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Brain-derived neurotrophic factor (BDNF) regulates a variety of physiological processes, and several studies have explored the role of BDNF in addiction-related brain regions like the nucleus accumbens core (NAcore). We sought to understand the rapid effects of endogenous BDNF on cocaine seeking. Rats were trained to self-administer cocaine and extinguished. We then microinjected two inhibitors of BDNF stimulation of tropomyosin receptor kinase B (TrkB), the non-competitive receptor antagonist ANA-12 and TrkB/Fc, a fusion protein that binds BDNF and prevents TrkB stimulation. Blocking TrkB or inactivating BDNF in NAcore potentiated active lever pressing, showing that endogenous BDNF tone was present and supplying inhibitory tone on cue-induced reinstatement. To determine if exogenous BDNF also negatively regulated reinstatement, BDNF was microinjected into NAcore 15 minutes before cue-induced reinstatement. BDNF decreased cocaine seeking through TrkB receptor binding, but had no effect on inactive lever pressing, spontaneous or cocaine-induced locomotion, or on reinstated sucrose seeking. BDNF-infusion potentiated within trial extinction when microinjected in the NAcore during cue- and context + cue induced reinstatement, and the inhibition of lever pressing lasted at least 3 days post injection. Although decreased reinstatement endured for 3 days when BDNF was administered prior to a reinstatement session, when microinjected before an extinction session or in the home cage, BDNF did not alter subsequent cued-reinstatement. Together, these data show that endogenous BDNF acts on TrKB to provide inhibitory tone on reinstated cocaine seeking, and this effect was recapitulated by exogenous BDNF. [ABSTRACT FROM AUTHOR]

Introduction: Few studies investigated the combined patterns of individual assets (e.g., social competence, positive identity) and mental health symptoms (MHS) in adolescents. This study examined the patterns of early adolescents' individual assets and MHS and whether identified patterns were associated with later adolescents' outcomes.Methods: Participants were 352 (164 boys, 188 girls) adolescents who were primarily African-American and from low socioeconomic status families, participating in a prospective study of the effects of prenatal cocaine exposure from birth in the Midwest United States. Individual assets, using the Developmental Assets Profile, and MHS, using the Youth Self-Report, were assessed at age 12. Substance use, via self-report and biologic assays, early (before age 15) sexual behaviors, and behavioral adjustment were assessed at age 15.Results: Latent profile analysis indicated four distinctive profiles: low assets with elevated MHS (P1, n = 54, 15.3%); adequate assets with thought and social problems (P2, n = 84, 23.9%); low assets without MHS (P3, n = 101, 28.7%); and high assets without MHS (P4, n = 113, 32.1%). Children in the profile with high assets without MHS (P4) were more likely to have a higher IQ and to be in a more optimal environment (higher parental monitoring and less family conflict) than those in other profiles. Although profiles with MHS were associated with adolescent risk behaviors, this relationship was more pronounced for girls than for boys.Conclusions: Girls in the low assets with elevated MHS (P1) should be a primary concern for preventive intervention. Our study demonstrates the heterogeneity of individual patterns of adaptation and maladaptation. [ABSTRACT FROM AUTHOR]

The presence of illicit drugs in the aquatic environment represents a new potential risk for aquatic organisms, due to their constant exposure to substances with strong pharmacological activity. Currently, little is known about the ecological effects of illicit drugs. The aim of this study was to evaluate the influence of environmental concentrations of cocaine, an illicit drug widespread in surface waters, on the skeletal muscle of the European eel ( Anguilla anguilla ). The skeletal muscle of silver eels exposed to 20 ng L −1 of cocaine for 50 days were compared to control, vehicle control and two post-exposure recovery groups (3 and 10 days after interruption of cocaine). The eels general health, the morphology of the skeletal muscle and several parameters indicative of the skeletal muscle physiology were evaluated, namely the muscle whole protein profile, marker of the expression levels of the main muscle proteins; cytochrome oxidase activity, markers of oxidative metabolism; caspase-3, marker of apoptosis activation; serum levels of creatine kinase, lactate dehydrogenase and aspartate aminotransferase, markers of skeletal muscle damages. Cocaine-exposed eels appeared hyperactive but they showed the same general health status as the other groups. In contrast, their skeletal muscle showed evidence of serious injury, including muscle breakdown and swelling, similar to that typical of rhabdomyolysis. These changes were still present 10 days after the interruption of cocaine exposure. In fact, with the exception of the expression levels of the main muscle proteins, which remained unchanged, all the other parameters examined showed alterations that persisted for at least 10 days after the interruption of cocaine exposure. This study shows that even low environmental concentrations of cocaine cause severe damage to the morphology and physiology of the skeletal muscle of the silver eel, confirming the harmful impact of cocaine in the environment that potentially affects the survival of this species. [ABSTRACT FROM AUTHOR]

Abstract Haplotypes of the Gabra2 gene encoding the α2-subunit of the GABA A receptor (GABA A R) are associated with drug abuse, suggesting that α2-GABA A Rs may play an important role in the circuitry underlying drug misuse. The genetic association of Gabra2 haplotypes with cocaine addiction appears to be evident primarily in individuals who had experienced childhood trauma. Given this association of childhood trauma, cocaine abuse and the Gabra2 haplotypes, we have explored in a mouse model of early life adversity (ELA) whether such events influence the behavioral effects of cocaine and if, as suggested by the human studies, α2-GABA A Rs in the nucleus accumbens (NAc) are involved in these perturbed behaviors. In adult mice prior ELA caused a selective decrease of accumbal α2-subunit mRNA, resulting in a selective decrease in the number and size of the α2-subunit (but not the α1-subunit) immunoreactive clusters in NAc core medium spiny neurons (MSNs). Functionally, in adult MSNs ELA decreased the amplitude and frequency of GABA A R-mediated miniature inhibitory postsynaptic currents (mIPSCs), a profile similar to that of α2 "knock-out" (α2−/−) mice. Behaviourally, adult male ELA and α2−/− mice exhibited an enhanced locomotor response to acute cocaine and blunted sensitisation upon repeated cocaine administration, when compared to their appropriate controls. Collectively, these findings reveal a neurobiological mechanism which may relate to the clinical observation that early trauma increases the risk for substance abuse disorder (SAD) in individuals harbouring haplotypic variations in the Gabra2 gene. Highlights • Early-life adversity (ELA) is a risk factor for adult psychopathology and drug abuse. • Gabra2 gene variations coupled with childhood trauma associate with cocaine abuse. • ELA selectively impaired accumbal α2-GABA A R expression and function in adult mice. • ELA and α2−/− mice displayed similar abnormal behavioral responses to cocaine. • The findings complement clinical associations of ELA, Gabra2 gene and drug abuse. [ABSTRACT FROM AUTHOR]

Background The predominant view of chronic cocaine use maintains that it causes a broad range of cognitive deficits. However, concerns about the possibly deleterious impact of cocaine on cognitive functioning have yet to be thoroughly vetted. This review addresses the impact of cocaine use on such cognitive domains as executive function, memory, language, and psychomotor speed. Additionally, relevant neuroimaging data is considered to understand the neural basis underlying cocaine-related effects on cognitive functioning. Methods We searched PubMed, Google Scholar, and Embase using the search terms “cocaine and cognition,” “cocaine and cognitive functioning,” and “cocaine and cognitive deficits or impairment.” To meet inclusion criteria we evaluated only cognitive and neuroimaging studies describing the long-term effects of cocaine on cognitive functioning published from 1999 to 2016. Results The majority of studies reported statistically significant differences between cocaine users and non-drug-using controls in brain structures, blood-oxygen-level dependent signals, and brain metabolism. However, differences in cognitive performance were observed on a minority of measures. Additionally, the majority of studies were not compared against normative data. Conclusions The current evidence does not support the view that chronic cocaine use is associated with broad cognitive deficits. The view that cocaine users have broad cognitive deficits is inaccurate based upon current evidence, and the perpetuation of this view may have negative implications for treatment programs and development of public policies. [ABSTRACT FROM AUTHOR]

