Characterization in the rat of the individual tendency to rely on alcohol to cope with distress and the ensuing vulnerability to drink compulsively.

Only some vulnerable individuals who recreationally drink alcohol eventually develop the compulsive drinking pattern that characterizes alcohol use disorder. A new frontier in biomedical research lies in understanding the neurobehavioural mechanisms of this individual vulnerability, a necessary step towards developing novel effective therapeutic strategies. Translational research has been hindered by the lack of valid, reliable and robust approaches that enable the study of the influence of the reliance on alcohol to cope with stress or self-medicate negative emotional states on the subsequent transition to alcohol use disorder.

Pan-striatal reduction in the expression of the astrocytic dopamine transporter precedes the development of dorsolateral striatum dopamine-dependent incentive heroin seeking habits.

The emergence of compulsive drug-seeking habits, a hallmark feature of substance use disorder, has been shown to be predicated on the engagement of dorsolateral striatal control over behaviour. This process involves the dopamine-dependent functional coupling of the anterior dorsolateral striatum (aDLS) with the nucleus accumbens core, but the mechanisms by which this coupling occurs have not been fully elucidated. The striatum is tiled by a syncytium of astrocytes that express the dopamine transporter (DAT), the level of which is altered in individuals with heroin use disorder.

From compulsivity to compulsion: the neural basis of compulsive disorders.

Compulsive behaviour, an apparently irrational perseveration in often maladaptive acts, is a potential transdiagnostic symptom of several neuropsychiatric disorders, including obsessive-compulsive disorder and addiction, and may reflect the severe manifestation of a dimensional trait termed compulsivity. In this Review, we examine the psychological basis of compulsions and compulsivity and their underlying neural circuitry using evidence from human neuroimaging and animal models. Several main elements of this circuitry are identified, focused on fronto-striatal systems implicated in goal-directed behaviour and habits.

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks.

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT).

Neurobehavioral Precursors of Compulsive Cocaine Seeking in Dual Frontostriatal Circuits.

Background: Only 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 development of compulsive coping behavior depends on dorsolateral striatum dopamine-dependent mechanisms.

Humans greatly differ in how they cope with stress, a natural behavior learnt through negative reinforcement. Some individuals engage in displacement activities, others in exercise or comfort eating, and others still in alcohol use. Across species, adjunctive behaviors, such as polydipsic drinking, are used as a form of displacement activity that reduces stress.

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Electrophysiological signature of the interplay between habits and inhibition in response to smoking-related cues in individuals with a smoking habit: An event-related potential study.

The rigid, stimulus-bound nature of drug seeking that characterizes substance use disorder (SUD) has been related to a dysregulation of motivational and early attentional reflexive and inhibitory reflective systems. However, the mechanisms by which these systems are engaged by drug-paired conditioned stimuli (CSs) when they promote the enactment of seeking habits in individuals with a SUD have not been elucidated. The present study aimed behaviourally and electrophysiologically to characterize the nature of the interaction between the reflexive and reflective systems recruited by CSs in individuals with a smoking habit.

The development of compulsive coping behaviour is associated with a downregulation of Arc in a Locus Coeruleus neuronal ensemble.

Some compulsive disorders have been considered to stem from the loss of control over coping strategies, such as displacement. However, the cellular mechanisms involved in the acquisition of coping behaviours and their subsequent compulsive manifestation in vulnerable individuals have not been elucidated. Considering the role of the locus coeruleus (LC) noradrenaline-dependent system in stress and related excessive behaviours, we hypothesised that neuroplastic changes in the LC may be associated with the acquisition of an adjunctive polydipsic water drinking, a prototypical displacement behaviour, and the ensuing development of compulsion in vulnerable individuals.

Towards a machine-learning assisted diagnosis of psychiatric disorders and their operationalization in preclinical research: Evidence from studies on addiction-like behaviour in individual rats.

Over the last few decades, there has been a progressive transition from a categorical to a dimensional approach to psychiatric disorders. Especially in the case of substance use disorders, interest in the individual vulnerability to transition from controlled to compulsive drug taking warrants the development of novel dimension-based objective stratification tools. Here we drew on a multidimensional preclinical model of addiction, namely the 3-criteria model, previously developed to identify the neurobehavioural basis of the individual's vulnerability to switch from controlled to compulsive drug taking, to test a machine-learning assisted classifier objectively to identify individual subjects as vulnerable/resistant to addiction.

Negative Urgency Exacerbates Relapse to Cocaine Seeking After Abstinence.

Background: The mechanisms through which drug-cue-induced negative affective states are involved in relapse have not been defined. We tested the hypothesis that in individuals having developed a dorsolateral striatum (DLS)-dependent cue-controlled cocaine-seeking habit, the loss of the opportunity to enact the drug-seeking response during abstinence results in an urge to act that exacerbates relapse severity mediated by negative urgency.

Methods: Eighty-seven male Sprague Dawley rats were trained to seek cocaine under the influence of the conditioned reinforcing properties of drug-paired cues or not.

Myelin: A gatekeeper of activity-dependent circuit plasticity?

The brain is responsive to an ever-changing environment, enabling the organism to learn and change behavior accordingly. Efforts to understand the underpinnings of this plasticity have almost exclusively focused on the functional and underlying structural changes that neurons undergo at neurochemical synapses. What has received comparatively little attention is the involvement of activity-dependent myelination in such plasticity and the functional output of circuits controlling behavior.

Individual differences in the engagement of habitual control over alcohol seeking predict the development of compulsive alcohol seeking and drinking.

