Compulsive Cocaine Seeking Research Articles

Neurobehavioral Precursors of Compulsive Cocaine Seeking in Dual Frontostriatal Circuits

BackgroundOnly some individuals who use drugs recreationally eventually develop a substance use disorder, characterized in part by the rigid engagement in drug foraging behavior (drug seeking), which is often maintained in the face of adverse consequences (i.e., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. MethodsUsing a prospective longitudinal study involving 39 male rats, we combined multidimensional characterization of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging to identify the structural and functional brain correlates of the later emergence of compulsive drug seeking in drug-naïve subjects. We developed a novel behavioral procedure to investigate the individual tendency to persist in drug-seeking behavior in the face of punishment in a drug-free state in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus. ResultsIn drug-naïve rats, the tendency to develop compulsive cocaine seeking was characterized by behavioral stickiness–related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula, and nucleus accumbens. ConclusionsThese findings show that the vulnerability to developing compulsive cocaine-seeking behavior stems from preexisting structural or functional changes in two distinct corticostriatal systems that underlie deficits in impulse control and goal-directed behavior.

Discriminating goal-directed and habitual cocaine seeking in rats using a novel outcome devaluation procedure.

Habits are theorized to play a key role in compulsive cocaine seeking, yet there is limited methodology for assessing habitual responding for intravenous (IV) cocaine. We developed a novel outcome devaluation procedure to discriminate goal-directed from habitual responding in cocaine-seeking rats. This procedure elicits devaluation temporarily and requires no additional training, allowing repeated testing at different time points. After training male rats to self-administer IV cocaine, we devalued the drug outcome via experimenter-administered IV cocaine (a "satiety" procedure) prior to a 10-min extinction test. Many rats were sensitive to outcome devaluation, a hallmark of goal-directed responding. These animals reduced responding when given a dose of experimenter-administered cocaine that matched or exceeded satiety levels during self-administration. However, other rats were insensitive to experimenter-administered cocaine, suggesting their responding was habitual. Importantly, reinforcement schedules and neural manipulations that produce goal-directed responding (i.e., ratio schedules or dorsolateral striatum lesions) caused sensitivity to outcome devaluation, whereas reinforcement schedules and neural manipulations that produce habitual responding (i.e., interval schedules or dorsomedial striatum lesions) caused insensitivity. Satiety-based outcome devaluation is an innovative new tool to dissect the neural and behavioral mechanisms underlying IV cocaine-seeking behavior.

Role of the GABAa and GABAb receptors of the central nucleus of the amygdala in compulsive cocaine-seeking behavior in male rats.

Compulsive cocaine use, defined as the continued use despite the dire consequences, is a hallmark of cocaine addiction. Thus, understanding the brain mechanism regulating the compulsive cocaine-seeking and cocaine-taking behaviors is essential to understand cocaine addiction and the key to identification of the molecular targets for the development of medications against this condition. This study aimed to determine how the GABAa and GABAb receptors of the central nucleus of the amygdala (CeA) regulate the compulsive cocaine-seeking behavior. Male Wistar outbred rats were trained to self-administer intravenous cocaine (0.4mg/kg/infusion) under a chained schedule. The compulsive cocaine-seeking behavior was measured as the cocaine-seeking behavior in the face of footshock punishment. The role of the GABA receptors of CeA in the regulation of such behavior was determined by measuring the dose-dependent effects of the GABAa agonist muscimol or the GABAb agonist baclofen bilaterally microinjected into the CeA on the punished cocaine-seeking behavior. The cocaine-seeking behavior was inhibited by footshock punishment in an intensity-dependent manner. Both muscimol and baclofen dose-dependently increased the punished cocaine-seeking behavior. However, the potency of muscimol but not baclofen was negatively correlated with the effects of punishment. These data indicate that the CeA GABAa receptors play a key role in the regulation of the compulsive cocaine-seeking behavior and suggest that an increase in the function of the GABAa receptors possibly induced by cocaine or genetic factors may be an important mechanism involved in the development of or vulnerability to the compulsive cocaine use and addiction.

Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking.