Although the role of cocaine- and amphetamine-regulated transcript peptide (CART) in modulating the mesolimbic reward pathway has been suggested, underlying cellular mechanisms have not been elucidated. Herein, we investigate the involvement of G i/o dependent protein kinase A (PKA)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling in CART induced reward behavior. The rat was implanted with a stimulating electrode targeted at the lateral hypothalamus (LH)-medial forebrain bundle (MFB) and conditioned to intracranial self-stimulation (ICSS) in an operant chamber. Intracerebroventricular (icv) administration of CART (55-102) dose-dependently lowered ICSS threshold suggesting reward promoting action, however, pretreatment with subeffective doses of G i/o inhibitor (pertussis toxin, PTX) or PKA inhibitor (Rp-cAMPS) or ERK inhibitor (U0126) via icv route, attenuated CART mediated reward experience. Operant conditioned rats showed increased pCREB levels in the nucleus accumbens shell (AcbSh), ventral tegmental area (VTA) and hypothalamic paraventricular nucleus (PVN). Infusion of CART (icv) in the conditioned rats augmented the population of pCREB positive cells in the AcbSh, VTA and PVN areas, but not in the arcuate nucleus (ARC). Pretreatment with U0126 significantly decreased CART induced pCREB activation in the AcbSh and VTA, but not in PVN and ARC. ICSS or CART induced CREB mRNA expression in Acb and VTA was attenuated by U0126. We suggest that recruitment of G i/o dependent PKA/ERK/CREB phosphorylation signaling in Acb and VTA might play an important role in CART induced reward behavior. [ABSTRACT FROM AUTHOR]

Introduction: There have been mixed findings assessing the impact of regular cocaine use on cognitive functioning. This study employed a comprehensive cognitive battery to compare the performance of individuals diagnosed with a cocaine use disorder (N = 3 abusers, N = 17 dependent) against the performance of two control groups: (a) non-drug-users, and (b) marijuana users who report no cocaine use (N = 7 marijuana abusers, N = 0 dependent, N = 13 marijuana users with no Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, DSM-IV, diagnosis). Method: This one-session, between-participants, outpatient study was conducted at the New York State Psychiatric Institute. Sixty research volunteers completed the study. Drug users in both groups had no signs of current intoxication, but had a positive urine toxicology—which indicated use within 72 hours in the cocaine use disorder group and within the past 30 days (depending on frequency of use) for the marijuana-using control group. The National Institutes of Health (NIH) Toolbox Cognition Battery was used to assess cognitive functioning across six domains: executive function, attention, episodic memory, working memory, processing speed, and language. Each participant’s score was also compared against a normative database adjusted for age. Results: Although the mean cognitive scores for all groups fell within the normal range for all tests, marijuana-using control participants outperformed those with a cocaine use disorder on a cognitive flexibility and language measure. Conclusions: Cognitive functioning of individuals diagnosed with cocaine use disorder was observed to be similar to that of control group participants on the majority of tasks and fell within the normal range when compared against normative data. [ABSTRACT FROM AUTHOR]

The current study evaluates a therapy for substance-dependent perpetrators of partner violence. Sixty-three males arrested for partner violence within the past year were randomized to a cognitive behavioral substance abuse-domestic violence (SADV; n = 29) or a drug counseling (DC; n = 34) condition. Seventy percent of offenders completed eight core sessions with no differences between SADV and DC conditions in the amount of substance or aggression at pretreatment. SADV participants had fewer cocaine-positive toxicology screens and breathalyzer results during treatment, were less likely to engage in aggressive behavior proximal to a drinking episode, and reported fewer episodes of violence than DC participants at posttreatment follow-up. SADV shows promise in decreasing addiction and partner violence among substance-dependent male offenders. [ABSTRACT FROM AUTHOR]

Background Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes. Methods We used virally mediated RNA interference to locally downregulate SERT expression and compared the results with those of constitutive SERT knockout. Rats were allowed either short access (ShA) (1 hour) or long access (LgA) (6 hours) to cocaine self-administration to model moderate versus compulsive-like cocaine taking. Results SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions and, like ShA cocaine self-administration, reduced corticotropin-releasing factor (CRF) immunodensity in the paraventricular nucleus of the hypothalamus. In contrast, SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions and, like LgA cocaine self-administration, reduced CRF immunodensity in the central nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior, as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific SERT knockdown. Conclusions Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine. [ABSTRACT FROM AUTHOR]

Characterization of the effects of long-term alcohol consumption on the brain would be aided by the development of behavioral assays that are relatively easy to implement in animal models of alcohol use disorders. Assessing unconditioned behaviors, such as drug-elicited yawning in models that permit long-term alcohol ingestion, may be a valuable complement to more invasive and costly procedures. The present studies investigated previous unexpected findings of ethanol-induced yawning in nonhuman primates. Subjects were adult male rhesus monkeys (n = 8), all of which had experience self-administering intravenous cocaine for several years. Four monkeys also had experience consuming 2.0 g/kg ethanol over 1 h per day, 5 days per week, for 6.8-12.0 months. All monkeys received saline or ethanol (0.25-1.0 g/kg) infused intravenously (i.v.) over 10 min, and the number of yawns elicited during the infusion was counted. A second experiment in the ethanol-experienced monkeys examined whether ethanol-induced yawning could be blocked by PG01037 (1.0, 3.0 mg/kg, i.v.), a selective antagonist at dopamine D3 receptors (D3R). Ethanol significantly and dose-dependently increased yawns in the ethanol-experienced animals, but not the ethanol-naïve animals. In the ethanol-experienced monkeys, this effect of ethanol was blocked by the D3R antagonist. The pharmacology of yawning is complex and a good deal of model development remains to be performed to characterize the potential involvement of other neurotransmitter systems. Nonetheless, drug-elicited yawning may be a useful unconditioned behavioral assay to assess the effects of long-term alcohol consumption in established nonhuman primate models. [ABSTRACT FROM AUTHOR]

Background Methylphenidate-based designer drugs are new psychoactive substances (NPS) that are used outside medical settings and their pharmacology is largely unexplored. The aim of the present study was to characterize the pharmacology of methylphenidate-based substances in vitro . Methods We determined the potencies of the methylphenidate-based NPS N -benzylethylphenidate, 3,4-dichloroethylphenidate, 3,4-dichloromethylphenidate, ethylnaphthidate, ethylphenidate, 4-fluoromethylphenidate, isopropylphenidate, 4-methylmethylphenidate, methylmorphenate, and propylphenidate and the potencies of the related compounds cocaine and modafinil with respect to norepinephrine, dopamine, and serotonin transporter inhibition in transporter-transfected human embryonic kidney 293 cells. We also investigated monoamine efflux and monoamine receptor and transporter binding affinities. Furthermore, we assessed the cell integrity under assay conditions. Results All methylphenidate-based substances inhibited the norepinephrine and dopamine transporters 4 to >1000-fold more potently than the serotonin transporter. Similar to methylphenidate and cocaine, methylphenidate-based NPS did not elicit transporter-mediated efflux of monoamines. Besides binding to monoamine transporters, several test drugs had affinity for adrenergic, serotonergic, and rat trace amine-associated receptors but not for dopaminergic or mouse trace amine-associated receptors. No cytotoxicity was observed after drug treatment at assay concentrations. Conclusion Methylphenidate-based substances had pharmacological profiles similar to methylphenidate and cocaine. The predominant actions on dopamine transporters vs . serotonin transporters may be relevant when considering abuse liability. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’ [ABSTRACT FROM AUTHOR]

A variety of new psychoactive substances (NPS) are appearing in recreational drug markets worldwide. NPS are compounds that target various receptors and transporters in the central nervous system to achieve their psychoactive effects. Chemical modifications of existing drugs can generate NPS that are not controlled by current legislation, thereby providing legal alternatives to controlled substances such as cocaine or amphetamine. Recently, 3-fluorophenmetrazine (3-FPM), a derivative of the anorectic compound phenmetrazine, appeared on the recreational drug market and adverse clinical effects have been reported. Phenmetrazine is known to elevate extracellular monoamine concentrations by an amphetamine-like mechanism. Here we tested 3-FPM and its positional isomers, 2-FPM and 4-FPM, for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We found that 2-, 3- and 4-FPM inhibit uptake mediated by DAT and NET in HEK293 cells with potencies comparable to cocaine (IC 50 values < 2.5 μM), but display less potent effects at SERT (IC 50 values >80 μM). Experiments directed at identifying transporter-mediated reverse transport revealed that FPM isomers induce efflux via DAT, NET and SERT in HEK293 cells, and this effect is augmented by the Na + /H + ionophore monensin. Each FPM evoked concentration-dependent release of monoamines from rat brain synaptosomes. Hence, this study reports for the first time the mode of action for 2-, 3- and 4-FPM and identifies these NPS as monoamine releasers with marked potency at catecholamine transporters implicated in abuse and addiction. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’ [ABSTRACT FROM AUTHOR]

