Nucleus accumbens neuronal ensembles vary with cocaine reinforcement in male and female rats.

Neuronal ensembles in the medial prefrontal cortex mediate cocaine self-administration via projections to the nucleus accumbens. We have recently shown that neuronal ensembles in the prelimbic cortex form rapidly to mediate cocaine self-administration. However, the role of neuronal ensembles within the nucleus accumbens in initial cocaine-seeking behaviour remains unknown. Here, we sought to expand the current literature by testing the necessity of the cocaine self-administration ensemble in the nucleus accumbens core (NAcCore) 1 day after male and female rats acquire cocaine self-administration by using the Daun02 inactivation procedure. We found that disrupting the NAcCore ensembles after a no-cocaine reward-seeking test increased subsequent cocaine seeking, while disrupting NAcCore ensembles following a cocaine self-administration session decreased subsequent cocaine seeking. We then characterized neuronal cell type in the NAcCore using RNAscope in situ hybridization. In the no-cocaine session, we saw reduced dopamine D1 type neuronal activation, while in the cocaine self-administration session, we found preferential dopamine D1 type neuronal activity in the NAcCore.

Intrinsic connectivity demonstrates a shared role of the posterior cingulate for cue reactivity in both gambling and cocaine use disorders.

Cue reactivity is relevant across addictive disorders as a process relevant to maintenance, relapse, and craving. Understanding the neurobiological foundations of cue reactivity across substance and behavioral addictions has important implications for intervention development. The present study used intrinsic connectivity distribution methods to examine functional connectivity during a cue-exposure fMRI task involving gambling, cocaine and sad videos in 22 subjects with gambling disorder, 24 with cocaine use disorder, and 40 healthy comparison subjects. Intrinsic connectivity distribution implicated the posterior cingulate cortex (PCC) at a stringent whole-brain threshold. Post-hoc analyses investigating the nature of the findings indicated that individuals with gambling disorder and cocaine use disorder exhibited decreased connectivity in the posterior cingulate during gambling and cocaine cues, respectively, as compared to other cues and compared to other groups. Brain-related cue reactivity in substance and behavioral addictions involve PCC connectivity in a content-to-disorder specific fashion. The findings suggesting that PCC-related circuitry underlies cue reactivity across substance and behavioral addictions suggests a potential biomarker for targeting in intervention development.

Tmod2 Is a Regulator of Cocaine Responses through Control of Striatal and Cortical Excitability and Drug-Induced Plasticity.

Drugs of abuse induce neuroadaptations, including synaptic plasticity, that are critical for transition to addiction, and genes and pathways that regulate these neuroadaptations are potential therapeutic targets. Tropomodulin 2 (Tmod2) is an actin-regulating gene that plays an important role in synapse maturation and dendritic arborization and has been implicated in substance abuse and intellectual disability in humans. Here, we mine the KOMP2 data and find that Tmod2 knock-out mice show emotionality phenotypes that are predictive of addiction vulnerability. Detailed addiction phenotyping shows that Tmod2 deletion does not affect the acute locomotor response to cocaine administration. However, sensitized locomotor responses are highly attenuated in these knock-outs, indicating perturbed drug-induced plasticity. In addition, Tmod2 mutant animals do not self-administer cocaine indicating lack of hedonic responses to cocaine. Whole-brain MR imaging shows differences in brain volume across multiple regions, although transcriptomic experiments did not reveal perturbations in gene coexpression networks. Detailed electrophysiological characterization of Tmod2 KO neurons showed increased spontaneous firing rate of early postnatal and adult cortical and striatal neurons. Cocaine-induced synaptic plasticity that is critical for sensitization is either missing or reciprocal in Tmod2 KO nucleus accumbens shell medium spiny neurons, providing a mechanistic explanation of the cocaine response phenotypes. Combined, these data, collected from both males and females, provide compelling evidence that Tmod2 is a major regulator of plasticity in the mesolimbic system and regulates the reinforcing and addictive properties of cocaine.

