Increased Impulsivity Retards the Transition to Dorsolateral Striatal Dopamine Control of Cocaine Seeking (original) (raw)
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High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking
Science, 2008
Both impulsivity and novelty-seeking have been suggested to be behavioral markers of the propensity to take addictive drugs. However, their relevance for the vulnerability to compulsively seek and take drugs, which is a hallmark feature of addiction, is unknown. We report here that whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration, high impulsivity in contrast predicts the development of addiction-like behavior in rats, including persistent or compulsive drug taking in the face of aversive outcomes. This study provides experimental evidence that a shift from impulsivity to compulsivity occurs during the development of addictive behavior, thereby providing important insights into the genesis and neural mechanisms of drug addiction.
Neuropsychopharmacology, 2012
The present study investigated the involvement of dopamine-dependent mechanisms in the anterior dorsolateral (aDLS) and posterior dorsomedial (pDMS) striatum during the early-and late-stage performance of cocaine-seeking behavior. Rats were trained to selfadminister cocaine under continuous reinforcement (fixed-ratio 1, FR1) with a 20-s light conditioned stimulus (CS) presented contingently upon each infusion. After a week, rats were challenged by a change in contingency to seek cocaine during a 15-min period uninfluenced by cocaine during which each response was reinforced by a 1-s CS presentation. Dopamine transmission blockade by intracranial infusions of a-flupenthixol only in the pDMS, but not in the aDLS, dose dependently reduced performance of cue-controlled cocaine seeking at the early stage of self-administration. One cohort of rats was then trained with increasing response requirements until completing 15 sessions under a second-order schedule [FI15(FR10:S)] so that cocaine-seeking performance became well established. At this stage, intra-aDLS, but not pDMS, a-flupenthixol infusions dose dependently reduced active lever presses. The second cohort of rats continued to self-administer cocaine under the FR1 schedule such that their drug intake was matched to the late-stage performance group. a-Flupenthixol in the pDMS, but not in the aDLS, again prevented the performance of cocaine seeking. These results show that dopamine transmission in the pDMS is required for initial performance of goal-directed cocaine seeking, and that its role is ultimately subverted and devolves instead to the aDLS only following training with high rates of cocaine-seeking behavior, supporting the theory of dynamic shifts in the striatal control over cocaine seeking between goal-directed and habitual performance.
Neurobehavioral precursors of compulsive cocaine-seeking in dual fronto-striatal circuits
Only some individuals using drugs recreationally eventually become addicted, and persist in drug seeking and taking despite adverse consequences. The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. We report that in drug naïve rats the future tendency to develop compulsive cocaine seeking is characterised 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. These findings show that the vulnerability to develop compulsive cocaine seeking behavior stems from pre-existing structural or functional changes in two distinct cortico-striatal systems that underlie deficits in impulse control and goal-directed behavior.
Impulsivity predicts the escalation of cocaine self-administration in rats
Pharmacology Biochemistry and Behavior, 2009
Impulsivity, as measured by the delay-discounting task, predicts the acquisition of cocaine selfadministration and reinstatement of cocaine seeking in rats. The purpose of this study was to extend these results to the escalation phase of drug self-administration. Female rats were initially screened for high (HiI) or low (LoI) impulsivity for food reinforcement using a delay-discounting procedure. They were then implanted with i.v. catheters and trained to lever press for cocaine infusions (0.8 mg/ kg). Once cocaine intake stabilized, rats were allowed to self-administer cocaine (0.4 mg/kg) under a fixed-ratio 1 (FR 1) schedule during 3, 2 hr short-access sessions. Subsequently, performance was briefly assessed under a progressive ratio (PR) schedule for 3 doses of cocaine (0.2, 0.8, and 3.2 mg/ kg). Following PR testing, the cocaine dose was then changed to 0.4 mg/kg. Session length was then extended to 6-hr for 21 days (extended access), and 0.4 mg/kg cocaine was available under a FR 1 schedule. After the 21-day extended access phase, responses and infusions under the short access and PR dose-response conditions were reassessed. The results indicated that HiI rats escalated cocaine-reinforced responding during the extended access condition, but LoI rats did not. HiI rats also earned significantly more infusions than LoI rats under the post-escalation short-access condition. However, HiI and LoI rats did not differ under the pre-and post-extended access PR conditions. This study suggests that individual differences in impulsivity predict escalation of cocaine self-administration in female rats, which may have implications in the prediction of binge-like patterns of cocaine intake in women.
Nucleus Accumbens D2/3 Receptors Predict Trait Impulsivity and Cocaine Reinforcement
Science, 2007
Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.