Alterations in gene expression within the neural networks of prefrontal cortex (PFC) and hippocampus (HPC) are known to contribute to behavioural phenotypes associated with drug intake. However, the functional consequences of regulated expression patterns of Fosb and Crem (cAMP response element modulator) in both brain regions in response to volitional intake of cocaine in social environment is yet to be explored. Here, we first exposed young adult mice to cocaine (300 mg/L) and water concurrently for 30 days in the IntelliCage to investigate consumption preference, and subsequently for 28 days during which persistent motivated drug seeking behaviours were examined. Thereafter, locomotor activity and memory performance of the mice were assessed. DNA methylation status in the promoters of Fosb and Crem genes were also evaluated. We show that mice that had extended access to cocaine exhibited motivational deficit and demonstrated decreased locomotor activity and intact recognition memory. These changes were accompanied by hypomethylation or hypermethylation in the promoters of Fosb and Crem genes in the PFC and HPC of the cocaine-experienced mice, respectively. Together, these findings correlate the molecular changes to behavioural effects of the treatment and further suggests a possible activation of prefrontal cortical networks by social interaction episodes in the IntelliCage which possibly enhanced behavioural control that dampens mice sensitivity to cocaine rewards. Furthermore, our data delineate the molecular response of Crem and Fosb to oral cocaine in group-housed mice and demonstrates differential regulation of activities within the substrate brain regions studied. [ABSTRACT FROM AUTHOR]

Background and aims: Childhood trauma is associated with increased levels of anxiety later in life, an increased risk for the development of substance use disorders, and neurodevelopmental abnormalities in the amygdala and frontostriatal circuitry. The aim of this study was to investigate the (neurobiological) link among childhood trauma, state anxiety, and amygdala-frontostriatal activity in response to cocaine cues in regular cocaine users. Methods: In this study, we included 59 non-treatment seeking regular cocaine users and 58 non-drug using controls. Blood oxygenation level-dependent responses were measured using functional magnetic resonance imaging while subjects performed a cue reactivity paradigm with cocaine and neutral cues. Psychophysiological interaction analyses were applied to assess functional connectivity between the amygdala and other regions in the brain. Self-report questionnaires were used to measure childhood trauma, state anxiety, drug use, drug use severity, and craving. Results: Neural activation was increased during the presentation of cocaine cues, in a widespread network including the frontostriatal circuit and amygdala in cocaine users but not in controls. Functional coupling between the amygdala and medial prefrontal cortex was reduced in response to cocaine cues, in both cocaine users and controls, which was further diminished with increasing state anxiety. Importantly, amygdala-striatal connectivity was positively associated with childhood trauma in regular cocaine users, while there was a negative association in controls. At the behavioral level, state anxiety was positively associated with cocaine use severity and craving related to negative reinforcement. Conclusion: Childhood trauma is associated with enhanced amygdala-striatal connectivity during cocaine cue reactivity in regular cocaine users, which may contribute to increased habit behavior and poorer cognitive control. While we cannot draw conclusions on causality, this study provides novel information on how childhood trauma may contribute to the development and persistence of cocaine use disorder. [ABSTRACT FROM AUTHOR]

We have used a combination of multiple stage mass spectrometry (MSn) experiments, hydrogen/ deuterium exchange experiments, and thermochemical data estimated by computational chemistry calculations at the B3LYP/6-31+G(d,p) level of theory to revisit the gas-phase fragmentation of protonated cocaine. The lone pair of nitrogen participates in major fragmentation routes of protonated cocaine, to generate cyclic iminium ions. The structure of product ion m/z 182, which has been previously proposed in the literature, was shown to be unstable; therefore, we have decided to revisit it. Here, we propose another ion structures for the product ion m/z 182 that is supported by thermochemical data. Compared with the formation of other product ions, the formation of the most intense product ions in the collision-induced dissociation spectrum of protonated cocaine (m/z 182 and m/z 82) is the most energetically favorable. We propose the structure and formation of m/z 122 and m/z 91 for the first time. We suggest that m/z 91 originates from m/z 122 instead of m/z 119, as fully supported by MSn experiments. The results of this study could help to study and quantify cocaine metabolites. [ABSTRACT FROM AUTHOR]

Aims: Despite alcohol being the most often used addictive substance among addicted patients, use of other substances such as cocaine has increased over recent years, and the combination of both drugs aggravates health impairment and complicates clinical assessment. The aim of this study is to identify and characterize heterogeneous subgroups of cocaine- and alcohol-addicted patients with common characteristics based on substance use disorders, psychiatric comorbidity and impulsivity. Methods: A total of 214 subjects with cocaine and/or alcohol use disorders were recruited from outpatient treatment programs and clinically assessed. A latent class analysis was used to establish phenotypic categories according to diagnosis of cocaine and alcohol use disorders, mental disorders, and impulsivity scores. Relevant variables were examined in the latent classes (LCs) using correlation and analyses of variance and covariance. Results: Four LCs of addicted patients were identified: Class 1 (45.3%) formed by alcohol-dependent patients exhibiting lifetime mood disorder diagnosis and mild impulsivity; Class 2 (14%) formed mainly by lifetime cocaine use disorder patients with low probability of comorbid mental disorders and mild impulsivity; Class 3 (10.7%) formed by cocaine use disorder patients with elevated probability to course with lifetime anxiety, ear and personality disorders, and greater impulsivity scores; and Class 4 (29.9%) formed mainly by patients with alcohol and cocaine use disorders, with elevated probability in ear and personality disorders and elevated impulsivity. Furthermore, there were significant differences among classes in terms of Diagnostic and Statistical Manual of Mental Disorders-4th Edition-Text Revision criteria for abuse and dependence: Class 3 showed more criteria for cocaine use disorders than other classes, while Class 1 and Class 4 showed more criteria for alcohol use disorders. Conclusion: Cocaine- and alcohol-addicted patients who were grouped according to diagnosis of substance use disorders, psychiatric comorbidity, and impulsivity show different clinical and sociodemographic variables. Whereas mood and anxiety disorders are more prevalent in alcohol-addicted patients, personality disorders are associated with cocaine use disorders and diagnosis of comorbid substance use disorders. Notably, increased impulsivity is a distinctive characteristic of patients with severe cocaine use disorder and comorbid personality disorders. Psychiatric disorders and impulsivity should be considered for improving the stratification of addicted patients with shared clinical and sociodemographic characteristics to select more appropriate treatments. [ABSTRACT FROM AUTHOR]

Netrin G1 is a presynaptic ligand involved in axonal projection. Although molecular mechanisms underlying cocaine addiction are still poorly understood, Netrin G1 might have a role as a regulator of anxiety, fear and spatial memory, behavioural traits impaired in the context of cocaine exposure. In this study, the Netrin G1 (Ntng1) expression was investigated in the nucleus accumbens of mice primarily conditioned to cocaine using a place preference paradigm. A genetic association study was then conducted on 146 multiplex families of the Collaborative study on Genetics of Alcoholism, in which seven single nucleotide polymorphisms located in the NTNG1 gene were genotyped. NTNG1 expression levels were also quantified in BA10, BA46 and the cerebellum of healthy controls (with no Axis 1 psychopathology). Decreased Ntng1 expression was initially observed in the nucleus accumbens of mice conditioned to cocaine. Significant genetic family-based associations were detected between NTNG1 polymorphisms and cocaine dependence. NTNG1 expression in BA10, BA46 and the cerebellum, however, were not significantly associated with any allele or haplotype of this gene. These results confirm that Ntng1 expression is disturbed in the nucleus accumbens of mice, after cocaine conditioning. A haplotype of NTNG1 was found to constitute a vulnerability factor for cocaine use disorder in patients, although none of its single nucleotide polymorphisms were associated with a differential expression pattern in healthy controls. The data suggest that change in the Ntng1 expression is a consequence of cocaine exposure, and that some of its genetic markers are associated with a greater risk for cocaine use disorder. [ABSTRACT FROM AUTHOR]

d-Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug-related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5-HTT-/- compared with 5-HTT+/+ rats. Based on this finding, we hypothesized a lower sensitivity to DCS in the 5-HTT-/- rats. To test this, rats were trained in a cocaine-induced conditioned place preference (CPP) paradigm. A significant extinction of CPP was observed in 5-HTT+/+ rats receiving 1 mg/kg i.v. DCS, while a similar effect was found in the 5-HTT-/- rats only after 5 mg/kg. Following CPP, we tested if DCS were able to reduce FosB/∆FosB protein expression, a molecular switch for cocaine-seeking behaviour. We observed an overall lower number of FosB/∆FosB positive cells in 5-HTT-/- ventromedial prefrontal cortex and amygdala and an overall effect of DCS treatment on the number of positive cells in the nucleus accumbens. In conclusion, in this study, we show that the dosing of DCS to facilitate the extinction of cocaine-seeking behaviour is, at least partially, determined by 5-HTT genotype. [ABSTRACT FROM AUTHOR]

