Biology subjects

Everitt, B. J.

Publications and source records attributed to Everitt, B. J..

6 recordsLinked to original sources

bioRxiv2022

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 naive 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.

neuroscience↗

bioRxiv2022

The development of compulsive coping behaviors depends on the engagement of 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 distress. Some individuals, in particular those that use alcohol to self-medicate, tend to lose control over such coping behaviors, which become excessive and compulsive. However, the psychological and neural mechanisms underlying this individual vulnerability have not been elucidated. Here we tested the hypothesis that the development of compulsive adjunctive behaviors stems from the functional engagement of the dorsolateral striatum (DLS) dopamine-dependent habit system after a prolonged history of adjunctive responding. We measured in longitudinal studies in male Sprague Dawley rats the sensitivity of early established vs compulsive polydipsic water or alcohol drinking to a bilateral infusion of the dopamine receptor antagonist -flupentixol into the anterior DLS (aDLS). While most rats acquired a polydipsic drinking response with water, others only did so with alcohol. Whether reliant on water or alcohol, the acquisition of this coping response was insensitive to aDLS dopamine receptor blockade. In contrast, after prolonged experience, adjunctive drinking became dependent on the aDLS dopamine-dependent habit system at a time it was compulsive in vulnerable individuals. These data suggest that habits may develop out of negative reinforcement and that the engagement of their underlying striatal system is necessary for the manifestation of adjunctive behaviors. Significance statementHarnessing the individual variability that rodents, like humans, show to engage in adaptive or maladaptive coping strategies, which can result in the development of compulsive disorders, here we demonstrate that the functional engagement of the dorsolateral striatum-dependent habit system precipitates the transition to compulsion in rats that have acquired a polydipsic adjunctive drinking response with water or alcohol as a means to cope with distress. The results of this study not only provide evidence for the emergence of instrumental habits under negative reinforcement, but they also reveal that compulsive behaviors that originate from the loss of control over coping strategies are mediated by the dorsolateral striatum-dependent habit system.

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bioRxiv2021

Maladaptive cue-controlled cocaine-seeking habits promote increased relapse severity in rats.

The inflexible pursuit of drug-seeking and great tendency to relapse that characterize addiction has been associated with the recruitment of the dorsolateral striatum-dependent habit system. However, the mechanisms by which maladaptive drug-seeking habits influence subsequent relapse are obscure. Here, we show that rats with a long history of cocaine-seeking, controlled by drug-paired cues and mediated by the habit system, show highly exacerbated drug-seeking at relapse that is not mediated by cocaine withdrawal. This heightened tendency to relapse is underpinned by transient engagement of the dorsomedial striatum goal-directed system and reflects emergent negative urgency resulting from the prevention of enacting the seeking habit during abstinence. These results reveal a novel mechanism underlying the pressure to relapse and indicate a target for preventing it. One Sentence SummaryInstrumental deprivation triggers flexibility in the well-established cue-controlled cocaine-seeking behaviour.

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bioRxiv2020

Individual differences in the engagement of habitual control over alcohol seeking predicts the development of compulsive alcoholseeking 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. Here, we tested the hypothesis that the development of habitual alcohol-seeking predicts the development of compulsive seeking and that, once developed, it is associated with compulsive alcohol drinking. Male alcohol-preferring rats were pre-exposed intermittently to a two-bottle choice procedure, and trained on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed punishment-resistant seeking behaviour. The associative basis of their seeking responses was probed with an outcome-devaluation procedure, early or late in training. After seeking behaviour was well established, subjects that had developed greater resistance to outcome-devaluation (were more habitual) were more likely to show punishment-resistant (compulsive) alcohol seeking. These individuals also drank more alcohol, despite quinine adulteration, even though having similar alcohol preference and intake before and during instrumental training. They were also less sensitive to changes in the contingency between seeking responses and alcohol outcome, providing further evidence of recruitment of the habit system. We therefore provide direct behavioural evidence that compulsive alcohol seeking emerges alongside compulsive drinking in individuals that have preferentially engaged the habit system.

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bioRxiv2020

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

While most individuals with access to alcohol drink it recreationally, about 5 % lose control over their intake and progressively develop an alcohol use disorder (AUD), characterised by compulsive alcohol drinking accompanied by decreased interest in alternative sources of reinforcement. The neural and molecular mechanisms underlying the vulnerability to switch from controlled to compulsive alcohol intake have not been fully characterized, so limiting the development of new treatments for AUD. It has recently 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. Here, we tested the hypothesis that the GABAB receptor agonist baclofen, which decreases GABA release, specifically decreases compulsive alcohol drinking in vulnerable individuals. In a large cohort of Sprague-Dawley rats allowed to drink alcohol under an intermittent two-bottle choice procedure, a cluster of individuals was identified that persisted in drinking alcohol despite adulteration or the availability of an alternative ingestive reinforcer, saccharin. In these rats, that were characterised by decreased GAT-3 mRNA levels in the central amygdala, acute baclofen administration (1.5 mg/kg, intraperitoneal) resulted in a decrease in compulsive drinking. These results indicate that low GAT-3 mRNA levels in the central amygdala represent an endophenotype of AUD and that the associated compulsive alcohol drinking characteristic is sensitive to baclofen.

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bioRxiv2020

The Basolateral amygdala --> Nucleus Accumbens core circuit mediates the conditioned reinforcing effects of cocaine-paired cues on cocaine seeking.

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 core of the nucleus accumbens (NAcC). However, the precise neuronal circuits underlying the acquisition of cue-controlled cocaine seeking behaviour have not been elucidated. Here we used a projection-specific Cre-dependent DREADD-mediated causal approach to test the hypothesis that the direct projections from the BLA to the NAcC are required for the acquisition of cue-controlled cocaine seeking behaviour. In Sprague Dawley rats with cre-mediated expression of the inhibitory DREADD Hm4Di in the NAcC projecting BLA neurons, treatment with CNO, but not vehicle, selectively prevented the impact of cocaine-associated conditioned reinforcement on cocaine seeking under a second-order schedule of reinforcement. This effect was attributable to the chemogenetic inhibition of the NAcC projecting BLA neurons as it was reversible, and absent in CNO-treated rats expressing an empty control virus. In contrast, chemogenetic inhibition of the anterior insula, which receives collateral projections from NAcC projecting BLA neurons, was without effect. These data demonstrate that the acquisition of cue-controlled cocaine seeking that depends on the conditioned reinforcing effects of cocaine cues require activity in the direct projections from the basolateral amygdala to the nucleus accumbens core.

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