Cuadros cutáneo-mucosos asociados al consumo de cocaína / Cutaneous and Mucosal Conditions Associated With Cocaine Use

El consumo de cocaína, junto con algunos de sus adulterantes más frecuentes como el levamisol, puede provocar múltiples procesos cutáneos y mucosos, ya sean de índole isquémico, dermatosis neutrofílicas, lesiones destructivas de la línea media y vasculitis asociadas a ANCA, entre otros. Generalmente no se asocia clínica sistémica llamativa.Todos estos cuadros pueden presentar anticuerpos antinucleares, antifosfolípido y contra distintos antígenos de los neutrófilos, en ocasiones con un patrón característico. El estudio histológico suele mostrar cambios vasculares como vasculitis leucocitoclástica, necrosis de la pared y trombos. En este artículo revisamos las características clínicas, serológicas e histológicas de estas entidades, junto con los mecanismos fisiopatológicos implicados, el diagnóstico diferencial y su tratamiento. (AU)

Cocaine and some of its main adulterants, such as levamisole, can cause multiple cutaneous and mucosal manifestations, including ischemic complications, neutrophilic dermatoses, midline destructive lesions, and vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). Striking systemic symptoms are generally not seen.In all these conditions, positive test results may be observed for antinuclear antibodies, antiphospholipid antibodies, and various ANCAs, sometimes with characteristic staining patterns. Histology typically shows vascular changes, such as leukocytoclastic vasculitis, necrotizing vasculitis, and thrombi. We review the clinical, serologic, and histologic features of cutaneous and mucosal conditions associated with the use of cocaine and also look at pathophysiologic mechanisms, differential diagnoses, and treatments. (AU)

[Translated article] Cutaneous and Mucosal Conditions Associated With Cocaine Use / Cuadros cutáneo-mucosos asociados al consumo de cocaína

Cocaine and some of its main adulterants, such as levamisole, can cause multiple cutaneous and mucosal manifestations, including ischemic complications, neutrophilic dermatoses, midline destructive lesions, and vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). Striking systemic symptoms are generally not seen. In all these conditions, positive test results may be observed for antinuclear antibodies, antiphospholipid antibodies, and various ANCAs, sometimes with characteristic staining patterns. Histology typically shows vascular changes, such as leukocytoclastic vasculitis, necrotizing vasculitis, and thrombi. We review the clinical, serologic, and histologic features of cutaneous and mucosal conditions associated with the use of cocaine and also look at pathophysiologic mechanisms, differential diagnoses, and treatments. (AU)

El consumo de cocaína, junto con algunos de sus adulterantes más frecuentes como el levamisol, puede provocar múltiples procesos cutáneos y mucosos, ya sean de índole isquémico, dermatosis neutrofílicas, lesiones destructivas de la línea media y vasculitis asociadas a ANCA, entre otros. Generalmente no se asocia clínica sistémica llamativa. Todos estos cuadros pueden presentar anticuerpos antinucleares, antifosfolípido y contra distintos antígenos de los neutrófilos, en ocasiones con un patrón característico. El estudio histológico suele mostrar cambios vasculares, como vasculitis leucocitoclástica, necrosis de la pared y trombos. En este artículo revisamos las características clínicas, serológicas e histológicas de estas entidades, junto con los mecanismos fisiopatológicos implicados, el diagnóstico diferencial y su tratamiento. (AU)

Silent Synapses in Cocaine-Associated Memory and Beyond.

Glutamatergic synapses are key cellular sites where cocaine experience creates memory traces that subsequently promote cocaine craving and seeking. In addition to making across-the-board synaptic adaptations, cocaine experience also generates a discrete population of new synapses that selectively encode cocaine memories. These new synapses are glutamatergic synapses that lack functionally stable AMPARs, often referred to as AMPAR-silent synapses or, simply, silent synapses. They are generated de novo in the NAc by cocaine experience. After drug withdrawal, some of these synapses mature by recruiting AMPARs, contributing to the consolidation of cocaine-associated memory. After cue-induced retrieval of cocaine memories, matured silent synapses alternate between two dynamic states (AMPAR-absent vs AMPAR-containing) that correspond with the behavioral manifestations of destabilization and reconsolidation of these memories. Here, we review the molecular mechanisms underlying silent synapse dynamics during behavior, discuss their contributions to circuit remodeling, and analyze their role in cocaine-memory-driven behaviors. We also propose several mechanisms through which silent synapses can form neuronal ensembles as well as cross-region circuit engrams for cocaine-specific behaviors. These perspectives lead to our hypothesis that cocaine-generated silent synapses stand as a distinct set of synaptic substrates encoding key aspects of cocaine memory that drive cocaine relapse.

Association between alcohol and crack: Prevalence, effects, associated factors and experiences of combined use.

