A cortical-brainstem circuit predicts and governs compulsive alcohol drinking

Siciliano, Cody A.; Noamany, Habiba; Chang, Chia-Jung; Brown, Alex; Chen, Xinhong; Leible, Daniel; Lee, Jennifer J.; Wang, Joyce; Vernon, Amanda; Weele, Caitlin M. Vander; Kimchi, Eyal Y.; Heiman, Myriam; Tye, Kay M.

doi:10.1126/science.aay1186

Cited by 177 publications

(198 citation statements)

References 48 publications

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“…Compulsive sucrose-seeking is relatively understudied, while many more previous studies have examined compulsive drug-seeking. Large individual variability in compulsivity has been observed in animals working for drugs such as cocaine and alcohol (Giuliano et al, 2019;Siciliano et al, 2019). Consistent with those findings, we also found large individual differences in compulsivity.…”

Section: Discussionsupporting

confidence: 92%

Dopamine Signaling in the Dorsomedial Striatum Promotes Compulsive Behavior

Jl¹,

Cv²,

Vn³

et al. 2020

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Habits and compulsions are two aspects of behavior that often develop in parallel and together lead to inflexible responding. Both habits and compulsions are hypothesized to be involved in psychiatric disorders such as drug addiction and obsessive-compulsive disorder (OCD), but they are distinct behaviors that may rely on different brain circuitries. We developed an experimental paradigm to track the development of both habits and compulsions in individual animals while recording neural activity. We performed fiber photometry measurements of dopamine axon activity while mice engaged in reinforcement learning on a random interval (RI60) schedule and found that the emergence of compulsion was predicted by the dopamine signal in the dorsomedial striatum (DMS). By amplifying this DMS dopamine signal throughout training using optogenetics, we accelerated animals' transitions to compulsion, irrespective of habit formation. These results establish DMS dopamine signaling as a key controller of compulsions.

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Section: Discussionsupporting

confidence: 92%

Dopamine Signaling in the Dorsomedial Striatum Promotes Compulsive Behavior

Jl¹,

Cv²,

Vn³

et al. 2020

Preprint

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“…These resistant rats displayed behaviours that have been suggested to be the operationalisation in rodents of two features that characterise AUD, namely compulsive drinking behaviour and decreased interest for reinforcers other than the drug itself [25][26][27] . In line with previous studies 26,34,40 , the development of compulsive drinking behaviour in vulnerable animals was shown not to be predicted by the individual tendency to drink high levels of alcohol, thereby confirming that the development of this behavioural feature of alcohol addiction is not simply related to the magnitude of pharmacological exposure to alcohol. This dissociation, which challenges a drug-centred view of drug addiction and further emphasising the importance of factors of vulnerability 41,42 , is not restricted to alcohol.…”

Section: Discussionsupporting

confidence: 87%

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

Martí‐Prats

Belin

Fouyssac

et al. 2020

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AbstractWhile 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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“…Interestingly, others have demonstrated that reductions in neural activity of dmPFC projections to the brainstem could induce compulsive alcohol drinking behavior in mice, supporting the idea that disengagement of the dmPFC contributes to compulsive action 55 .…”

Section: Discussionmentioning

confidence: 80%

Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior

Davis

Minerva

Lario

et al. 2020

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AbstractObsessive-Compulsive Disorder (OCD), characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions), is associated with dysfunction in fronto-striatal circuits. There are currently no fastacting pharmacological treatments for OCD. However, recent clinical studies demonstrated that an intravenous infusion of ketamine rapidly reduces OCD symptoms. To probe mechanisms underlying ketamine’s therapeutic effect on OCD-like behaviors, we used the SAPAP3 knockout (KO) mouse model of compulsive grooming. Here we recapitulate the fast-acting therapeutic effect of ketamine on compulsive behavior, and show that ketamine increases activity of dorsomedial prefrontal neurons projecting to the dorsomedial striatum in KO mice. Optogenetically mimicking this increase in fronto-striatal activity rescued compulsive grooming behavior in KO mice. Conversely, inhibiting this circuit in wild-type mice increased grooming. These studies demonstrate that ketamine increases activity in a fronto-striatal circuit that causally controls compulsive grooming behavior, suggesting this circuit may be important for ketamine’s therapeutic effects in OCD.

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A cortical-brainstem circuit predicts and governs compulsive alcohol drinking

Cited by 177 publications

References 48 publications

Dopamine Signaling in the Dorsomedial Striatum Promotes Compulsive Behavior

Dopamine Signaling in the Dorsomedial Striatum Promotes Compulsive Behavior

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

Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior

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