 mg/day) is safe for use and enhances smoking cessation rates compared with placebo in nicotine-dependent cigarette smokers.
Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function. We aimed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence.
We did a double-blind randomised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence. Of these 150 individuals, 75 were assigned to receive topiramate (escalating dose of 25-300 mg per day) and 75 had placebo as an adjunct to weekly standardised medication compliance management. Primary efficacy variables were: self-reported drinking (drinks per day, drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) and plasma gamma-glutamyl transferase, an objective index of alcohol consumption. The secondary efficacy variable was self-reported craving.
At study end, participants on topiramate, compared with those on placebo, had 2.88 (95% CI -4.50 to -1.27) fewer drinks per day (p=0.0006), 3.10 (-4.88 to -1.31) fewer drinks per drinking day (p=0.0009), 27.6% fewer heavy drinking days (p=0.0003), 26.2% more days abstinent (p=0.0003), and a log plasma gamma-glutamyl transferase ratio of 0.07 (-0.11 to -0.02) less (p=0.0046). Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them.
Topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence.
There are nearly 1.1 billion users of nicotine and tobacco products worldwide. Tobacco use through cigarette smoking is the leading preventable cause of death in the world and kills nearly four million people annually. However, although some cigarette smokers are able to quit, many are not, and standard medications to assist in smoking cessation (e.g. nicotine-replacement therapies and sustained-release bupropion) are ineffective in many remaining smokers. Recent developments in our understanding of the neurobiology of nicotine dependence have identified several neurotransmitter systems that might contribute to the process of smoking maintenance and relapse, including dopamine, noradrenaline, 5-hydroxytryptamine, acetylcholine, endogenous opioids, GABA, glutamate and endocannabinoids. Several existing medications are being tested as treatments for nicotine dependence and novel investigational agents are under development as effective treatments for nicotine dependence in the 'hard to treat' tobacco user.
This screening trial evaluated whether the GABAB agonist baclofen demonstrated sufficient clinical efficacy to recommend an adequately powered trial of the medication as a pharmacotherapy for cocaine dependence.
Participants with cocaine dependence verified by the Structured Clinical Interview for DSM-IV were randomly assigned to baclofen (N = 35; 20 mg t.i.d.) or placebo conditions (N = 35; identical in appearance and dosage rate) using a 2-group, experimental, 16-week double-blind design featuring thrice-weekly cognitive-behavioral drug counseling groups. Outcomes were retention, cocaine use, cocaine craving, and adverse events.
A generalized estimating equation (GEE) model showed that participants assigned to receive baclofen demonstrated statistically significant reductions in cocaine use over those assigned to receive placebo as indicated by urine drug screening results (chi(2) = 5.34, df = 1, p =.021). Confirming the GEE model, longitudinal analyses showed that participants assigned to receive baclofen demonstrated significant and stepwise increases in the probability of providing benzoylecgonine-free urine samples throughout the trial as the number of benzoylecgonine-positive samples increased during baseline (chi(2) = 10.63, df = 1, p =.001). Participants assigned to placebo demonstrated no such association. Univariate analyses of aggregates of urine drug screening showed generally favorable outcomes for baclofen, but not at statistically significant levels. There was no statistical significance observed for retention, cocaine craving, or incidence of reported adverse events by treatment condition.
Project findings demonstrated initial clinical efficacy of baclofen over placebo in reducing cocaine use when delivered concurrent with thrice-weekly drug abuse counseling sessions. The effects of baclofen were particularly apparent for those participants with chronic levels of cocaine use at baseline and provide support for a full-scale efficacy trial for baclofen, especially among this subgroup of patients.
