Compulsive alcohol seeking results from a failure to disengage dorsolateral striatal control over behavior

Abstract

The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control over drug seeking progressively devolves to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms. The causal importance of this functional recruitment of aDLS in the switch from controlled to compulsive drug use in vulnerable individuals remains to be established. Here we tested the hypothesis that individual differences in the susceptibility to aDLS dopaminedependent control over alcohol seeking predicts and underlies the development of compulsive alcohol seeking. Male alcohol-preferring rats, the alcohol-preferring phenotype of which was confirmed in an intermittent two-bottle choice procedure, were implanted bilaterally with cannulae above the aDLS and trained instrumentally on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed compulsive seeking behavior. The susceptibility to aDLS dopamine control over behavior was investigated before and after the development of compulsivity by measuring the extent to which bilateral aDLS infusions of the dopamine receptor antagonist ␣-flupenthixol (0, 5, 10, and 15 g/side) decreased alcohol seeking at different stages of training, as follows: (1) after acquisition of instrumental taking responses for alcohol; (2) after alcohol-seeking behavior was well established; and (3) after the development of punishment-resistant alcohol seeking. Only alcohol-seeking, not alcohol-taking, responses became dependent on aDLS dopamine. Further, marked individual differences in the susceptibility of alcohol seeking to aDLS dopamine receptor blockade actually predicted the vulnerability to develop compulsive alcohol seeking, but only in subjects dependent on aDLS dopamine-dependent control.

Dopamine Signaling in the Dorsomedial Striatum Promotes Compulsive Behavior

“…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.…”

“…Dopamine signaling in the DLS is required for habit (Faure et al, 2005), and blocking dopamine signaling in the DLS can inhibit drug seeking for cocaine or alcohol (Corbit et al, 2012;Hodebourg et al, 2018;Murray et al, 2012;Pacchioni et al, 2011;Vanderschuren et al, 2005). The inhibition of drug seeking by DLS dopamine signaling blockade precedes the development of compulsive drugseeking, but can predict which animals will develop it (Giuliano et al, 2019;Willuhn et al, 2012).…”

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

“…The observation that cocaine seeking under a FI15 schedule of reinforcement is impervious to the inhibition of the BLA NAcC pathway at first sight seems inconsistent with the previous demonstration response-contingent optogenetic activation of this pathway in mice supports instrumental responding under continuous reinforcement (36). However, these results taken together with the present data, provide further evidence that instrumental seeking responses are mediated by neural circuits that are dissociable from those mediating directly reinforced taking responses (25), even when emitted within the same behavioural sequence (2). Finally the present results confirm that the BLA is necessary for the acquisition and early onset performance of cue-controlled cocaine seeking, but not its longer-term maintenance (39).…”

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

“…Considering the role of the aDLS in mediating drug-seeking habits (Belin-Rauscent, Everitt, & Belin, 2012;Corbit et al, 2012) and compulsive drug seeking (Giuliano et al, 2019;Jonkman et al, 2012), these data suggest that astrocyte-dependent alterations in the homeostasis of corticostriatal glutamatergic synapses span the different corticostriatal functional loops (Haber, 2016), far beyond the PL → AcbC synapse. Indeed, the PL also projects to the posterior dorsomedial striatum (pDMS) (Vertes, 2004), which is involved in mediating instrumental responses underlined by action-outcome (A-O) associations and early established cue-controlled cocaine seeking behaviour (Murray, Belin, & Everitt, 2012a).…”

“…The progressive transition from ventral to dorsolateral striatal dopamine-dependent control over behaviour has been shown to be a gateway for the development of compulsive drug seeking (Giuliano, Belin, & Everitt, 2019) and, at the neural systems level, to be reliant on dopamine-dependent functional connectivity between the AcbC and the DLS (Belin & Everitt, 2008).…”