OBJECTIVE: To estimate the prevalence and factors associated with the effect of alcohol on crack cocaine use and to analyze experiences related to combined use. Materials and methods: sequential mixed methods (qualitative and quantitative) research, carried out between August 2014 and August 2015 with people who use crack. In the quantitative approach, a cross-sectional study was conducted with 1,062 participants. Factors associated with "alcohol use with the effect of increasing the effect of crack/crack craving" were estimated by multiple regression. In the qualitative approach, 39 interviews were conducted using Bardin's content analysis technique. RESULTS: 871 (82.0%) participants reported consuming alcohol, among them, 668 (76.7%) used alcohol combined with crack: 219 (32.8%) reported feeling an effect of reduction in paranoia and/or crack craving and 384 (57.5%) reported feeling an increase in the effect of crack and in the craving to consume the drug. This relationship was also observed in the narratives of the people who use crack, with the possibility of a cyclic effect of consumption of the two substances. Those who related alcohol use to the effect of increasing crack craving (384) were more likely to use alcohol before crack (OR: 1.81; 95%CI: 1.13-2.89); to consume more than 20 stones daily (OR: 1.48; 95%CI: 1.01-2.16); to remain in abstinence from crack for less than one month (OR: 3.20; 95%CI: 1.91-5.35); to use dependence treatment services (OR: 1.85; 95%CI: 1.26-2.71); and to commit physical violence (OR:1.67; 95%CI:1.08-2.56). CONCLUSION: The findings of this study indicate that the modulation of the effect of alcohol use on crack cocaine depends on the moment when the drugs are consumed, and the use of alcohol before crack consumption is associated with characteristics that suggest a greater vulnerability to patterns of harmful crack use. Even though combined use is referred to as a way of reducing the negative effects of crack, the damage of this association may be greater than its possible benefits.

Enhancement of the GluN2B subunit of glutamatergic NMDA receptors in rat brain areas after cocaine abstinence.

BACKGROUND: Cocaine use disorder is associated with compulsive drug-seeking and drug-taking, whereas relapse may be induced by several factors, including stress, drug-related places, people, and cues. Recent observations strongly support the involvement of the N-methyl-D-aspartate (NMDA) receptors in cocaine use disorders and abstinence, whereas withdrawal in different environments may affect the intensification of relapse. METHODS: The aim of this study was to examine the GluN2B subunit expression and its association with the postsynaptic density protein 95 (PSD95) in several brain structures in rats with a history of cocaine self-administration and housed either in an enriched environment or in an isolated condition. Furthermore, a selective antagonist of the GluN2B subunit-CP 101,606 (10 and 20 mg/kg) administered during exposure to cocaine or a drug-associated conditional stimulus (a cue) was used to evaluate seeking behavior in rats. RESULTS: In rats previously self-administering cocaine, we observed an increase in the GluN2B expression in the total homogenate from the dorsal hippocampus under both enriched environment and isolation. Cocaine abstinence under isolation conditions increased the GluN2B and GluN2B/PSD95 complex levels in the PSD fraction of the prelimbic cortex in rats previously self-administering cocaine. Administration of CP 101,606 attenuated cue-induced cocaine-seeking behavior only in isolation-housed rats. CONCLUSION: In summary, in this study we showed region-specific changes in both the expression of GluN2B subunit and NMDA receptor trafficking during cocaine abstinence under different housing conditions. Furthermore, we showed that the pharmacological blockade of the GluN2B subunit may be useful in attenuating cocaine-seeking behavior.

Impaired Learning From Negative Feedback in Stimulant Use Disorder: Dopaminergic Modulation.

BACKGROUND: Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. METHODS: We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. RESULTS: Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. CONCLUSION: Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.

Spontaneously Hypertensive Rat substrains show differences in model traits for addiction risk and cocaine self-administration: Implications for a novel rat reduced complexity cross.