Almost 3 million Americans have abused heroin. The most effective treatment for this concerning epidemic is opioid replacement therapy. Although, from a historical perspective, acceptance of this therapy has been slow, growing evidence supports its efficacy. There are 3 approved medications for opioid maintenance therapy: methadone hydrochloride, levomethadyl acetate, and buprenorphine hydrochloride. Each has unique characteristics that determine its suitability for an individual patient. Cardiac arrhythmias have been reported with methadone and levomethadyl, but not with buprenorphine. Due to concerns about cardiac risk, levomethadyl use has declined and the product may ultimately be discontinued. These recent safety concerns, specifics about opioid detoxification and maintenance, and new federal initiatives were studied. Opioid detoxification has a role in both preventing acute withdrawal and maintaining long-term abstinence. Although only a minority of eligible patients are engaged in treatment, opioid maintenance therapy appears to offer the greatest public health benefits. There is growing interest in expanding treatment into primary care, allowing opioid addiction to be managed like other chronic illnesses. This model has gained wide acceptance in Europe and is now being implemented in the United States. The recent Drug Addiction Treatment Act enables qualified physicians to treat opioid-dependent patients with buprenorphine in an office-based setting. Mainstreaming opioid addiction treatment has many advantages; its success will depend on resolution of ethical and delivery system issues as well as improved and expanded training of physicians in addiction medicine.
Both GABAergic and glutamatergic neurons appear to be important modulators of the brain reward system and medications that affect GABA and glutamatergic neurotransmission may reduce the rewarding properties of cocaine and reduce cocaine craving. Topiramate, an anticonvulsant, raises cerebral GABA levels, facilitates GABAergic neurotransmission and inhibits glutametergic activity at AMPA/kainite receptors. Thus, it may be useful for treating cocaine dependence.
The efficacy of topiramate for cocaine dependence was tested in a 13-week, double-blind, placebo-controlled pilot trial (n = 40). Topiramate was titrated gradually over 8 weeks to a dose of 200 mg daily. The primary outcome measure was cocaine abstinence verified by twice weekly urine benzoylecgonine tests (UBT).
Eighty-two percent of subjects completed the trial. Analysis of the UBT using a GEE model showed that after week 8, when the dose titration was completed, topiramate-treated subjects were more likely to be abstinent from cocaine compared to placebo-treated subjects (Z = 2.67, P = 0.01). Topiramate-treated subjects were also more likely to attain 3 weeks of continuous abstinence from cocaine (chi2 = 3.9, d.f. = 1, P = 0.05).
Topiramate may be effective for the treatment of cocaine dependence.
This study examined the safety and efficacy of gamma vinyl-GABA (GVG, vigabatrin) for the treatment of methamphetamine and/or cocaine addiction. A total of 30 subjects, who met DSM-IV criteria for methamphetamine and/or cocaine dependence, were enrolled in an open label 9-week safety study. The protocol was specifically designed to include extensive visual field monitoring as well as outcome measures of therapeutic efficacy. Patients were screened twice weekly for the presence of urinary cocaine, methamphetamine, heroin, alcohol, and marijuana. In total, 18/30 subjects completed the study and 16/18 tested negative for methamphetamine and cocaine during the last 6 weeks of the trial. GVG did not produce any visual field defects or alterations in visual acuity. Furthermore, it did not produce changes in vital signs even with continued use of methamphetamine and cocaine. Thus, under conditions that appear to be appropriate for the successful treatment of methamphetamine and/or cocaine addiction, GVG is safe.
A decrease in dopamine type 2 receptors (D2) and mesolimbic dopamine transmission predisposes animals to consume alcohol. This study measured D2 receptors and dopamine transmission in human alcohol-dependent (AD) subjects using positron emission tomography (PET) and [11C]raclopride.
Fifteen AD and 15 healthy control (HC) subjects were scanned before and after a psychostimulant challenge (amphetamine .3 mg/kg intravenous). The outcome measures for baseline D2 receptor availability were binding potential (BP) and the equilibrium partition coefficient (V3''). Amphetamine-induced [11C]raclopride displacement was measured as the difference in V3'' between the two scans.