Abuse of synthetic psychostimulants like synthetic cathinones has risen in recent years. 3,4-Methylenedioxypyrovalerone (MDPV) is one such synthetic cathinone that demonstrates a mechanism of action similar to cocaine. Compared to cocaine, MDPV is more potent at blocking dopamine and norepinephrine reuptake and is readily self-administered by rodents. The present study compared the rewarding and reinforcing properties of MDPV and cocaine using systemic injection dose-response and self-administration models. Fifty kilohertz ultrasonic vocalizations (USVs) were recorded as an index of positive affect throughout experiments. In Experiment 1, MDPV and cocaine dose-dependently elicited 50-kHz USVs upon systemic injection, but MDPV increased USVs at greater rates and with greater persistence relative to cocaine. In Experiment 2, latency to begin MDPV self-administration was shorter than latency to begin cocaine self-administration, and self-administered MDPV elicited greater and more persistent rates of 50-kHz USVs versus cocaine. MDPV-elicited 50-kHz USVs were sustained over the course of drug load-up whereas cocaine-elicited USVs waned following initial infusions. Notably, we observed a robust presence of context-elicited 50-kHz USVs from both MDPV and cocaine self-administering rats. Collectively, these data suggest that MDPV has powerfully rewarding and reinforcing effects relative to cocaine at one-tenth doses. Consistent with prior work, we additionally interpret these data in supporting that MDPV has significant abuse risk based on its potency and subjectively positive effects. Future studies will be needed to better refine therapeutic strategies targeted at reducing the rewarding effects of cathinone analogs in efforts to ultimately reduce abuse liability. [ABSTRACT FROM AUTHOR]

A major challenge for treating cocaine addiction is the propensity for abstinent users to relapse. Two important triggers for relapse are cues associated with prior drug use and stressful life events. To study their interaction in promoting relapse during abstinence, we used the incubation model of craving and relapse in which cue-induced drug seeking progressively intensifies ('incubates') during withdrawal from extended-access cocaine self-administration. We tested rats for cue-induced cocaine seeking on withdrawal day (WD) 1. Rats were then subjected to repeated restraint stress or control conditions (seven sessions held between WD6 and WD14). All rats were tested again for cue-induced cocaine seeking on WD15, 1 day after the last stress or control session. Although controls showed a time-dependent increase in cue-induced cocaine seeking (incubation), rats exposed to repeated stress in early withdrawal exhibited a more robust increase in seeking behavior between WD1 and WD15. In separate stressed and control rats, equivalent cocaine seeking was observed on WD48. These results indicate that repeated stress in early withdrawal accelerates incubation of cocaine craving, although craving plateaus at the same level were observed in controls. However, 1 month after the WD48 test, rats subjected to repeated stress in early withdrawal showed enhanced cue-induced cocaine seeking following acute (24 hours) food deprivation stress. Together, these data indicate that chronic stress exposure enhances the initial rate of incubation of craving during early withdrawal, resulting in increased vulnerability to cue-induced relapse during this period, and may lead to a persistent increase in vulnerability to the relapse-promoting effects of stress. [ABSTRACT FROM AUTHOR]

Evidence suggests that the infralimbic cortex (IL), a subregion of the ventromedial prefrontal cortex (vmPFC), suppresses cocaine-seeking behavior in a self-administration paradigm, whereas the more anterior vmPFC subregion, the medial orbitofrontal cortex (mOFC), has received very little attention in this regard. Despite the established dopaminergic innervation of the vmPFC, whether dopamine receptor blockade in each subregion alters the reinstatement of cocaine seeking is unclear. To address this issue, male Sprague-Dawley rats underwent 2 weeks of cocaine self-administration, followed by extinction training and reinstatement testing. Immediately prior to each reinstatement test, rats received microinjections of the D1 receptor antagonist SCH 23390, the D2 receptor antagonist sulpiride or their respective vehicles. D1 receptor blockade in the IL reduced cued reinstatement but had no effect on cocaine prime and cue + cocaine-prime reinstatement, whereas D2 receptor blockade in the IL had no effect on reinstatement. For the mOFC, however, D1 receptor blockade reduced cocaine seeking in all reinstatement types, whereas blocking D2 receptors in the mOFC had no effect on any form of cocaine seeking. These findings suggest different roles for D1 receptors in the IL versus the mOFC in regulating cocaine-seeking behavior. Moreover, even as previous work indicates that IL inactivation does not affect reinstatement but, rather, induces cocaine seeking during extinction, the present findings suggest that dopamine receptor activation in the IL is necessary for cocaine seeking under some circumstances. [ABSTRACT FROM AUTHOR]

Hypothalamic orexin/hypocretin (Orx/Hcrt) neurons are thought to mediate both food-reinforced behaviors and behavior motivated by drugs of abuse. However, the relative role of the Orx/Hcrt system in behavior motivated by food versus drugs of abuse remains unclear. This investigation addressed this question by contrasting hypothalamic Orx/Hcrt neuronal activation associated with reinstatement of reward seeking induced by stimuli conditioned to cocaine (COC) versus highly palatable food reward, sweetened condensed milk (SCM). Orx/Hcrt neuronal activation in the lateral hypothalamus, dorsomedial hypothalamus and perifornical area, determined by dual c-fos/orx immunocytochemistry, was quantified in rat brains, following reinstatement of reward seeking induced by a discriminative stimulus (S+ ) conditioned to COC or SCM. The COC S+ and SCM S+ initially produced the same magnitude of reward seeking. However, over four subsequent tests, behavior induced by the SCM S+ decreased to extinction levels, whereas reinstatement induced by the COC S+ perseverated at undiminished levels. Following both the first and fourth tests, the percentage of Orx/Hcrt cells expressing Fos was significantly increased in all hypothalamic subregions in rats tested with the COC S+ but not rats tested with the SCM S+ . These findings point toward a role for the Orx/Hcrt system in perseverating, compulsive-like COC seeking but not behavior motivated by palatable food. Moreover, analysis of the Orx/Hcrt recruitment patterns suggests that failure of Orx/Hcrt neurons in the lateral hypothalamus to respond to inhibitory inputs from Orx/Hcrt neurons in the dorsomedial hypothalamus/perifornical area may contribute to the perseverating nature of COC seeking. [ABSTRACT FROM AUTHOR]

Rationale: Previous work indicated that progesterone (PRO) reduced impulsive choice for cocaine in female but not male rats (Smethells et al. Psychopharmacology 233:2999-3008, 2016). Impulsive action, typically measured by responding for a reinforcer during a signaled period of nonavailability of natural reinforcers, predicts initiation and escalation of drug use in animals and humans. The present study examined impulsive action for cocaine using PRO in male and female rats trained on a go/no-go task. Objective: Rats were trained on a go/no-go task to respond for cocaine infusions (0.4 mg/kg/inf). During the 'go' component, responding was reinforced on a VI 30-s schedule, whereas during the 'no-go' component, withholding a response was reinforced on a differential reinforcement of other behavior (DRO) 30-s schedule. A response during the no-go component resets the DRO timer and served as a measure of impulsive action. After baseline responding was established, rats were pretreated with vehicle (VEH) or PRO (0.5 mg/kg), and DRO resets and responding during the go component for cocaine were compared in males vs. females. Results: DRO resets were significantly lower following PRO treatment compared to VEH in female, but not male, rats. Response rates and overall infusions during the go component were not significantly altered by PRO in either females or males. Conclusion: Treatment with PRO resulted in a sex-specific reduction in impulsive action for cocaine, while not affecting cocaine self-administration. [ABSTRACT FROM AUTHOR]

Exposure to cocaine-associated contextual cues contributes significantly to relapse. Extinction of these contextual associations, which involves a new form of learning, reduces cocaine-seeking behavior; however, the molecular mechanisms underlying this process remain largely unknown. We report that extinction, but not acquisition, of cocaine conditioned place preference (CPP) in male mice increased Cav1.2 L-type Ca2 + channel mRNA and protein in postsynaptic density (PSD) fractions of the hippocampus, a brain region involved in drug- context associations. Moreover, viral-mediated deletion of Cav1.2 in the dorsal hippocampus attenuated extinction of cocaine CPP. Molecular studies examining downstream Cav1.2 targets revealed that extinction recruited calcium/calmodulin (Ca2+/CaMK)- dependent protein kinase 11 (CaMKII) to the hippocampal PSD. This occurred in parallel with an increase in phosphorylation of the AMPA GluAl receptor subunit at serine 831 (S831), a CaMKII site, along with an increase in total PSDGluAl. The necessity of S831 GluAl was further demonstrated by the lack of extinction in S831A GluAl phosphomutant mice. Of note hippocampal GluAl levels remained unaltered at the PSD, but were reduced near the PSD and at perisynaptic sites of dendritic spines in extinction-resistant S831A mutant mice. Finally, conditional knock-out of Cav1.2 in dopamine D1 receptor (DlR)-expressing cells resulted in attenuation of cocaine CPP extinction and lack of extinction-dependent changes in hippocampal PSD CaMKII expression and S831 GluAl phosphorylation. In summary, we demonstrate an essential role for the hippocampal Cav 1.2/CaMKII/S831 GluA 1 pathway in cocaine CPP extinction, with data supporting contribution of hippocampal DIR-expressing cells in this process. These findings demonstrate a novel role for Cav1.2 channels in extinction of contextual cocaine-associated memories. [ABSTRACT FROM AUTHOR]