Forward genetic mapping of F2 crosses between closely related substrains of inbred rodents - referred to as a reduced complexity cross (RCC) - is a relatively new strategy for accelerating the pace of gene discovery for complex traits, such as drug addiction. RCCs to date were generated in mice, but rats are thought to be optimal for addiction genetic studies. Based on past literature, one inbred Spontaneously Hypertensive Rat substrain, SHR/NCrl, is predicted to exhibit a distinct behavioral profile as it relates to cocaine self-administration traits relative to another substrain, SHR/NHsd. Direct substrain comparisons are a necessary first step before implementing an RCC. We evaluated model traits for cocaine addiction risk and cocaine self-administration behaviors using a longitudinal within-subjects design. Impulsive-like and compulsive-like traits were greater in SHR/NCrl than SHR/NHsd, as were reactivity to sucrose reward, sensitivity to acute psychostimulant effects of cocaine, and cocaine use studied under fixed-ratio and tandem schedules of cocaine self-administration. Compulsive-like behavior correlated with the acute psychostimulant effects of cocaine, which in turn correlated with cocaine taking under the tandem schedule. Compulsive-like behavior also was the best predictor of cocaine seeking responses. Heritability estimates indicated that 22 %-40 % of the variances for the above phenotypes can be explained by additive genetic factors, providing sufficient genetic variance to conduct genetic mapping in F2 crosses of SHR/NCrl and SHR/NHsd. These results provide compelling support for using an RCC approach in SHR substrains to uncover candidate genes and variants that are of relevance to cocaine use disorders.

Attention bias modification in drug addiction: Enhancing control of subsequent habits.

A relapse in addiction is often precipitated by heightened attention bias to drug-related cues, underpinned by a subcortically mediated transition to habitual/automatized responding and reduced prefrontal control. Modification of such automatized attention bias is a fundamental, albeit elusive, target for relapse reduction. Here, on a trial-by-trial basis, we used electroencephalography and eye tracking with a task that assessed, in this order, drug cue reactivity, its instructed self-regulation via reappraisal, and the immediate aftereffects on spontaneous (i.e., not instructed and automatized) attention bias. The results show that cognitive reappraisal, a facet of prefrontal control, decreased spontaneous attention bias to drug-related cues in cocaine-addicted individuals, more so in those with less frequent recent use. The results point to the mechanisms underlying the disruption of automatized maladaptive drug-related attention bias in cocaine addiction. These results pave the way for future studies to examine the role of such habit disruption in reducing compulsive drug seeking outside the controlled laboratory environment, with the ultimate goal of developing a readily deployable cognitive-behavioral and personalized intervention for drug addiction.

Assessing combinatorial effects of HIV infection and former cocaine dependence on cognitive control processes: A high-density electrical mapping study of response inhibition.

Stimulant drug use in HIV + patients is associated with poor personal and public health outcomes, including high-risk sexual behavior and faster progression from HIV to AIDS. Inhibitory control--the ability to withhold a thought, feeling, or action--is a central construct involved in the minimization of risk-taking behaviors. Recent neuroimaging and behavioral evidence indicate normalization of inhibitory control processes in former cocaine users as a function of the duration of drug abstinence, but it is unknown whether this recovery trajectory persists in former users with comorbid HIV. Here, we investigate the neural correlates of inhibitory control in 103 human subjects using high-density EEG recording as participants performed a Go/NoGo response inhibition task. Four groups of participants were recruited, varying on HIV and cocaine-dependence status. Electrophysiological responses to successful inhibitions and behavioral task performance were compared among groups. Results indicate persistent behavioral and neurophysiological impairment in HIV+ patients' response inhibition despite current abstinence from cocaine. Analysis of task performance showed that HIV+ abstinent cocaine-dependent participants demonstrate the lowest performance of all groups across all metrics of task accuracy. Planned comparisons of electrophysiological components revealed a main effect of scalp site and an interaction between HIV-status and scalp site on N2 amplitudes during successful inhibitions. Analysis of the P3 time region showed a main effect of scalp site and an interaction between HIV-status and cocaine dependence. These results suggest synergistic alterations in the neurophysiology of response inhibition and indicate that abstinence-related recovery of inhibitory control may be attenuated in patients with HIV.

Increased cocaine motivation in tree shrews is modulated by striatal dopamine D1 receptor-mediated upregulation of Cav 1.2.

The progressively increased motivation for cocaine during abstinence is closely associated with the dysfunction of dopamine (DA) system. As DA receptors also dynamically regulate L-type calcium channels (LTCCs), in this study we examined how DA receptors (D1R or D2R) and LTCCs (Cav 1.2 or Cav 1.3) exert their influences on cocaine-seeking in a tree shrew (Tupaia belangeri chinensis) model. First, we demonstrated the 'incubation' effect by showing tree shrews exhibited a significantly higher seeking behaviour on withdrawal day (WD) 45 than on WD1. Then, we confirmed that longer abstinence period induced higher D1R expression in the nucleus accumbens (NAc). Next, we showed that LTCCs in the NAc participated in drug seeking. Moreover, Cav 1.2 expression in the NAc was increased on WD45, and disruption of the Cav 1.2 inhibited drug seeking. Finally, we found that D1R antagonist blocked the increase of Cav 1.2 on drug-seeking test. Collectively, these findings suggest that D1R-mediated upregulation of Cav 1.2 is involved in the incubation of cocaine craving.

