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Context has an important role in addictive disorders: exposure to contexts previously associated with drug use promotes relapse, whereas exposure to contexts associated with abstinence can protect against such relapse. In a new study, Gibson et al. describe the opposing roles of two nucleus accumbens output pathways in context-specific relapse of alcohol seeking in rats.

The shell of the nucleus accumbens (AcbSh) contributes to the contextual control of both relapse and abstinence, but how it mediates these opposing effects is unknown. Here, Gibson et al. found that two discrete populations of dopamine 1 receptor-expressing neurons in AcbSh project to the ventral tegmental area (VTA) and lateral hypothalamus (LH), where they make monosynaptic inhibitory connections with GABAergic neurons.

To investigate the contributions of these projections to the promotion or prevention of relapse, the authors used a well-established model of context-induced reinstatement. Rats were trained to respond with a particular behaviour to receive an alcoholic reward in one context, and then extinction training took place in a second context, in which the response produced no reward. As expected, animals re-exposed to the initial context rapidly reinstated their behavioural response; however, optogenetic inhibition of VTA-projecting AcbSh neurons or chemogenetic excitation of the VTA GABAergic neurons to which they project prevented this reinstatement, indicating that the AcbSh–VTA projection is necessary for context-induced relapse.

the AcbSh–VTA projection is necessary for context-induced relapse

Optogenetic inhibition of the AcbSh–LH pathway had no effect on context-induced reinstatement; however, optogenetic excitation of this pathway prevented reinstatement. Furthermore, inhibition of the AcbSh–LH pathway or chemogenetic excitation of LH GABAergic neurons prevented the extinction of drug-seeking behaviour in a single-context paradigm, indicating a role for this pathway in the prevention of relapse.

This study demonstrates that distinct output pathways of a single brain subregion mediate the opposing effects of context on drug-seeking behaviour. Understanding these complex control pathways may provide new avenues for their therapeutic manipulation in addictive disorders.