Rationale: The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability. Objectives: The present study examined the effects of several novel 'norepinephrine (NE)-preferring' monoamine releasers relative to non-selective monoamine releasers, d-amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329 < l-methamphetamine < PAL-169). Methods: Adult rhesus macaques were trained to discriminate 0.4 mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine. Results: Results show that cocaine, d-amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the 'NE-preferring' releasers, PAL-329 and l-methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine's discriminative stimulus effects. Conclusions: These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine-like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other 'NE-preferring' monoamine releasers should provide insight into their potential for the management of cocaine addiction. [ABSTRACT FROM AUTHOR]

Caffeine is the world's most popular psychostimulant and is frequently used as an active adulterant in many illicit drugs including cocaine. Previous studies have shown that caffeine can potentiate the stimulant effects of cocaine and cocaine-induced drug seeking behavior. However, little is known about the effects of this drug combination on reward-related learning, a key process in the maintenance of addiction and vulnerability to relapse. The goal of the present study was thus to determine caffeine and cocaine combined effects on the Conditioned Place Preference (CPP) test and to determine potential differential mRNA expression in the Nucleus Accumbens (NAc) and medial prefrontal cortex (mPFC) of immediate-early genes (IEGs) as well as dopamine and adenosine receptor subunits. Mice were treated with caffeine (5 mg/kg, CAF), cocaine (10mg/kg, COC), or their combination (caffeine 5mg/kg+cocaine 10mg/kg, CAF-COC) and trained in the CPP test or treated with repeated injections inside the home cage. NAc and mPFC tissues were dissected immediately after the CPP test, after a single conditioning session or following psychostimulant injection in the home cage for mRNA expression analysis. CAF-COC induced a marked change of preference to the drug conditioned side of the CPP and a significant increase in locomotion compared to COC. Gene expression analysis after CPP test revealed specific up-regulation in the CAF-COC group of Drd1a, cFos, and FosB in the NAc, and cFos, Egr1, and Npas4 in the mPFC. Importantly, none of these changes were observed when animals received same treatments in their home cage. With a single conditioning session, we found similar effects in both CAF and CAF-COC groups: increased Drd1a and decreased cFos in the NAc, and increased expression of Drd1a and Drd2, in the mPFC. Interestingly, we found that cFos and Npas4 gene expression were increased only in the mPFC of the CAF-COC. Our study provides evidence that caffeine acting as an adulterant could potentiate reward-associated memories elicited by cocaine. This is associated with specific changes in IEGs expression that were observed almost exclusively in mice that received the combination of both psychostimulants in the context of CPP memory encoding and retrieval. Our results highlight the potential relevance of caffeine in the maintenance of cocaine addiction whichmight bemediated bymodifying neural plasticity mechanisms that strengthen learning of the association between drug and environment. [ABSTRACT FROM AUTHOR]

Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2β position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane , MFZ 2–24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2–24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2–24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (−)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site and the importance of the tropane moiety in competitive mechanisms of DA uptake inhibition. These findings set a structure-function baseline for comparison of typical and atypical DAT inhibitors and how their interactions with DAT could lead to the loss of cocaine-like behaviors. [ABSTRACT FROM AUTHOR]

Background The potential of abused drugs to induce addiction and compulsive drug-related behavior is associated with their ability to alter dopamine signaling. Dopamine plays a key role in reward signaling and it has been of great interest to investigate how various drugs of abuse alter reward-related behavior. Comparison with existing methods In rodents, the rewarding effects of drugs have often been assessed in self-administration or place preference paradigms; both involving repeated drug exposure and weeks of training and testing. New method Our investigation describes a valid approach to assess the initial rewarding effects of cocaine in mice with a single exposure place preference (sePP) paradigm, avoiding repeated drug injections. Results We present the sePP paradigm with a 3-day protocol to assess the initial rewarding effects of cocaine. Interestingly, only male mice exhibit sePP to cocaine. To assess subsequent drug-related behavior, the protocol was extended by 3 days of extinction followed by reinstatement on day 10. Conclusion The sePP paradigm provides a reliable and convenient approach to assess the initial rewarding effects of cocaine, circumventing the need for repeated drug injections. The sePP protocol allows further dissection of the mechanism and influence of initial cocaine exposure on subsequent drug-related behaviors by including extinction and reinstatement. The lack of sePP in female mice may reflect a biologically relevant sex difference in the initial subjective perception of cocaine-induced reward. This could relate to and explain why males and females have been reported to respond differently to cocaine and cocaine-associated cues. [ABSTRACT FROM AUTHOR]

Previous studies have indicated that neural changes induced by early nutritional insult cause an altered response to pharmacological treatments, including addictive drugs. This study evaluates the influence of perinatal protein malnutrition in developing cross-sensitization to cocaine-induced rewarding effects in animals pre-exposed to morphine. Different groups of well-nourished (C-rats) and protein-deprived animals (D-rats) were treated twice a day for three days with increasing doses of morphine or with saline. After 3 days, the incentive motivational effects of cocaine were assessed in a Conditioned Place Preference paradigm in both groups. In saline pre-treated animals, dose-response curves to cocaine revealed a conditioning effect in D-rats at doses of 5, 7.5 and 10 mg/kg, while this effect was observed in C-rats only with 10 and 15 mg/kg. Furthermore, when animals of both groups were pre-treated with escalating doses of morphine, cross-sensitization to the conditioning effect of cocaine was elicited only in D-rats with low doses of cocaine (5 and 7.5 mg/kg). In contrast, under the same experimental conditions, C-rats show no cross-sensitization. To correlate this differential rewarding response with a molecular substrate linked to the behavioral changes observed after repeated drug exposure, ΔFosB expression was assessed in different brain regions. D-rats showed a significant increase in this transcription factor in the nucleus accumbens, amygdala and medial prefrontal cortex. These results demonstrated that perinatal protein deprivation facilitates rewarding effects and the development of cross-sensitization to cocaine, which correlates with an upregulation of ΔFosB in brain areas related to the reward circuitry. [ABSTRACT FROM AUTHOR]

Rationale: The low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding. Objective: The objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats. Methods: Levels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats. Results: HS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LS rats, but not in HS animals, while high-dose cocaine augmented activity only in HS rats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HS rats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors. Conclusions: Diminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HS rats and an altered dose-effect relationship for cocaine-induced locomotor activity. [ABSTRACT FROM AUTHOR]

Rationale: Preclinical studies report that free access to a high-fat diet (HFD) alters the response to psychostimulants. Objectives: The aim of the present study was to examine how HFD exposure during adolescence modifies cocaine effects. Gene expression of CB1 and mu-opioid receptors (MOr) in the nucleus accumbens (N Acc) and prefrontal cortex (PFC) and ghrelin receptor (GHSR) in the ventral tegmental area (VTA) were assessed. Methods: Mice were allowed continuous access to fat from PND 29, and the locomotor (10 mg/kg) and reinforcing effects of cocaine (1 and 6 mg/kg) on conditioned place preference (CPP) were evaluated on PND 69. Another group of mice was exposed to a standard diet until the day of post-conditioning, on which free access to the HFD began. Results: HFD induced an increase of MOr gene expression in the N Acc, but decreased CB1 receptor in the N Acc and PFC. After fat withdrawal, the reduction of CB1 receptor in the N Acc was maintained. Gene expression of GHSR in the VTA decreased during the HFD and increased after withdrawal. Following fat discontinuation, mice exhibited increased anxiety, augmented locomotor response to cocaine, and developed CPP for 1 mg/kg cocaine. HFD reduced the number of sessions required to extinguish the preference and decreased sensitivity to drug priming-induced reinstatement. Conclusion: Our results suggest that consumption of a HFD during adolescence induces neurobiochemical changes that increased sensitivity to cocaine when fat is withdrawn, acting as an alternative reward. [ABSTRACT FROM AUTHOR]

