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Plasma corticosterone (CORT) levels. (A) Basal CORT (ng/ml). (B) ND-groups. (C) LgA-groups. Data are expressed as mean6SEM, **p,0.01; *p,0.05. doi:10.1371/journal.pone.0042092.g002
Source publication
Relapse, even following an extended period of withdrawal, is a major challenge in substance abuse management. Delayed neurobiological effects of the drug during prolonged withdrawal likely contribute to sustained vulnerability to relapse. Stress is a major trigger of relapse, and the hippocampus regulates the magnitude and duration of stress respon...
Contexts in source publication
Context 1
... was an increase in CORT on Day 1 of withdrawal (p,0.01, Figure 2A) relative to the other two withdrawal time-points. Further, there was a time- dependent decrease among LgA groups (F 2,17 = 5.896, p,0.05 vs. Day 1, Figure 2C), but no differences in CORT among control groups ( Figure 2B). ...
Context 2
... was an increase in CORT on Day 1 of withdrawal (p,0.01, Figure 2A) relative to the other two withdrawal time-points. Further, there was a time- dependent decrease among LgA groups (F 2,17 = 5.896, p,0.05 vs. Day 1, Figure 2C), but no differences in CORT among control groups ( Figure 2B). Taken together, these results suggest that the enhanced HPA response mediated by cocaine 24 h after the last SA session (Day 1) normalized with the course of withdrawal. ...
Context 3
... was an increase in CORT on Day 1 of withdrawal (p,0.01, Figure 2A) relative to the other two withdrawal time-points. Further, there was a time- dependent decrease among LgA groups (F 2,17 = 5.896, p,0.05 vs. Day 1, Figure 2C), but no differences in CORT among control groups ( Figure 2B). Taken together, these results suggest that the enhanced HPA response mediated by cocaine 24 h after the last SA session (Day 1) normalized with the course of withdrawal. ...
Similar publications
Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is likely mediated in part through the dense projections to the PVT from hypothalamic peptide transmitter systems such as orexin, and cocaine- and amphetamine-regulated transcript (CART), both of which play key roles...
Background:
5-HT1B receptor (5-HT1BR) agonists enhance cocaine intake during daily self-administration sessions, but decrease cocaine intake when tested after prolonged abstinence. We examined if 5-HT1BR agonists produce similar abstinence-dependent effects on methamphetamine intake.
Methods:
Male rats were trained to self-administer methampheta...
Citations
... In our study, we observed lower corticosterone concentration accompanied by an increase in POMC and β-endorphin levels in the plasma of the CB rats. The escalating-dose cocaine administration has been proved to lead to dysregulation of the HPA axis [57][58][59]. An increase in plasma corticosterone level was observed at the beginning of the chronic binge cocaine administration, while it was reduced on the 14th day of the applied regimen followed by a return to its basal level after 10 days of the withdrawal period [57]. ...
... An increase in plasma corticosterone level was observed at the beginning of the chronic binge cocaine administration, while it was reduced on the 14th day of the applied regimen followed by a return to its basal level after 10 days of the withdrawal period [57]. In the study by García-Fuster et al. [59] corticosterone levels progressively decreased during the course of withdrawal from extended daily access of cocaine the Mann-Whitney U test. Control-group receiving saline (n = 8-9), cocaine 'binge'-cocaine 'binge' group (n = [8][9]. ...
Background
Long-term cocaine exposure leads to dysregulation of the reward system and initiates processes that ultimately weaken its rewarding effects. Here, we studied the influence of an escalating-dose cocaine regimen on drug-associated appetitive behavior after a withdrawal period, along with corresponding molecular changes in plasma and the prefrontal cortex (PFC).
Methods
We applied a 5 day escalating-dose cocaine regimen in rats. We assessed anxiety-like behavior at the beginning of the withdrawal period in the elevated plus maze (EPM) test. The reinforcement properties of cocaine were evaluated in the Conditioned Place Preference (CPP) test along with ultrasonic vocalization (USV) in the appetitive range in a drug-associated context. We assessed corticosterone, proopiomelanocortin (POMC), β-endorphin, CART 55–102 levels in plasma (by ELISA), along with mRNA levels for D2 dopaminergic receptor (D2R), κ-receptor (KOR), orexin 1 receptor (OX1R), CART 55–102, and potential markers of cocaine abuse: miRNA-124 and miRNA-137 levels in the PFC (by PCR).