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats.

BACKGROUND: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. AIMS: We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. METHODS: Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21-60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions). RESULTS: Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion. CONCLUSIONS: CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT1BR agonists may have clinical efficacy as anti-relapse medications for cocaine use disorders.

Effects of cocaine and HIV on decision-making abilities.

Our study aimed to understand the impact of cocaine dependence on high-risk decision-making abilities in individuals with the human immunodeficiency virus (HIV) and individuals with cocaine dependence. We recruited 99 participants (27 HIV/Cocaine, 20 HIV Only, 26 Cocaine Only, and 26 Healthy Controls). The Iowa Gambling Task (IGT) was applied to assess decision-making abilities. Independent and interactive effects of HIV status and cocaine dependence were examined using 2 × 2 factorial ANCOVA with premorbid IQ (WRAT-4: WR) as the covariate. We found cocaine dependence had a significant adverse effect on overall IGT performance (p = 0.015). We also found individuals who were HIV-positive tended to have less total money at the end of the game than individuals who were HIV-negative (p = 0.032), suggesting individuals living with HIV had less focus on long-term gains and more focus on short-term gains. Our findings highlight the significant impact of cocaine dependence on decision-making abilities and the difficulty individuals with HIV have in adequately weighing the cost and benefits of their decisions and making appropriate changes for the future.

The sensation seeking trait confers a dormant susceptibility to addiction that is revealed by intermittent cocaine self-administration in rats.

Heightened sensation seeking is associated with an increased risk of substance use disorder in clinical populations. In rats, sensation seeking is often examined by measuring locomotor reactivity to a novel environment. So-called high responders (HR) acquire self-administration of psychostimulants more quickly and consume higher amounts of drug compared to low responder (LR) rats, indicating that the HR trait might confer a stronger addiction propensity. However, studies of addiction-like behaviors in HR vs LR rats have typically utilized self-administration paradigms that do not dissociate individual differences in the hedonic/reinforcing and motivational properties of a drug. Moreover, little attention has been given to whether HR rats are more susceptible to drug-access conditions that promote a state-dependent addiction phenotype. We report that on a behavioral economics task, HR rats have higher preferred brain-cocaine levels compared to LR rats but do not differ with respect to their demand elasticity for cocaine. In contrast, when tested on an intermittent access schedule of cocaine self-administration, which has been shown to promote several addiction-related endophenotypes, HR rats exhibit greater escalation of intake and more drastic reductions in cocaine demand elasticity. Together, these data indicate that the HR trait does not confer higher extant addiction behavior, but rather that this phenotype is associated with a propensity for addiction that remains dormant until it is actuated by intermittent drug intake. These findings reveal a 'trait' (HR) by 'state' (intermittent drug intake) interaction that produces a strong addiction-like phenotype. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.

Reward-Related Responses and Tonic Craving in Cocaine Addiction: An Imaging Study of the Monetary Incentive Delay Task.

BACKGROUND: Cocaine addiction is associated with altered sensitivity to natural reinforcers and intense drug craving. However, previous findings on reward-related responses were mixed, and few studies have examined whether reward responses relate to tonic cocaine craving. METHODS: We combined functional magnetic resonance imaging and a monetary incentive delay task to investigate these issues. Imaging data were processed with published routines, and the results were evaluated with a corrected threshold. We compared reward responses of 50 cocaine-dependent individuals (CDs) and 45 healthy controls (HCs) for the ventral striatum (VS) and the whole brain. We also examined the regional responses in association with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ) in CDs. We performed mediation analyses to evaluate the relationship between regional responses, CCQ score, and recent cocaine use. RESULTS: The VS showed higher activation to large as compared with small or no wins, but this reward-related activity did not differ between CDs and HCs. The precentral gyrus (PCG), anterior insula, and supplementary motor area showed higher activation during large vs no wins in positive correlation with the CCQ score in CDs. Mediation analyses suggested that days of cocaine use in the prior month contributed to higher CCQ scores and, in turn, PCG reward responses. CONCLUSIONS: The results highlight a unique relationship between reward responses of the primary motor cortex, tonic cocaine craving, and recent cocaine use. The motor cortex may partake in the cognitive motor processes critical to drug-seeking behavior in addicted individuals.