BackgroundThe hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing regimen that endeavored to mimic the characteristic of escalating drug intake in human addicts. Tropisetron is a 5-HT3 receptor antagonist and α7-nicotinic receptor partial agonist. Utilizing rats trained on the escalated-dosing regimen, we examined the effects of tropisetron on control over compulsive drug-seeking behavior that was defined as footshock-resistant lever pressing.MethodsRats were trained to self-administer cocaine with incremental-infusion doses (from 0.6 to 2.4 mg/kg/infusion) across training sessions (3 h/session) or with a long-access paradigm (i.e., 0.6 mg/kg/infusion, 6 h/d training session). The drug-seeking motivations of 2 groups were estimated by the patterns of drug intake and progressive-ratio schedule. The compulsivity for drug seeking of the group with an escalated dose was further evaluated using the footshock-associated seeking-taking chain task.ResultsThe rats trained on the dose-escalated protocol achieved the same levels of motivated drug seeking as those subjected to a long-access paradigm, as indicated by cocaine intake per training session and breakpoints on a progressive ratio schedule. Tropisetron attenuated compulsive behavior of rats when pressing of the seeking lever potentially led to footshock. Intriguingly, tropisetron did not change the motivation to seek cocaine when footshock was absent. Tropisetron had no effect on locomotor activities or saccharin self-administration.ConclusionsThese results demonstrate that tropisetron restored control over compulsive cocaine seeking, and they indicate that 5-HT3/α7-nicotinic receptors may be potential therapeutic targets for relieving compulsive drug seeking.

Addictive behaviour in experimental animals: prospects for translation.

Since the introduction of intravenous drug self-administration methodology over 50 years ago, experimental investigation of addictive behaviour has delivered an enormous body of data on the neural, psychological and molecular mechanisms of drug reward and reinforcement and the neuroadaptations to chronic use. Whether or not these behavioural and molecular studies are viewed as modelling the underpinnings of addiction in humans, the discussion presented here highlights two areas-the impact of drug-associated conditioned stimuli-or drug cues-on drug seeking and relapse, and compulsive cocaine seeking. The degree to which these findings translate to the clinical state of addiction is considered in terms of the underlying neural circuitry and also the ways in which this understanding has helped develop new treatments for addiction. The psychological and neural mechanisms underlying drug memory reconsolidation and extinction established in animal experiments show particular promise in delivering new treatments for relapse prevention to the clinic.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Reward Sensitivity and Waiting Impulsivity: Shift towards Reward Valuation away from Action Control

BackgroundImpulsivity and reward expectancy are commonly interrelated. Waiting impulsivity, measured using the rodent 5-Choice Serial Reaction Time task, predicts compulsive cocaine seeking and sign (or cue) tracking. Here, we assess human waiting impulsivity using a novel translational task, the 4-Choice Serial Reaction Time task, and the relationship with reward cues.MethodsHealthy volunteers (n=29) performed the monetary incentive delay task as a functional MRI study where subjects observe a cue predicting reward (cue) and wait to respond for high (£5), low (£1), or no reward. Waiting impulsivity was tested with the 4-Choice Serial Reaction Time task.ResultsFor high reward prospects (£5, no reward), greater waiting impulsivity on the 4-CSRT correlated with greater medial orbitofrontal cortex and lower supplementary motor area activity to cues. In response to high reward cues, greater waiting impulsivity was associated with greater subthalamic nucleus connectivity with orbitofrontal cortex and greater subgenual cingulate connectivity with anterior insula, but decreased connectivity with regions implicated in action selection and preparation.ConclusionThese findings highlight a shift towards regions implicated in reward valuation and a shift towards compulsivity away from higher level motor preparation and action selection and response. We highlight the role of reward sensitivity and impulsivity, mechanisms potentially linking human waiting impulsivity with incentive approach and compulsivity, theories highly relevant to disorders of addiction.