Prenatal cocaine exposure (PCE) may increase adolescent substance use through alterations of neurotransmitter systems affecting fetal brain development. The relationship between PCE and substance use at 15 and 17 years was examined. Subjects (365: 186 PCE; 179 non-cocaine exposed (NCE)) supplied biologic and self-report data using the Youth Risk Behavior Surveillance System (YRBSS) and Computerized Diagnostic Interview Schedule for Children (C-DISC 4) at ages 15 and 17. The relationship between PCE and substance use was assessed using General Estimating Equation (GEE) analyses controlling for confounding factors including violence exposure and preschool lead level. Teens with PCE vs. NCE teens were 2 times more likely to use tobacco (OR=2.1; 95% CI 1.21-3.63; p<.001) and marijuana (OR=1.85; CI 1.18-2.91; p<.001) and have a substance use disorder at age 17 (OR=2.51; CI 1.00-6.28; p<.05). Evaluation of PCE status by gender revealed an association between PCE and marijuana use that was more pronounced for boys than girls at 17 years. Violence exposure was also a significant predictor of alcohol (p<.001), tobacco (p<.05), and marijuana (p<.0006) use and substance abuse/dependence (p<.01). Externalizing behavior at age 12 fully mediated the effects of PCE on substance use disorder at age 17 and partially mediated effects of PCE on tobacco use, but did not mediate effects on marijuana use. The percentage of substance use reported increased between 15 and 17 years, with no differences between the PCE and NCE groups. Data suggest specialized drug use prevention measures for children with PCE may benefit this high risk group. [ABSTRACT FROM AUTHOR]

Lewis (LEW) and Fischer 344 (F344) rats are considered a model of genetic vulnerability to drug addiction. We previously showed important differences in spatial learning and memory between them, but in contrast with previous experiments demonstrating cocaine-induced enhanced learning in Morris water maze (MWM) highly demanding tasks, the eight-arm radial maze (RAM) performance was not modified either in LEW or F344 rats after chronic cocaine treatment. In the present work, chronically cocaine-treated LEW and F344 adult rats have been evaluated in learning and memory performance using the Y-maze, two RAM protocols that differ in difficulty, and a reversal protocol that tests cognitive flexibility. After one of the RAM protocols, we quantified dendritic spine density in hippocampal CA1 neurons and compared it to animals treated with cocaine but not submitted to RAM. LEW cocaine treated rats showed a better performance in the Y maze than their saline counterparts, an effect that was not evident in the F344 strain. F344 rats significantly took more time to learn the RAM task and made a greater number of errors than LEW animals in both protocols tested, whereas cocaine treatment induced deleterious effects in learning and memory in the highly difficult protocol. Moreover, hippocampal spine density was cocaine-modulated in LEW animals whereas no effects were found in F344 rats. We propose that differences in addictive-like behavior between LEW and F344 rats could be related to differences in hippocampal learning and memory processes that could be on the basis of individual vulnerability to cocaine addiction. [ABSTRACT FROM AUTHOR]

Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparably rapid change in the ability of cocaine to increase extracellular DA concentrations in the ventral striatum. To address this question we used fast-scan cyclic voltammetry (FSCV) in awake-behaving rats to measure DA responses in the NAc shell following an initial intravenous cocaine injection, and then again 2-h later. Both injections quickly elevated DA levels in the NAc shell, but the second cocaine infusion produced a greater effect than the first, indicating sensitization. This suggests that a single injection of cocaine induces sensitization-related plasticity very rapidly within the mesolimbic DA system. [ABSTRACT FROM AUTHOR]

Cocaine abuse remains a significant worldwide health problem. Patients with cardiovascular toxicity from cocaine abuse frequently present to the emergency department for treatment. These patients may be tachycardic, hypertensive, agitated, and have chest pain. Several pharmacological options exist for treatment of cocaine-induced cardiovascular toxicity. For the past 3 decades, the phenomenon of unopposed α-stimulation after β-blocker use in cocaine-positive patients has been cited as an absolute contraindication, despite limited and inconsistent clinical evidence. In this review, the authors of the original studies, case reports, and systematic review in which unopposed α-stimulation was believed to be a factor investigate the pathophysiology, pharmacology, and published evidence behind the unopposed α-stimulation phenomenon. We also investigate other potential explanations for unopposed α-stimulation, including the unique and deleterious pharmacologic properties of cocaine in the absence of β-blockers. The safety and efficacy of the mixed β-/α-blockers labetalol and carvedilol are also discussed in relation to unopposed α-stimulation. [ABSTRACT FROM AUTHOR]

Rationale and objectives: Among the changes caused by repeated exposure to drugs of abuse, structural rearrangements play a critical role, setting the stage for maladaptive responses to environmental challenges and sustaining drug-taking and drug-seeking behaviors. Given that adolescents are more vulnerable to drug abuse than adults and based on our recent data showing that a single exposure to cocaine during adolescence is sufficient to change the adolescent brain, we decided to investigate whether acute cocaine exposure may alter actin remodeling in reward-related brain regions. Methods: Accordingly, we decided to evaluate if F-actin/G-actin ratio was altered by a single injection of cocaine (20 mg/kg) at postnatal day 35. We also evaluated whether the first administration of cocaine influences such a ratio in response to a second injection (10 mg/kg) provided 24 h or 7 days later. Results: Within the medial prefrontal cortex, a single cocaine injection increases the F-actin/G-actin ratio. This effect lasts 1 week, and it is not affected by the second injection of cocaine, indicating a persistent effect of the first exposure. In the nucleus accumbens, cocaine reduces the F-actin/G-actin ratio 24 h later. Seven days later, instead, such a ratio is markedly increased: notably, the additional exposure to the psychostimulant normalizes the F-actin/G-actin ratio. Conclusions: These results suggest that a single cocaine injection during adolescence causes possible changes in actin dynamics and influences the response to a second challenge of the psychostimulant, indicating that early cocaine priming might affect mechanisms regulating synaptic structural plasticity in specific brain regions [ABSTRACT FROM AUTHOR]

Background Relapse is a two-component process consisting of a highly motivated drug-seeking phase that, if successful, is followed by a drug-using phase resulting in temporary satiation. In rodents, cue-induced drug seeking requires transient synaptic potentiation (t-SP) of cortical glutamatergic synapses on nucleus accumbens core medium spiny neurons, but it is unknown how achieving drug use affects this plasticity. We modeled the two phases of relapse after extinction from cocaine self-administration to assess how cocaine use affects t-SP associated with cue-induced drug seeking. Methods Rats were trained to self-administer cocaine ( n = 96) or were used as yoked-saline control animals ( n = 21). After extinction, reinstatement was initiated by 10 minutes of cue-induced drug seeking, followed by 45 minutes with contingent cocaine access, after which cocaine was discontinued and unreinforced lever pressing ensued. Three measures of t-SP were assayed during reinstatement: dendritic spine morphology, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to N -methyl-D-aspartate (NMDA) ratios, and matrix metalloproteinase activity. Results We found that cocaine use for 10 minutes collapsed all three measures of cue-potentiated t-SP back to baseline. Moreover, when cocaine use was discontinued 45 minutes later, dendritic spine morphology and AMPA to NMDA ratios were restored as animals became motivated to engage unrewarded lever pressing. Nonreinforced drug seeking was positively correlated with changes in spine morphology, and cocaine access reversed this relationship. Conclusions Using a novel modification of the reinstatement paradigm, we show that achieving cocaine use reversed the synaptic plasticity underpinning the motivation to seek the drug. [ABSTRACT FROM AUTHOR]

Background Cocaine use during adolescence increases vulnerability to drug dependence and decreases the likelihood that individuals will seek treatment as adults. Understanding how early-life cocaine exposure influences decision-making processes in adulthood is thus critically important. Methods Adolescent or adult mice were exposed to subchronic cocaine, then behavioral sensitivity to changes in the predictive relationship between actions and their consequences was tested. Dendritic spines on the principal pyramidal neurons of the orbitofrontal prefrontal cortex (oPFC) were also imaged and enumerated. To determine whether cytoskeletal regulatory systems in the oPFC influenced decision-making strategies, we then inhibited the activity of Abl family and Rho kinases as well as NR2B-containing N -methyl-D-aspartate receptors. We also attempted to block the reinstatement of cocaine seeking in cocaine self-administering mice. Results Adult mice with a history of subchronic cocaine exposure in adolescence engaged habit-based response strategies at the expense of goal-directed decision-making strategies and had fewer dendritic spines in the oPFC. Inhibition of the cytoskeletal regulatory Abl family kinases in the oPFC recapitulated these neurobehavioral deficiencies, whereas Rho kinase inhibition corrected response strategies. Additionally, the NR2B-selective N -methyl-D-aspartate receptor antagonists ifenprodil and CP-101,606 blocked cocaine-induced habits; this was dependent on Abl family signaling in the oPFC. Ifenprodil also mitigated cue-induced reinstatement of cocaine seeking in mice self-administering cocaine. Conclusions We suggest that adolescent cocaine exposure confers a bias toward habit-based behavior in adulthood via long-term cellular structural modifications in the oPFC. Treatments aimed at mitigating the durable consequences of early-life cocaine use may benefit from targeting cytoskeletal regulatory systems. [ABSTRACT FROM AUTHOR]