Excessive drinking is an important behavioural characteristic of alcohol addiction, but not the only one. Individuals addicted to alcohol crave alcoholic beverages, spend time seeking alcohol despite negative consequences and eventually drink to intoxication. With prolonged use, control over alcohol seeking devolves to anterior dorsolateral striatum, dopamine-dependent mechanisms implicated in habit learning and individuals in whom alcohol seeking relies more on these mechanisms are more likely to persist in seeking alcohol despite the risk of punishment.

Chronic exposure to glucocorticoids induces suboptimal decision-making in mice.

Anxio-depressive symptoms as well as severe cognitive dysfunction including aberrant decision-making (DM) are documented in neuropsychiatric patients with hypercortisolaemia. Yet, the influence of the hypothalamo-pituitary-adrenal (HPA) axis on DM processes remains poorly understood. As a tractable mean to approach this human condition, adult male C57BL/6JRj mice were chronically treated with corticosterone (CORT) prior to behavioural, physiological and neurobiological evaluation.

Baclofen decreases compulsive alcohol drinking in rats characterized by reduced levels of GAT-3 in the central amygdala.

While most individuals with access to alcohol drink it recreationally, some vulnerable individuals eventually lose control over their intake and progressively develop compulsive alcohol drinking and decreased interest in alternative sources of reinforcement, two key features of addiction. The neural and molecular mechanisms underlying this vulnerability to switch from controlled to compulsive alcohol intake have not been fully elucidated. It has been shown that rats having reduced levels of expression of the gamma-aminobutyric acid (GABA) transporter, GAT-3, in the amygdala tend to persist in seeking and drinking alcohol even when adulterated with quinine, suggesting that pharmacological interventions aimed at restoring GABA homeostasis in these individuals may provide a targeted treatment to limit compulsive alcohol drinking.

Environment-dependent behavioral traits and experiential factors shape addiction vulnerability.

The transition from controlled drug use to drug addiction depends on an interaction between a vulnerable individual, their environment and a drug. Here we tested the hypothesis that conditions under which individuals live influence behavioral vulnerability traits and experiential factors operating in the drug taking environment to determine the vulnerability to addiction. The role of behavioral vulnerability traits in mediating the influence of housing conditions on the tendency to acquire cocaine self-administration was characterized in 48 rats housed in either an enriched (EE) or a standard (SE) environment.

The Basolateral Amygdala to Nucleus Accumbens Core Circuit Mediates the Conditioned Reinforcing Effects of Cocaine-Paired Cues on Cocaine Seeking.

Background: Individuals addicted to cocaine spend much of their time foraging for the drug. Pavlovian drug-associated conditioned stimuli exert a major influence on the initiation and maintenance of drug seeking often long into abstinence, especially when presented response-contingently, acting as conditioned reinforcers that bridge delays to drug use. The acquisition of cue-controlled cocaine seeking has been shown to depend on functional interactions between the basolateral amygdala (BLA) and the nucleus accumbens core (NAcC).

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse.

The anterior insular cortex (AIC) has been implicated in addictive behaviour, including the loss of control over drug intake, craving and the propensity to relapse. Evidence suggests that the influence of the AIC on drug-related behaviours is complex as in rats exposed to extended access to cocaine self-administration, the AIC was shown to exert a state-dependent, bidirectional influence on the development and expression of loss of control over drug intake, facilitating the latter but impairing the former. However, it is unclear whether this influence of the AIC is confined to stimulant drugs that have marked peripheral sympathomimetic and anxiogenic effects or whether it extends to other addictive drugs, such as opiates, that lack overt acute aversive peripheral effects.

Correction: Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Beyond drug-induced alteration of glutamate homeostasis, astrocytes may contribute to dopamine-dependent intrastriatal functional shifts that underlie the development of drug addiction: A working hypothesis.

The transition from recreational drug use to compulsive drug-seeking habits, the hallmark of addiction, has been shown to depend on a shift in the locus of control over behaviour from the ventral to the dorsolateral striatum. This process has hitherto been considered to depend on the aberrant engagement of dopamine-dependent plasticity processes within neuronal networks. However, exposure to drugs of abuse also triggers cellular and molecular adaptations in astrocytes within the striatum which could potentially contribute to the intrastriatal transitions observed during the development of drug addiction.

Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis.

Addiction is regarded as a disorder of inflexible choice with behavior dominated by immediate positive rewards over longer-term negative outcomes. However, the psychological mechanisms underlying the effects of self-administered drugs on behavioral flexibility are not well understood. To investigate whether drug exposure causes asymmetric effects on positive and negative outcomes we used a reversal learning procedure to assess how reward contingencies are utilized to guide behavior in rats previously exposed to intravenous cocaine self-administration (SA).

Impaired decision making following escalation of cocaine self-administration predicts vulnerability to relapse in rats.

Impairments in cost-benefit decision making represent a cardinal feature of drug addiction. However, whether these alterations predate drug exposure, thereby contributing to facilitating loss of control over drug intake, or alternatively arise as a result of drug use and subsequently confer vulnerability to relapse has yet to be determined. Male Sprague-Dawley rats were trained to self-administer (SA) cocaine during 19 daily long-access (12-h) sessions; conditions reliably shown to promote escalation.

Nigrostriatal Dopaminergic Denervation Does Not Promote Impulsive Choice in the Rat: Implication for Impulse Control Disorders in Parkinson's Disease.

Impulse control disorders (ICDs) are frequent behavioral complications of dopaminergic (DA) replacement therapies (DRTs) in Parkinson's disease (PD). Impulsive choice, which refers to an inability to tolerate delays to reinforcement, has been identified as a core pathophysiological process of ICDs. Although impulsive choices are exacerbated in PD patients with ICDs under DRTs, some clinical and preclinical studies suggest that the DA denervation of the dorsal striatum induced by the neurodegenerative process as well as a pre-existing high impulsivity trait, may both contribute to the emergence of ICDs in PD.