Striatal-insula circuits in cocaine addiction: implications for impulsivity and relapse risk
The American Journal of Drug and Alcohol Abuse, 2013
Background: Dysregulated striatal functioning coupled with executive control deficits arising from abnormal frontal cortical function are considered key mechanisms in the development and maintenance of cocaine addiction. The same features are thought to underlie high trait impulsivity observed in cocaine-addicted populations. Objectives: Employing resting state functional connectivity, the current study sought to identify cortico-striatal circuit alterations in cocaine addiction and examine the degree to which circuit connectivity contributes to relapse risk and impulsivity among cocaine-addicted individuals. Methods: Whole-brain restingstate functional magnetic resonance imaging connectivity was assessed in 45 cocaine-addicted individuals relative to 22 healthy controls using seed volumes in the left and right caudate, putamen and nucleus accumbens. Cocaine-addicted individuals completed scans in the final week of a 2-4 weeks residential treatment episode. Relapse by day 30 post-discharge served to separate cocaine-addicted individuals into relapse and non-relapse groups. All participants completed the Barratt Impulsivity Scale (BIS-11a). Results: Cocaine-addicted individuals exhibited reduced positive connectivity between the bilateral putamen and posterior insula and right postcentral gyrus. Group differences were primarily driven by reduced connectivity in relapse individuals relative to controls. No relapse versus non-relapse differences emerged. Impulsivity (BIS-11a) was higher in cocaine-addicted participants, an effect that was partially mediated by reduced putamen-posterior insula connectivity in this group. Conclusion: Cocaine addiction, relapse risk and impulsivity were associated with reduced connectivity in putamenposterior insula/postcentral gyrus circuits implicated in temporal discounting and habitual responding. Findings provide new insight into the neurobiological mechanisms underlying impulsivity and relapse in cocaine addiction.
Recent Translational Findings on Impulsivity in Relation to Drug Abuse
Current Addiction Reports, 2014
Impulsive behavior is strongly implicated in drug abuse, as both a cause and a consequence of drug use. To understand how impulsive behaviors lead to and result from drug use, translational evidence from both human and nonhuman animal studies is needed. Here, we review recent (2009 or later) studies that have investigated two major components of impulsive behavior, inhibitory control and impulsive choice, across preclinical and clinical studies. We concentrate on the stop-signal task as the measure of inhibitory control and delay discounting as the measure of impulsive choice. Consistent with previous reports, recent studies show greater impulsive behavior in drug users compared with non-users. Additionally, new evidence supports the prospective role of impulsive behavior in drug abuse, and has begun to identify the neurobiological mechanisms underlying impulsive behavior. We focus on the commonalities and differences in findings between preclinical and clinical studies, and suggest future directions for translational research.
Psychopharmacology, 2004
Rationale: Previous research in humans suggests a relationship between drug abuse and impulsivity as shown by selection of a smaller immediate reward over a larger delayed reward. However, it is not clear whether impulsivity precedes drug abuse or drug abuse influences impulsivity. Objective: The hypothesis of the present experiment was that rats selected for choosing smaller, immediate over larger, delayed food would acquire IV cocaine self-administration faster than those choosing larger, delayed food rewards. Methods: Female rats were screened for locomotor activity and trained on a delay discounting procedure that allowed them access to two response levers and a food pellet dispenser. Under a fixed-ratio (FR) 1 schedule, responding on one lever resulted in immediate delivery of one 45 mg pellet, while responding on the other lever resulted in delivery of three 45 mg pellets after a variable delay that increased after responses on the delay lever and decreased after responses on the immediate lever. For each rat, a mean adjusted delay (MAD) was calculated for each daily session, and stability was defined as MADs varying less than 5 s across 5 days. Based on their average MADs, rats were separated into low impulsive (LoI) and high impulsive (HiI) groups, implanted with an indwelling IV catheter, and trained to lever press for cocaine (0.2 mg/kg) under an FR1 schedule. Results: There were no differences in locomotor activity between the LoI and HiI groups; however, a greater percentage of the HiI group acquired cocaine selfadministration, and they did so at a significantly faster rate than the LoI rats. Conclusions: Performance on the delay discounting model of impulsivity predicted vulnerability to subsequent acquisition of cocaine self-administration.
Dissecting impulsivity and its relationships to drug addictions
Annals of the New York Academy of Sciences, 2014
Addictions are often characterized as forms of impulsive behavior. That said, it is often noted that impulsivity is a multidimensional construct, spanning several psychological domains. This review describes the relationship between varieties of impulsivity and addiction-related behaviors, the nature of the causal relationship between the two, and the underlying neurobiological mechanisms that promote impulsive behaviors. We conclude that the available data strongly support the notion that impulsivity is both a risk factor for, and a consequence of, drug and alcohol consumption. While the evidence indicating that subtypes of impulsive behavior are uniquely informative—either biologically or with respect to their relationships to addictions—is convincing, multiple lines of study link distinct subtypes of impulsivity to low dopamine D2 receptor function and perturbed serotonergic transmission, revealing shared mechanisms between the subtypes. Therefore, a common biological framework involving monoaminergic transmitters in key frontostriatal circuits may link multiple forms of impulsivity to drug self-administration and addiction-related behaviors. Further dissection of these relationships is needed before the next phase of genetic and genomic discovery will be able to reveal the biological sources of the vulnerability for addiction indexed by impulsivity.
Philosophical Transactions of the Royal Society B: Biological Sciences, 2008
We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drugseeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D 2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.