[11C]raclopride BP was significantly reduced by 16.6% in the limbic striatum, 19.2% in the associative striatum, and 21.3% in the sensorimotor striatum in AD subjects compared with HC. The alcohol-dependent subjects showed a blunting of amphetamine-induced dopamine release in the limbic striatum: [11C]raclopride displacement was -5.2% +/- 3.6% in AD subjects compared with -13.0% +/- 8.8% in HC. However, no significant difference in [11C]raclopride displacement was seen in the associative (-4.6% +/- 5.8% in AD subjects vs. -6.7 +/- 5.4% in HC) and sensorimotor (-12.3% +/- 7.3% in AD subjects vs. -13.7 +/- 7.5% in HC) subdivisions of the striatum between the two groups.
Alcohol dependence was associated with a decrease in D2 receptors in each striatal subdivision, whereas amphetamine-induced dopamine release was reduced in the limbic striatum only.
Antibody therapy (as either active or passive immunization) is designed primarily to prevent drugs of abuse from entering the central nervous system (CNS). Antidrug antibodies reduce rush, euphoria, and drug distribution to the brain at doses that exceed the apparent binding capacity of the antibody. This is accomplished through a pharmacokinetic antagonism, which reduces the amount of drug in the brain, the rate of clearance across the blood-brain barrier, and the volume of drug distribution. Because the antibodies remain primarily in the circulatory system, they have no apparent central nervous system side effects. Active immunization with drug-protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with 1 cocaine and 3 nicotine vaccines in Phase 2 human trials. Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine (PCP) in preclinical animal models. Antibodies have 2 immediate clinical applications in drug abuse treatment: to treat drug overdose and to reduce relapse to drug use in addicted patients. The specificity of the therapies, the lack of addiction liability, minimal side effects, and long-lasting protection against drug use offer major therapeutic benefit over conventional small molecule agonists and antagonists. Immunotherapies can also be combined with other antiaddiction medications and enhance behavioral therapies. Current immunotherapies already show efficacy, but improved antigen design and antibody engineering promise highly specific and rapidly developed treatments for both existing and future addictions.
Not the mere procurement and use of drugs, but the fact that patterns of seeking and taking become compulsive after prolonged drug use is a defining characteristic of drug addiction. Development of a therapy that targets the compulsive aspects of drug use and thus addresses addiction at its core would therefore be very desirable. In the present review, we will discuss animal studies that attempt to model loss of control over drug use. Furthermore, we will try to put these studies in a theoretical perspective, and discuss the hypothesized underlying neural and behavioral mechanisms.
Oral naltrexone can completely antagonize the effects produced by opioid agonists. However, poor compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence.
To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence.
Randomized, double-blind, placebo-controlled, 8-week trial conducted at 2 medical centers.
Sixty heroin-dependent adults.
Participants were stratified by sex and years of heroin use (> or = 5 vs < 5) and then were randomized to receive placebo or 192 or 384 mg of depot naltrexone. Doses were administered at the beginning of weeks 1 and 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit.
Retention in treatment and percentage of opioid-negative urine samples.
Retention in treatment was dose related, with 39%, 60%, and 68% of patients in the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively, remaining in treatment at the end of 2 months. Time to dropout had a significant main effect of dose, with mean time to dropout of 27, 36, and 48 days for the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively. The percentage of urine samples negative for opioids, methadone, cocaine, benzodiazepines, and amphetamine varied significantly as a function of dose. When the data were recalculated without the assumption that missing urine samples were positive, a main effect of group was not found for any drugs tested except cocaine, where the percentage of cocaine-negative urine samples was lower in the placebo group. Adverse events were minimal and generally mild. This formulation of naltrexone was well tolerated and produced a robust, dose-related increase in treatment retention.
These data provide new evidence of the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence.