Dorsolateral prefrontal cortex TMS reduces cocaine use: A pilot study

Background: Recent animal studies demonstrate that compulsive cocaine seeking strongly reduces prelimbic frontal cortex activity, while optogenetic stimulation of this brain area significantly inhibits compulsive cocaine seeking, providing a strong rationale for applying brain stimulation to reduce cocaine consumption. Thus, we employed repetitive transcranial magnetic stimulation (rTMS), to test if dorsolateral prefrontal cortex (DLPFC) stimulation might prevent cocaine use in humans.

Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: A pilot study

Recent animal studies demonstrate that compulsive cocaine seeking strongly reduces prelimbic frontal cortex activity, while optogenetic stimulation of this brain area significantly inhibits compulsive cocaine seeking, providing a strong rationale for applying brain stimulation to reduce cocaine consumption. Thus, we employed repetitive transcranial magnetic stimulation (rTMS), to test if dorsolateral prefrontal cortex (DLPFC) stimulation might prevent cocaine use in humans. Thirty-two cocaine-addicted patients were randomly assigned to either the experimental group (rTMS) on the left DLPFC, or to a control group (pharmacological agents) during a 29-day study (Stage 1). This was followed by a 63-day follow-up (Stage 2), during which all participants were offered rTMS treatment. Amongst the patients who completed Stage 1, 16 were in the rTMS group (100%) and 13 in the control group (81%). No significant adverse events were noted. During Stage 1, there were a significantly higher number of cocaine-free urine drug tests in the rTMS group compared to control (p=0.004). Craving for cocaine was also significantly lower in the rTMS group compared to the controls (p=0.038). Out of 13 patients who completed Stage 1 in the control group, 10 patients received rTMS treatment during Stage 2 and showed significant improvement with favorable outcomes becoming comparable to those of the rTMS group. The present preliminary findings support the safety of rTMS in cocaine-addicted patients, and suggest its potential therapeutic role for rTMS-driven PFC stimulation in reducing cocaine use, providing a strong rationale for developing larger placebo-controlled studies.Trial name: Repetitive transcranial magnetic stimulation (rTMS) in cocaine abusers, URL:〈http://www.isrctn.com/ISRCTN15823943?q=&filters=&sort=&offset=8&totalResults=13530&page=1&pageSize=10&searchType=basic-search〉, Registration number: ISRCTN15823943

Distinct miRNA expression in dorsal striatal subregions is associated with risk for addiction in rats.

Recently, we published data using an animal model that allowed us to characterize animals into two groups, addiction vulnerable and addiction resilient, where we identified that addiction/relapse vulnerability was associated with deficits in synaptic plasticity-associated gene expression in the dorsal striatum (DS). Notable was the strong reduction in expression for activity-regulated cytoskeleton-associated protein (Arc) considered a master regulator of synaptic plasticity. In the present study, we confirmed that Arc messenger RNA was significantly decreased in the DS, but importantly, we identified that this reduction was restricted to the dorsomedial (DMS) and not dorsolateral striatum (DLS). There is recent evidence of microRNA (miRNA)-associated posttranscriptional suppression of Arc and animal models of addiction have identified a key role for miRNA in the regulation of addiction-relevant genes. In further support of this link, we identified several differentially expressed miRNA with the potential to influence addiction-relevant plasticity genes, including Arc. A key study recently reported that miR-212 expression is protective against compulsive cocaine-seeking. Supporting this hypothesis, we found that miR-212 expression was significantly reduced in the DMS but not DLS of addiction-vulnerable animals. Together, our data provide strong evidence that miRNA promote ongoing plasticity deficits in the DS of addiction-vulnerable animals.

Differential roles of the prefrontal cortical subregions and basolateral amygdala in compulsive cocaine seeking and relapse after voluntary abstinence in rats