Results
Rats subjected to the escalating-dose cocaine binge regimen spent less time in the cocaine-paired compartment, and presented a lower number of appetitive USV episodes. These changes were accompanied by a decrease in corticosterone and CART levels, an increase in POMC and β-endorphin levels in plasma, and an increase in the mRNA for D2R and miRNA-124 levels, but a decrease in the mRNA levels for KOR, OX1R, and CART 55–102 in the PFC.
Conclusions
The presented data reflect a part of a bigger picture of a multilevel interplay between neurotransmitter systems and neuromodulators underlying processes associated with cocaine abuse.
... Accordingly, we constructed a circRNA-miRNAhub gene subnetwork. In the cocaine self-administration model, HSP90AA1 had a significant decrease in PFC after withdrawal of 15 days (Bhattacherjee et al., 2019), however, the expression of HSP90AA1 in posterior hippocampus increased significantly after 28 days of withdrawal (García-Fuster et al., 2012). These delayed neurobiological effects of HSP90AA1 likely contribute to sustained vulnerability to cocaine relapse, which may be regulated by circMTHFD2L. ...
Increasing evidence has indicated that circular RNAs (circRNAs) act as competing endogenous RNAs (ceRNAs) regulatory network to regulate the expression of target genes by sponging microRNAs (miRNAs), and therefore play an essential role in many neuropsychiatric disorders, including cocaine use disorder. However, the functional roles and regulatory mechanisms of circRNAs as ceRNAs in dorsolateral prefrontal cortex (dlPFC) of patients with cocaine use disorder remain to be determined. In this study, an expression profiling for dlPFC in 19 patients with cocaine use disorder and 17 controls from Gene Expression Omnibus datasets was used for the differentially expressed circRNAs analysis and the differentially expressed mRNAs analysis. Several tools were used to predict the miRNAs targeted by the circRNAs and the miRNAs targeted mRNAs, which then overlapped with the cocaine-associated differentially expressed mRNAs to determine the functional roles of circRNAs. Functional analysis for the obtained mRNAs was performed via Gene Ontology (GO) in Metascape database. Integrated bioinformatics analysis was conducted to further characterize the circRNA–miRNA–mRNA regulatory network and identify the functions of distinct circRNAs. We found a total of 41 differentially expressed circRNAs, and 98 miRNAs were targeted by these circRNAs. The overlapped mRNAs targeted by the miRNAs and the differentially expressed mRNAs constructed a circRNA–miRNA–mRNA regulation network including 24 circRNAs, 43 miRNAs, and 82 mRNAs in the dlPFC of patients with cocaine use disorder. Functional analysis indicated the regulation network mainly participated in cell response-related, receptor signaling-related, protein modification-related and axonogenesis-related pathways, which might be involved with cocaine use disorder. Additionally, we determined four hub genes ( HSP90AA1 , HSPA1B , YWHAG , and RAB8A ) from the protein–protein interaction network and constructed a circRNA–miRNA-hub gene subnetwork based on the four hub genes. In conclusion, our findings provide a deeper understanding of the circRNAs-related ceRNAs regulatory mechanisms in the pathogenesis of cocaine use disorder.
... Extra slides using spare experimental tissue were run concurrently to confirm optimal exposure time. The specificity of the probe was verified using sense strand controls similar to previous studies (Garcia-Fuster et al., 2012;Kabbaj et al., 2000). ...
Cues, or stimuli in the environment, attain the ability to guide behavior via learned associations. As predictors, cues can elicit adaptive behavior and lead to valuable resources (e.g., food). For some individuals, however, cues are transformed into incentive stimuli and can elicit maladaptive behavior. The goal-tracker/sign-tracker animal model captures individual differences in cue-motivated behaviors, with reward-associated cues serving as predictors of reward for both goal-trackers and sign-trackers, but becoming incentive stimuli only for sign-trackers. While these distinct phenotypes are characterized based on Pavlovian conditioned approach behavior, they exhibit differences on a number of behaviors of relevance to psychopathology. To further characterize the neurobehavioral endophenotype associated with individual differences in cue-reward learning, we investigated neuroendocrine and behavioral profiles associated with negative valence in male goal-trackers, sign-trackers, and intermediate responders. We found that baseline corticosterone increases with Pavlovian learning, and that this increase is positively associated with the development of sign-tracking. We did not observe significant differences between goal-trackers and sign-trackers in behavior during an elevated plus maze or open field test, nor did we see differences in the corticosterone response to the open field test or physiological restraint. We did, however, find that sign-trackers have greater glucocorticoid receptor mRNA expression in the ventral hippocampus, with no phenotypic differences in the dorsal hippocampus. These findings suggest that goal-trackers and sign-trackers do not differ on indices of negative valence; rather, differences in neuroendocrine measures between these phenotypes can be attributed to distinct cue-reward learning styles.