Background Addiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive. Methods Acute cocaine-treated mice were used for quantitative reverse-transcriptase polymerase chain reaction, immunocytochemistry, and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc -deficient mice and their wild-type littermates. Results Arc messenger RNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an extracellular-signal regulated kinase–dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription, where it colocalizes with phospho-Ser10-histone H3, an important component of nucleosomal response. In vitro, Arc overexpression downregulates phospho-Ser10-histone H3 without modifying extracellular-signal regulated kinase phosphorylation in the nucleus. In vivo, Arc -deficient mice display decreased heterochromatin domains, a high RNA-polymerase II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine. Conclusions Cocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction. [ABSTRACT FROM AUTHOR]

Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D 1 - and D 2 -like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1 mg/kg or 25 mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3 mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D 2 -like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3 mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D 2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D 1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated. [ABSTRACT FROM AUTHOR]

In humans, reward cues, including drug cues in individuals experiencing addiction, are especially effective in biasing attention towards them, so much so they can disrupt ongoing task performance. It is not known, however, whether this happens in rats. To address this question, we developed a behavioral paradigm to assess the capacity of an auditory drug (cocaine) cue to evoke cocaine-seeking behavior, thus distracting thirsty rats from performing a well-learned sustained attention task (SAT) to obtain a water reward. First, it was determined that an auditory cocaine cue (tone-CS) reinstated drug-seeking equally in sign-trackers (STs) and goal-trackers (GTs), which otherwise vary in the propensity to attribute incentive salience to a localizable drug cue. Next, we tested the ability of an auditory cocaine cue to disrupt performance on the SAT in STs and GTs. Rats were trained to self-administer cocaine intravenously using an Intermittent Access self-administration procedure known to produce a progressive increase in motivation for cocaine, escalation of intake, and strong discriminative stimulus control over drug-seeking behavior. When presented alone, the auditory discriminative stimulus elicited cocaine-seeking behavior while rats were performing the SAT, but it was not sufficiently disruptive to impair SAT performance. In contrast, if cocaine was available in the presence of the cue, or when administered non-contingently, SAT performance was severely disrupted. We suggest that performance on a relatively automatic, stimulus-driven task, such as the basic version of the SAT used here, may be difficult to disrupt with a drug cue alone. A task that requires more top-down cognitive control may be needed. [ABSTRACT FROM AUTHOR]

Rationale: Synthetic cathinones are chemical derivatives of cathinone that are pharmacologically similar to cocaine and methamphetamine. Recently, abuse of synthetic cathinones among young people has increased. Objectives: The present study aimed to characterize the behavioral effects of alpha-pyrrolidinopentiothiophenone (PVT), an analog of alpha-pyrrolidinovalerophenone and second-generation synthetic cathinone, as well as to evaluate its abuse potential, using conditioned place preference, intravenous self-administration (SA), and drug discrimination paradigms in rodent models. Results: Alpha-PVT produced a significant place preference in mice at doses of 10, 30, and 50 mg/kg. In the SA experiment, alpha-PVT (0.1, 0.3, and 1.0 mg/kg/infusion) produced an inverted U-shaped dose-effect curve in rats. Under a progressive ratio schedule of reinforcement, there appeared to be a positive relationship between alpha-PVT dose and the breakpoints for alpha-PVT reinforcement. Additionally, alpha-PVT fully substituted for the discriminative stimulus effects of both cocaine and methamphetamine in rats. Conclusions: Our results indicate that alpha-PVT has rewarding and reinforcing effects and shares the interoceptive effects of cocaine and methamphetamine. To the best of our knowledge, the present study is the first to show that alpha-PVT has reinforcing properties when delivered on its own, which suggests possible abuse liability in humans. [ABSTRACT FROM AUTHOR]

Rationale We have previously demonstrated that treatment with ziprasidone and aripiprazole selectively inhibit the development of behavioral sensitization to cocaine in mice. We now investigate their effects on a counter-conditioning strategy in mice and the importance of the treatment environment for this phenomenon. Objective Evaluate the context-specificity of ziprasidone and aripiprazole on conditioned locomotion to cocaine and cocaine-induced hyperlocomotion and behavioral sensitization in a counter-conditioning strategy in mice. Methods Animals were sensitized with saline or cocaine injections in the open-field apparatus in a 15-day intermittent treatment and subsequently treated with vehicle, 5 mg/kg ziprasidone or 0.1 mg/kg aripiprazole paired to the open-field or the home-cage for 4 alternate days. Mice were then challenged with saline and cocaine in the open-field apparatus on subsequent days. Results While treatment with ziprasidone decreased spontaneous locomotion and conditioned locomotion alike, treatment with aripiprazole specifically attenuated the expression of conditioned hyperlocomotion to cocaine. Ziprasidone and aripiprazole had no effects on cocaine-induced conditioned hyperlocomotion observed during saline challenge after drug withdrawal. Treatment with either ziprasidone or aripiprazole when previously given in the cocaine-paired environment attenuated the subsequent expression of behavioral sensitization to cocaine. Animals treated with aripiprazole in the open-field, but not in the home-cage, showed a blunted response to cocaine when receiving a cocaine challenge for the first time. Conclusions Both neuroleptic drugs showed a context-dependent effectiveness in attenuating long-term expression of cocaine-induced behavioral sensitization when administered in the cocaine-associated environment, with aripiprazole also showing effectiveness in blocking the expression of acute cocaine effects. [ABSTRACT FROM AUTHOR]

Rationale: Cocaine produces significant aversive/anxiogenic actions whose underlying neurobiology remains unclear. A possible substrate contributing to these actions is the serotonergic (5-HT) pathway projecting from the dorsal raphé (DRN) to regions of the extended amygdala, including the bed nucleus of the stria terminalis (BNST) which have been implicated in the production of anxiogenic states. Objectives: The present study examined the contribution of 5-HT signaling within the BNST to the anxiogenic effects of cocaine as measured in a runway model of drug self-administration. Methods: Male Sprague-Dawley rats were fitted with bilateral infusion cannula aimed at the BNST and then trained to traverse a straight alley once a day for a single 1 mg/kg i.v. cocaine infusion delivered upon goal-box entry on each of 16 consecutive days/trials. Intracranial infusions of CP 94,253 (0, 0.25, 0.5, or 1.0 μg/side) were administered to inhibit local 5-HT release via activation of 5-HT autoreceptors. To confirm receptor specificity, the effects of this treatment were then challenged by co-administration of the selective 5-HT antagonist NAS-181. Results: Intra-BNST infusions of the 5-HT autoreceptor agonist attenuated the anxiogenic effects of cocaine as reflected by a decrease in runway approach-avoidance conflict behavior. This effect was reversed by the 5-HT antagonist. Neither start latencies (a measure of the subject's motivation to seek cocaine) nor spontaneous locomotor activity (an index of motoric capacity) were altered by either treatment. Conclusions: Inhibition of 5-HT signaling within the BNST selectively attenuated the anxiogenic effects of cocaine, while leaving unaffected the positive incentive properties of the drug. [ABSTRACT FROM AUTHOR]

Rationale: Individuals prone to attribute incentive salience to food-associated stimuli ('cues') are also more sensitive to cues during drug seeking and drug taking. This may be due in part to a difference in sensitivity to the affective or other stimulus properties of the drug. In rats, these properties are associated with 50-kHz ultrasonic vocalizations (USVs), in that they are elicited during putative positive affective and motivational states, including in response to drugs of abuse. Objectives: We sought to determine whether individual differences in the tendency to attribute incentive salience to a food cue (as measured by approach) were associated with differences in cocaine-induced USVs. We also tested whether the food cue would elicit USVs and if this response was related to approach to the food cue. Methods: In experiment 1, rats underwent Pavlovian conditioned approach (PavCA) training where they learned to associate a cue (an illuminated lever) with the delivery of a food pellet into a food cup. Subjects were categorized based on their approach to the cue ('sign-trackers') or to the food cup ('goal-trackers'). Rats subsequently underwent nine testing days in which they were given saline or cocaine (10 mg/kg i.p) and placed into a locomotor chamber. In experiment 2, rats were first tested in the locomotor chambers for one saline-treated day followed by one cocaine-treated day and then trained in PavCA. USVs were recorded from a subset of individuals during the last day of PavCA to determine if the food cue would elicit USVs. Results: Sign-trackers produced 5-24 times more cocaine-induced 50 kHz USVs compared to goal-trackers for all days of experiment 1, and this response sensitized with repeated cocaine, only in sign-trackers. Similarly in experiment 2, individuals that produced the most cocaine-induced USVs on a single exposure also showed the greatest tendency to sign-track during PavCA. Lastly, while sign-trackers produced more USVs during PavCA generally, the cue itself did not elicit additional USVs in sign- or goal-trackers. Conclusions: These results indicate a robust and consistent relationship between approach to a food cue and cocaine-induced USV production. Thus, these USVs may index the neurobiological differences underlying the behavioral distinctions of sign- and goal-trackers. [ABSTRACT FROM AUTHOR]