Synaptic Adaptations at the Rostromedial Tegmental Nucleus Underlie Individual Differences in Cocaine Avoidance Behavior.

Although cocaine is powerfully rewarding, not all individuals are equally prone to abusing this drug. We postulate that these differences arise in part because some individuals exhibit stronger aversive responses to cocaine that protect them from cocaine seeking. Indeed, using conditioned place preference (CPP) and a runway operant cocaine self-administration task, we demonstrate that avoidance responses to cocaine vary greatly between individual high cocaine-avoider and low cocaine-avoider rats. These behavioral differences correlated with cocaine-induced activation of the rostromedial tegmental nucleus (RMTg), measured using both in vivo firing and c-fos, whereas slice electrophysiological recordings from ventral tegmental area (VTA)-projecting RMTg neurons showed that relative to low avoiders, high avoiders exhibited greater intrinsic excitability, greater transmission via calcium-permeable AMPA receptors (CP-AMPARs), and higher presynaptic glutamate release. In behaving animals, blocking CP-AMPARs in the RMTg with NASPM reduced cocaine avoidance. Hence, cocaine addiction vulnerability may be linked to multiple coordinated synaptic differences in VTA-projecting RMTg neurons.SIGNIFICANCE STATEMENT Although cocaine is highly addictive, not all individuals exposed to cocaine progress to chronic use for reasons that remain unclear. We find that cocaine's aversive effects, although less widely studied than its rewarding effects, show more individual variability, are predictive of subsequent propensity to seek cocaine, and are driven by variations in RMTg in response to cocaine that arise from distinct alterations in intrinsic excitability and glutamate transmission onto VTA-projecting RMTg neurons.

Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking.

In individuals with substance use disorders, stress is a critical determinant of relapse susceptibility. In some cases, stressors directly trigger cocaine use. In others, stressors interact with other stimuli to promote drug seeking, thereby setting the stage for relapse. Here, we review the mechanisms and neurocircuitry that mediate stress-triggered and stress-potentiated cocaine seeking. Stressors trigger cocaine seeking by activating noradrenergic projections originating in the lateral tegmentum that innervate the bed nucleus of the stria terminalis to produce beta adrenergic receptor-dependent regulation of neurons that release corticotropin releasing factor (CRF) into the ventral tegmental area (VTA). CRF promotes the activation of VTA dopamine neurons that innervate the prelimbic prefrontal cortex resulting in D1 receptor-dependent excitation of a pathway to the nucleus accumbens core that mediates cocaine seeking. The stage-setting effects of stress require glucocorticoids, which exert rapid non-canonical effects at several sites within the mesocorticolimbic system. In the nucleus accumbens, corticosterone attenuates dopamine clearance via the organic cation transporter 3 to promote dopamine signaling. In the prelimbic cortex, corticosterone mobilizes the endocannabinoid, 2-arachidonoylglycerol (2-AG), which produces CB1 receptor-dependent reductions in inhibitory transmission, thereby increasing excitability of neurons which comprise output pathways responsible for cocaine seeking. Factors that influence the role of stress in cocaine seeking, including prior history of drug use, biological sex, chronic stress/co-morbid stress-related disorders, adolescence, social variables, and genetics are discussed. Better understanding when and how stress contributes to drug seeking should guide the development of more effective interventions, particularly for those whose drug use is stress related.

Subthalamic low-frequency oscillations predict vulnerability to cocaine addiction.

Identifying vulnerable individuals before they transition to a compulsive pattern of drug seeking and taking is a key challenge in addiction to develop efficient prevention strategies. Oscillatory activity within the subthalamic nucleus (STN) has been associated with compulsive-related disorders. To study compulsive cocaine-seeking behavior, a core component of drug addiction, we have used a rat model in which cocaine seeking despite a foot-shock contingency only emerges in some vulnerable individuals having escalated their cocaine intake. We show that abnormal oscillatory activity within the alpha/theta and low-beta bands during the escalation of cocaine intake phase predicts the subsequent emergence of compulsive-like seeking behavior. In fact, mimicking STN pathological activity in noncompulsive rats during cocaine escalation turns them into compulsive ones. We also find that 30 Hz, but not 130 Hz, STN deep brain stimulation (DBS) reduces pathological cocaine seeking in compulsive individuals. Our results identify an early electrical signature of future compulsive-like cocaine-seeking behavior and further advocates the use of frequency-dependent STN DBS for the treatment of addiction.