Significance Statement
While the goal-tracker/ sign-tracker animal model derives from individual differences in Pavlovian conditioned approach behavior, other traits, including some of relevance to addiction and post-traumatic stress disorder, have been shown to co-exist with the propensity to sign-track. The extent to which this model encompasses differences in negative valence systems, however, remains largely unexplored. Here we show that behavioral and corticosterone response to paradigms associated with negative valence do not differ between goal-trackers and sign-trackers; but baseline corticosterone levels appear to be linked to the development of sign-tracking, as do differences in glucocorticoid receptor expression in the ventral hippocampus. These findings suggest that neuroendocrine measures typically associated with negative valence may, in fact, play an important role in positive valence systems.
... Human postmortem studies show gene expression alterations within brain regions that regulate the stress-and affect-systems, including altered ratios of MR and GR mRNAs in the HPC of depressed patients (Lopez et al., 1998). Animal studies using the MR/GR ratio as an indicator of HPA function report either an increased or decreased ratio concomitant with chronic stress or long-term adaptation to stress (Brureau et al., 2013;Garcia-Fuster et al., 2012;Ladd et al., 2004;Liberzon et al., 1999;Topic et al., 2008;Zhang et al., 2011). Our laboratory has previously shown a time of day effect in the MR/GR mRNA ratio in the HPC, with a higher ratio in the morning compared to the afternoon (Kerman et al., 2012), consistent with the current findings in C57Bl/6J mice single housed for 7 days. ...
For basic research, rodents are often housed in individual cages prior to behavioral testing. However, aspects of the experimental design, such as duration of isolation and timing of animal manipulation, may unintentionally introduce variance into collected data. Thus, we examined temporal correlates of acclimation of C57Bl/6J mice to single housing in a novel environment following two commonly used experimental time periods (7 or 14 days, SH7 or SH14). We measured circulating stress hormones (adrenocorticotropic hormone and corticosterone), basally or after injection stress, hippocampal gene expression of transcripts implicated in stress and affect regulation: the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), including the MR/GR ratio, and fibroblast growth factor 2 (FGF2). We also measured signaling in the mammalian target of rapamycin (mTOR) pathway. The basal elevation of stress hormones in the SH14 group is accompanied by a blunting in the circadian rhythms of GR and FGF2 hippocampal gene expression, and the MR/GR ratio, that is observed in SH7 mice. Following mild stress, the endocrine response and hippocampal mTOR pathway signaling are decreased in the SH14 mice. These neural and endocrine changes at 14 days of single housing likely underlie increased anxiety-like behavior measured in an elevated plus maze test. We conclude that multiple measures of stress responsiveness change dynamically between one and two weeks of single housing. The ramifications of these alterations should be considered when designing animal experiments since such hidden sources of variance might cause lack of replicability and misinterpretation of data.
... -Early relapse: defined as the relapse in the first four weeks after detoxification admission. This period (one month) is habitually used in research because some neurobiological modifications have been reported in the first month after cocaine withdrawal in humans and animal models 20,21 . ...
... -Early relapse: defined as the relapse in the first four weeks after detoxification admission. This period (one month) is habitually used in research because some neurobiological modifications have been reported in the first month after cocaine withdrawal in humans and animal models 20,21 . ...
Introduction:
Cocaine dependence is a disorder where relapses are frequently presented and many factors are involved. Furthermore, cocaine dependence is associated with poor health-related quality of life (HRQoL) outcomes. This study aims to explore perceived HRQoL as an indicator of drug relapse in cocaine-dependent patients (CDP).
Subjects and methods:
A longitudinal study was carried out in CDP during 23 weeks. A consecutive sampling method was applied, 39 participants composed the initial sample (mean age 35.6 years), only 15 participants completed outpatient follow-up period. CDP were assessed with psychiatric and HRQoL instruments (SCID-I, SCID-II, BDI, STAI scale and SF-36) in different points of the study. The patients were followed up, and cocaine relapses were assessed. The sample was divided according with the relapse (early vs. late relapse). Data were compared and analyzed in order to evaluate whether HRQoL measure could be related to cocaine relapse.
Results:
There are differences in perceived HRQoL measures between CDP with/without early relapse, especially in Mental health and Social functioning dimensions (p<0.05). Furthermore, Late/relapse-patients have higher improvement of HRQoL than patients with early relapse.