Rationale: In order to improve understanding of the nature of drug-associated memory, the current studies addressed whether conditioned place preference (CPP) could develop under conditions in which there was a delay between presentation of context and drug exposure (i.e., retrograde or trace conditioning). Objectives: The objective was to assess development of CPP when cocaine or methamphetamine was injected simultaneously with exposure to a salient context (S+), or after delays differing in length. Methods: Dose response curves for conventional CPP were established using separate groups of Swiss-Webster mice injected with cocaine or methamphetamine just prior to S+ exposure. To assess the development of retrograde CPP, other groups received trace conditioning, where cocaine (15 mg/kg) or methamphetamine (0.5 mg/kg) was injected after a delay of 15, 60, 120, 180, 240, or 480 min following the end of the S+ session. Results: Mice receiving conventional CPP with cocaine or methamphetamine during S+ showed significant place preference. None of the groups receiving delayed methamphetamine showed significant CPP; however, CPP was evident in mice receiving cocaine after delays of up to 4 h following S+. In a separate study, delayed methamphetamine also did not result in significant place preference when presented in doses of 0.25 or 1 mg/kg. Conclusions: These results suggest that psychostimulant drug taking may be broadly generalized to context through retrograde association with events in recent memory, a factor that may contribute to drug-seeking and relapse following abstinence. [ABSTRACT FROM AUTHOR]

Several behavioral findings highlight the importance of glutamatergic transmission and its metabotropic receptor type 5 (mGlu 5 ) in the controlling of cocaine reward and seeking behaviors. The molecular or neurochemical nature of such interactions is not well recognized, so in the present paper we determine if cocaine self-administration and extinction/reinstatement models with the yoked triad control procedure alter mGlu 5 receptor density in rats. [³H]MPEP was used to evaluate mGlu 5 receptors density and affinity in selected brain structures, while immunofluorescence analysis was used to detect changes in mGlu 5 receptors’ brain location. Cocaine self-administration and yoked cocaine delivery evoked a significant elevation in mGlu 5 receptors’ density in the dorsal striatum, while receptor protein expression was importantly elevated in the substantia nigra and reduced in the nucleus accumbens shell. Cocaine administration followed by 10 extinction training sessions resulted in biphasic mGlu 5 receptor density changes in the prefrontal cortex-nucleus accumbens pathway. mGlu 5 receptors’ up-regulation was noted for cocaine self-administration and extinction training in the hippocampus and in yoked cocaine controls following drug abstinence in the dorsal striatum. A cocaine priming dose (but not a saline priming) resulted in a significant decrease of mGlu 5 receptors’ density in the nucleus accumbens of rats previously treated with the drug and in the hippocampus of rats previously self-administered cocaine. The latter decrease in mGlu 5 receptors’ density and protein expression in the hippocampus was parallel to an increase in [³H]MPEP affinity and opposite to a rise observed after single cocaine administration (ip) to drug-naïve yoked saline controls. Additionally, we also observed a significant elevation in the protein expression of the tested receptors in the limbic cortex in both cocaine groups. The present results shown modality dependent and brain-region specific changes in mGlu 5 receptors’ localization and membrane specific binding. [ABSTRACT FROM AUTHOR]

N-methyl- d -aspartate receptors (NMDARs) are profound regulators of glutamate neurotransmission and behavior. To coordinate components of the limbic system, the dorsal and ventral striatum integrate cognitive and emotional information towards the execution of complex behaviors. Striatal outflow is conveyed by medium spiny neurons (MSNs), which can be dichotomized by expression of dopamine receptor subtype 1 (D1) or adenosine receptor subtype 2A (A2A). To examine how striatal NMDAR function modulates reward-related behaviors, we generated D1- and A2A-specific genetic deletions of the obligatory GluN1 subunit. Interestingly, we observed no differences in any GluN1 −/− genotype in reward learning as assessed by acquisition or extinction of cocaine conditioned place preference (CPP). Control and A2A-GluN −/− mice exhibited robust cocaine-primed reinstatement, however this behavior was markedly absent in D1-GluN −/− mice. Interestingly, dual D1-/A2A-GluN −/− mice displayed an intermediate reinstatement phenotype. Next, we examined models of exploration, anxiety, and despair, states often associated with relapse to addiction-related behavior, to determine NMDAR contribution in D1 and A2A cell types to these behaviors. D1-GluN1 −/− mice displayed aberrant exploratory locomotion in a novel environment, but the phenotype was absent in dual D1/A2A-GluN1 −/− mice. In contrast A2A-GluN1 −/− mice displayed a despair-resistant phenotype, and this phenotype persisted in dual D1/A2A-GluN −/− mice. These data support the hypothesis that cell type-specific NMDAR signaling regulates separable behavioral outcomes related to locomotion, despair, and relapse. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’. [ABSTRACT FROM AUTHOR]

The presence of companions renders decreases in cocaine-stimulated dopamine release in the nucleus accumbens and cocaine-induced conditioned place preference (CPP) magnitude. Limbic systems are widely believed to underlie the modulation of accumbal dopamine release and cocaine conditioning. Thus, this study aimed to assess whether intact basolateral nucleus of amygdala (BLA), dorsal hippocampus (DH), and dorsolateral striatum (DLS) is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Three cage mates, serving as companions, were arranged to house with the experimental mice in the cocaine conditioning compartment throughout the cocaine conditioning sessions. Approximately 1 week before the conditioning procedure, intracranial ibotenic acid infusions were done in an attempt to cause excitotoxic lesions targeting bilateral BLA, DH and DLS. Albeit their BLA, DH, and DLS lesions, the lesioned mice exhibited comparable cocaine-induced CPP magnitudes compared to the intact and sham lesion controls. Bilateral BLA, but not DH or DLS, lesions abolished the companions-exerted suppressive effect on the cocaine-induced CPP. Intact mice receiving intra-BLA infusion of raclopride, a selective D2 antagonist, 30 min prior to the cocaine conditioning did not exhibit the companions-exerted suppressive effect on the cocaine-induced CPP. Intra-BLA infusion of Sch23390, a selective D1 antagonist, did not affect the companions-exerted suppressive effect on the CPP. These results, taken together, prompt us to conclude that the intactness of BLA is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Importantly, activation of D2 receptor in the BLA is required for such suppressive effect on the CPP. [ABSTRACT FROM AUTHOR]

Cocaine self-administration induces dysfunctional neuroadaptations in the prefrontal cortex that underlie relapse to cocaine-seeking. Cocaine self-administration disturbs glutamatergic transmission in the nucleus accumbens that is prevented by infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic area of the prefrontal cortex. Intra-prelimbic infusion of BDNF decreases cocaine-seeking in a TrkB-ERK MAP kinase-dependent manner. Neuronal activity triggers an interaction between TrkB receptors and NMDA receptors, leading to ERK activation. In the present study, infusion of the GluN2A-containing NMDA receptor antagonist, TCN-201, or the GluN2B-containing NMDA receptor antagonist, Ro-25-6981, into the prelimbic cortex of rats blocked the suppressive effect of BDNF on cocaine-seeking. During early withdrawal from cocaine self-administration, tyrosine phosphorylation of ERK, GluN2A, and GluN2B in the prelimbic cortex was reduced and this reduction of phospho-proteins was prevented by intra-prelimbic BDNF infusion. TCN-201 infusion into the prelimbic cortex inhibited the BDNF-mediated increase in pERK and pGluN2A whereas Ro-25-6981 infusion into the prelimbic cortex blocked BDNF-induced elevation of pERK and pGluN2B, indicating that both GluN2A- and GluN2B-containing NMDA receptors underlie BDNF-induced ERK activation. These data demonstrate that BDNF-mediated activation of GluN2A- and GluN2B-containing NMDA receptors underlies ERK activation in the prelimbic cortex during early withdrawal, preventing subsequent relapse to cocaine-seeking. [ABSTRACT FROM AUTHOR]