Compulsive drug use and a persistent vulnerability to relapse are key features of addiction. Imaging studies have suggested that these features may result from deficits in prefrontal cortical structure and function, and thereby impaired top-down inhibitory control over limbic–striatal mechanisms of drug-seeking behaviour. We tested the hypothesis that selective damage to distinct subregions of the prefrontal cortex, or to the amygdala, after a short history of cocaine taking would: (i) result in compulsive cocaine seeking at a time when it would not usually be displayed; or (ii) facilitate relapse to drug seeking after abstinence. Rats with selective, bilateral excitotoxic lesions of the basolateral amygdala or anterior cingulate, prelimbic, infralimbic, orbitofrontal or anterior insular cortices were trained to self-administer cocaine under a seeking–taking chained schedule. Intermittent mild footshock punishment of the cocaine-seeking response was then introduced. No prefrontal cortical lesion affected the ability of rats to withhold their seeking responses. However, rats with lesions to the basolateral amygdala increased their cocaine-seeking responses under punishment and were impaired in their acquisition of conditioned fear. Following a 7-day abstinence period, rats were re-exposed to the drug-seeking environment for assessment of relapse in the absence of punishment or cocaine. Rats with prelimbic cortex lesions showed decreased seeking responses during relapse, whereas those with anterior insular cortex lesions showed an increase. Combined, these results show that acute impairment of prefrontal cortical function does not result in compulsive cocaine seeking after a short history of self-administering cocaine, but further implicates subregions of the prefrontal cortex in relapse.

Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking

Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.

Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use

A hallmark of addiction is the loss of control over drug intake, which is seen only in a fraction of those exposed to stimulant drugs like cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use are still unknown. Here we show that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience towards compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine while optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in nucleus accumbens functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.

Baseline-dependent effects of cocaine pre-exposure on impulsivity and D2/3 receptor availability in the rat striatum: possible relevance to the attention-deficit hyperactivity syndrome.

We have previously shown that impulsivity in rats predicts the emergence of compulsive cocaine seeking and taking, and is coupled to decreased D2/3 receptor availability in the ventral striatum. As withdrawal from cocaine normalises high impulsivity in rats, we investigated, using positron emission tomography (PET), the effects of response-contingent cocaine administration on D2/3 receptor availability in the striatum. Rats were screened for impulsive behavior on the five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [18F]fallypride, rats were trained to self-administer cocaine for 15 days under a long-access schedule. As a follow-up, rats were assessed for impulsivity and underwent a second [18F]fallypride PET scan. At baseline, we found that D2/3 receptor availability was significantly lower in the left, but not right, ventral striatum of high-impulsive rats compared with low-impulsive rats. While the number of self-administered cocaine infusions was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine. This effect was accompanied by a significant increase in D2/3 receptor availability in the left, but not right, ventral striatum. We further report that D2/3 receptor availability was inversely related to baseline D2/3 receptor availability in the ventral striatum of high-impulsive rats, as well as to the left and right dorsal striatum of both low-impulsive and high-impulsive rats. These findings indicate that the reduction in impulsivity in high-impulsive rats by prior cocaine exposure may be mediated by a selective correction of deficient D2/3 receptor availability in the ventral striatum. A similar baseline-dependent mechanism may account for the therapeutic effects of stimulant drugs in clinical disorders such as ADHD.

Reduced Forebrain Serotonin Transmission is Causally Involved in the Development of Compulsive Cocaine Seeking in Rats

Whereas the majority of cocaine users quit as they experience the negative consequences of drug use, some lose control over their drug taking and compulsively seek drugs. We report that 20% of rats compulsively seek cocaine despite intermittent negative outcomes after escalating their cocaine self-administration. This compulsive subgroup showed marked reductions in forebrain serotonin utilization; increasing serotonin transmission reduced their compulsive cocaine seeking. Depleting forebrain serotonin induced compulsive cocaine seeking in rats with a limited cocaine taking history; this was reversed by systemic treatment with a 5-hydroxytryptamine (5-HT2C) receptor agonist and mimicked by systemic treatment with a 5-HT2C receptor antagonist in intact animals. These results indicate the causal involvement of reduced serotoninergic transmission in the emergence of compulsive drug seeking after a long cocaine-taking history.