Conclusions:
Perceived HRQoL might predict early relapse and could be a possible predictor tool of potential future relapses. More research in this field is needed.
... Acute stress exposure has also been found to produce an immediate 3-fold increase of free corticosterone levels in the dorsal hippocampus [241]. GR/MR ratio is also altered in the dorsal hippocampus during psychostimulant withdrawal [114,241]. ...
... Acute stress exposure has also been found to produce an immediate 3-fold increase of free corticosterone levels in the dorsal hippocampus [241]. GR/MR ratio is also altered in the dorsal hippocampus during psychostimulant withdrawal [114,241]. In Ref. [241] an increase in GR/MR mRNA ratio was observed in the dorsal dentate and CA1 in response to withdrawal from extended access to daily cocaine self-administration, accompanied by increased GR mRNA in the dentate and CA3, and increased MR mRNA in the dentate. ...
... GR/MR ratio is also altered in the dorsal hippocampus during psychostimulant withdrawal [114,241]. In Ref. [241] an increase in GR/MR mRNA ratio was observed in the dorsal dentate and CA1 in response to withdrawal from extended access to daily cocaine self-administration, accompanied by increased GR mRNA in the dentate and CA3, and increased MR mRNA in the dentate. In contrast, others have shown that repeated amphetamine administration selectively down-regulates GR mRNA in the dorsal hippocampus (when sampled as a whole) [242][243][244][245]. Furthermore, in Ref. [114] a reduction in dorsal hippocampal GR/MR protein ratio was observed in response to repeated amphetamine exposure during acute (24 h) withdrawal, even though neither GR nor MR protein expression were signiicantly reduced [114]. ...
... In addition, whereas some brain regions show spontaneous recovery of normal metabolic activity after protracted abstinence, in LgA rats, a few brain structures (the DStr, the ACC, the SN/VTA, the Amyg, the Hipp and the insula) show persistent changes in metabolic activity that may contribute to long-lasting risks of relapse. These results are consistent with separate previous studies that have shown that withdrawal from cocaine self-administration is associated with neuroadaptations in the DStr (Hearing et al, 2008;Pomierny-Chamiolo et al, 2015), ACC (Pomierny-Chamiolo et al, 2015;Zavala et al, 2007;Zorrilla et al, 2001), VTA (mostly with no change in the SN (Arroyo et al, 2000;Chen et al, 2008;Grimm et al, 2003;Lu et al, 2003), Amyg (Lee et al, 2013;Lu et al, 2005a;Zorrilla et al, 2001) and Hipp (Garcia-Fuster et al, 2012;Noonan et al, 2008;Pomierny-Chamiolo et al, 2015;Thompson et al, 2004). Importantly, each of these regions has been shown to be involved in cocaine craving and relapse in animal models (Cosme et al, 2015;Fuchs et al, 2005Fuchs et al, , 2006Grimm and See, 2000;Lu et al, 2005b;McFarland and Kalivas, 2001;Torregrossa et al, 2013). ...
The chronic and relapsing nature of addiction suggests that drugs produce persistent adaptations in the brain that make individuals with drug addiction particularly sensitive to drug-related cues and stress and incapable of controlling drug-seeking and drug-taking behavior. In animal models, several long-lasting neuroadaptations have been described. However, few studies have used brain-imaging techniques to provide a complete picture of brain functioning in the course of withdrawal from cocaine. In this study, we allowed rats to self-administer cocaine under short-access (1-h/day) or long-access (6-h/day) conditions and used 2-deoxy-2-((18)F)fluoro-d-glucose ((18)FDG) positron emission tomography (PET) scanning to investigate the longitudinal changes in metabolic activity 1 and 4 weeks after discontinuation of cocaine self-administration. We found that compared to naive rats, both long-access and short-access rats showed significant disruptions in basal brain metabolic activity. However, compared to short-access, long-access rats showed more intense and long lasting neuroadaptations in a network of brain areas. In particular, abstinence from extended access to cocaine was associated with decreased metabolic activity in the anterior cingulate cortex, the insular cortex and the dorsolateral striatum and increased metabolic activity in the mesencephalon, the amygdala and the hippocampus. This pattern is strikingly similar to that described in humans that has led to the proposal of the I-RISA (Impaired Response Inhibition and Salience Attribution) model of addiction. These results demonstrate that extended access to cocaine leads to persistent neuroadaptations in brain regions involved in motivation, salience attribution, memory, stress, and inhibitory control that may underlie increased risks of relapse.Neuropsychopharmacology accepted article preview online, 29 May 2017. doi:10.1038/npp.2017.109.