Recent studies have shown that the endocannabinoid system is involved in the common neurobiological mechanism underlying drug addiction. This system participates in the primary rewarding effects of cannabinoids, nicotine, alcohol and opioids, through the release of endocannabinoids in the ventral tegmental area. Endocannabinoids are also involved in the motivation to seek drugs by a dopamine-independent mechanism, demonstrated for psychostimulants and opioids. The endocannabinoid system also participates in the common mechanisms underlying relapse to drug-seeking behaviour by mediating the motivational effects of drug-related environmental stimuli and drug re-exposure. In agreement, clinical trials have suggested that the CB(1) cannabinoid antagonist rimonabant can cause smoking cessation. Thus, CB(1) cannabinoid antagonists could represent a new generation of compounds to treat drug addiction.
Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Alcoholic subjects have low levels of dopamine D(2) receptors in striatum, and increasing D(2) receptor levels in laboratory animals reduces alcohol consumption.
To test whether high levels of D(2) receptors may be protective against alcoholism and whether this is mediated by their modulation of activity in orbitofrontal cortex and cingulate gyrus (regions involved in salience attribution, emotional reactivity, and inhibitory control).
Research (nonalcoholic subjects with a family history of alcoholism) and comparison (nonalcoholic subjects with a negative family history) sample.
Outpatient setting.
Fifteen nonalcoholic subjects who had an alcoholic father and at least 2 other first- or second-degree relatives who were alcoholics (family-positive group) and 16 nonalcoholic controls with no family history of alcoholism (family-negative group).
Results of positron emission tomography with raclopride C 11 to assess D(2) receptors and with fludeoxyglucose F 18 to assess brain glucose metabolism (marker of brain function). Personality measures were obtained with the Multidimensional Personality Questionnaire.
Availability of D(2) receptors was significantly higher in caudate and ventral striatum in family-positive than family-negative subjects. In family-positive but not family-negative subjects, striatal D(2) receptors were associated with metabolism in anterior cingulate (Brodmann area 24/25) and orbitofrontal (Brodmann area 11) and prefrontal (Brodmann area 9/10) cortices, and with personality scores of positive emotionality.
The higher-than-normal D(2) receptor availability in nonalcoholic members of alcoholic families supports the hypothesis that high levels of D(2) receptors may protect against alcoholism. The significant associations between D(2) receptors and metabolism in frontal regions involved with emotional reactivity and executive control suggest that high levels of D(2) receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions.
In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [(11)C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.
Recent preclinical studies implicate N-acetylcysteine (NAC), a cysteine prodrug, as a potential medication for preventing relapse to cocaine use; however, little is known about the safety and tolerability of NAC in cocaine-dependent subjects in an outpatient setting. This pilot study examines the safety and tolerability of 3 doses of NAC for the treatment of cocaine dependence. Twenty three treatment-seeking cocaine-dependent patients participated in a 4-week medication trial and received NAC at doses of 1200 mg/day, 2400 mg/day or 3600 mg/day. Results suggested that the three doses were well tolerated. Overall, the retention rates appeared to favor higher doses of NAC (2400 mg/day and 3600 mg/day). The majority of subjects who completed the study (n=16) either terminated use of cocaine completely or significantly reduced their use of cocaine during treatment. Overall the findings suggest that it is feasible to treat cocaine-dependent treatment seekers with N-acetylcysteine on an outpatient basis.
Effective medications for cocaine dependence are needed to improve outcome in this chronic, relapsing disorder. Medications affecting glutamate function are reasonable candidates for investigation, given the involvement of glutamate circuits in reward-related brain regions and evidence of cocaine-induced glutamatergic dysregulation. In addition, it is increasingly apparent that glutamatergic mechanisms underlie several clinical aspects of cocaine dependence, including euphoria, withdrawal, craving, and hedonic dysfunction. Even denial, traditionally viewed as purely psychological, may result, in part, from dysfunctional glutamate-rich cortical regions. We review the involvement of glutamate in reward-related circuits, the acute and chronic effects of cocaine on these pathways, and glutamatergic mechanisms that contribute to the neurobiology of cocaine dependence. We also present preliminary data from our research of modafinil, a glutamate-enhancing agent with promise in the treatment of cocaine-addicted individuals.