Drug Intake is Sufficient, but Conditioning is not Necessary for the Emergence of Compulsive Cocaine Seeking After Extended Self-Administration

Compulsive drug seeking, which is characterized by continued instrumental effort despite contingent punishment, has been shown to emerge after extended drug self-administration. Exactly what aspect of drug self-administration drives the appearance of addictive behavior is unclear, but the mechanistic explanations that have been offered differ in one key respect. On one hand, it has been suggested that dysfunctional conditioning during self-administration drives unrealistic reward expectations, ultimately producing resistance to punishment. If this is indeed the pathological process that drives compulsive behavior, then compulsivity should be apparent only in the presence of the pavlovian and instrumental stimuli that underwent frequent pairing with the drug reward. On the other hand, it has also been suggested that extended drug intake produces general changes to reward and decision-making circuits that manifest as compulsive drug seeking. Unfortunately, conditioning history and drug intake are generally intrinsically intertwined. However, here we used an animal model of compulsive cocaine seeking to selectively manipulate drug intake and the degree of conditioning in the test context, to investigate which of the two is more important for the emergence of compulsive cocaine seeking. The results show that extended drug intake alone is sufficient, but extended conditioning in the test context is not necessary for the emergence of compulsive cocaine seeking, resolving a fundamental question in addiction research.

A ventral tegmental CRF–glutamate–dopamine interaction in addiction

Stress-induced reinstatement of cocaine-seeking is blocked by antagonists for the stress-related neurohormone corticotropin-releasing factor (CRF). One site of this action is the ventral tegmental area (VTA), where mild footshock stress causes CRF release, glutamate release, and dopaminergic activation in cocaine-experienced but not cocaine-naive animals. Infusion of CRF into VTA has similar effects to footshock in cocaine-experienced animals but fails to cause significant VTA glutamate release or dopaminergic activation in cocaine-naive animals. The reinstatement, glutamate release, and dopamine release are prevented by VTA infusions of CRF-receptor 2 (CRF-R2) but not CRF-R1 antagonists. Reinstatement is triggered by some but not all CRF-R2 agonists and some but not all CRF-R1 agonists; the common denominator of the effective agonists is that they bind to the CRF-binding protein (CRF-BP), which appears to be essential for the behavioral and VTA effects of stress and CRF in cocaine-experienced animals. In situ hybridization reveals mRNA for CRF-R1 and CRF-BP but not CRF-R2 in a subset of VTA dopamine neurons. Electron microscopy reveals primarily asymmetric synapses between a subset of VTA terminals containing glutamate and CRF and a subset of VTA dopaminergic neurons and primarily symmetric synapses between a subset of CRF terminals that do not contain glutamate and a subset of GABAergic neurons in VTA. Thus, a complex and not yet fully understood interaction of CRF, glutamate, and the mesocorticolimbic dopamine system is established by experience with cocaine, and this alteration appears to contribute importantly to the transition from casual to compulsive cocaine-seeking.

Behavioural characterisation of high impulsivity on the 5-choice serial reaction time task: Specific deficits in ‘waiting’ versus ‘stopping’

Impulsivity is a core deficit of a number of neuropsychiatric disorders including attention-deficit hyperactivity disorder (ADHD), anti-social conduct disorder and drug addiction. Recent research has highlighted the multifaceted nature of impulsivity and the myriad of putative neural and psychological mechanisms thought to underpin behavioural syndromes of impaired self-control. Here we report a novel conceptualisation of impulsivity based on ‘waiting’ and ‘stopping’ efficiency with explanatory value in defining the psychological and neural basis of impulsivity and the high co-morbidity of brain disorders such as ADHD and drug addiction. Rats selected for high levels of impulsivity on a reaction time task analogous to the continuous performance test in humans exhibited correspondingly high levels of impulsive decision-making on a delay-of-reward task. The same rats, however, were unimpaired on a stop-signal task requiring inhibition of an already initiated motor response. The specific nature of this deficit in ‘waiting impulsivity’ was confirmed by unimpaired acquisition of appetitive Pavlovian conditioning, a putative ancillary measure of impulsive behaviour. These findings are significant in light of recent evidence linking impulsivity in rats to high levels of cocaine self-administration and development of compulsive cocaine seeking behaviour. We thus suggest that an inability to bridge delays to future rewards and reward-related stimuli is a candidate behavioural endophenotype that pre-disposes to clinical psychopathology.