... Nevertheless, acute or repeated cocaine administration has clearly been shown to increase peripheral glucocorticoid levels and blunt the inhibitory feedback of the HPA axis in pre-clinical studies [169][170][171]. Plasma corticosterone levels become progressively normalized during cocaine withdrawal, but dysregulation of the expression of stress-related genes has been observed in the hippocampus, including increased GR and MR expression in the DG [172]. In clinical studies, cocaine addiction usually occurs concomitantly with an altered emotional state [130,156], and studies of cocaine addicts have confirmed a strong dysregulation of the HPA axis. ...
After discovering that addictive drugs alter adult neurogenesis, the potential role of adult-born hippocampal neurons in drug addiction has become a promising research field, in which cocaine is the most frequently investigated drug. Although a substantial amount of pre-clinical evidence has accumulated, additional studies are required to reveal the mechanisms by which cocaine modulates adult hippocampal neurogenesis (AHN) and determine whether these adult-born neurons have a role in cocaine-related behaviors, such as cocaine-mediated cognitive symptoms. First, this review will summarize the cocaine-induced alterations in a number of neurobiological factors (neurotransmitters, neurotrophins, glucocorticoids, inflammatory mediators) that likely regulate both hippocampal-dependent learning and adult hippocampal neurogenesis after cocaine exposure. A separate section will provide a detailed review of the available literature that challenges the common view that cocaine reduces adult hippocampal neurogenesis. In fact, cocaine has a short-term anti-proliferative role, but the young adult-born neurons are apparently spared, or even enhanced, following certain cocaine protocols. Thus, we will try to reconcile this evidence with the hippocampal-dependent cognitive symptoms that are typically observed in cocaine addicts, and we will propose new directions for future studies to test the relevant hypothesis. Based on the evidence presented here, the regulation of adult hippocampal neurogenesis might be one of the many mechanisms by which cocaine sculpts hippocampus-dependent learning.
... Animal models of cocaine addiction and abstinence help to understand the neurobiological background leading to drug-taking and drug-seeking behavior. A growing body of evidence supports the persistent molecular changes that contribute to continued cocaine craving during drug abstinence (Freeman et al., 2010;García-Fuster, Flagel, Mahmood, Watson, & Akil, 2012). Chronic cocaine may induce epigenetic alterations that contribute to long-lasting changes in gene expression (Robison and Nestler, 2011); however, the epigenetic mechanisms that underlie incubation of cocaine craving are still unknown. ...
... Thus far, investigations into the pathophysiology of drug abuse have focused on the accumbal dopaminergic reward system. However, recently, the hippocampus has received increasing attention because of neural connections with the reward system and its involvement in context-evoked craving and drug-seeking behavior (Everitt & Robbins, 2005;García-Fuster et al., 2012;Volkow & Flower, 2000). The evidence provided by Taubenfeld, Muravieva, Garcia-Osta, & Alberini (2010) indicated that hippocampal mechanisms are crucial for not only establishing a drug-induced place preference but also linking the place preference memory with context-conditioned withdrawal. ...
Drug craving and relapse risk during abstinence from cocaine are thought to be caused by persistent changes in transcription and chromatin regulation. Although several brain regions are involved in these processes, the hippocampus seems to play an important role in context-evoked craving and drug-seeking behavior. Only a few studies have examined epigenetic alterations during a period of cocaine abstinence. To investigate the effects of cocaine abstinence on DNA methylation and gene expression, rats that self-administered the drug underwent cocaine abstinence in two time points with extinction training. During the cocaine extinction, we observed elevated global 5-hydroxymethylcytosine(5-hmC) levels with a concurrent increase in Tet3 transcript levels. Moreover, we did not find significant alterations in the levels of Tet3 mRNA and 5-hmC in rats subjected to cocaine abstinence without extinction training (abstinence). Additionally, our findings demonstrated that the expression of Tet3 target genes was activated. Besides, altered DNA methylation was detected at promoter regions of miRNAs, such as miR-30d and miR-let7i. Further in silico analysis provided evidence that these two molecules targeted the 3'UTR region of theTet3gene and thus may contribute to its post-transcriptional regulation. This study has presented novel findings in the hippocampus of rats that underwent extinction training following cocaine self-administration. The alterations in the Tet3 gene expression and the level of 5-hmC may play an important role in extinction learning and the reduction of subsequent cocaine seeking. This article is protected by copyright. All rights reserved.
