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Abstract
Alcohol use disorder is a chronic, debilitating condition with current treatments characterised by a persistent propensity to relapse. Improving understanding of relapse is imperative to the development of more effective treatments. This thesis examined the role of nucleus accumbens shell (AcbSh) and its major output pathways in promoting and preventing relapse in a rat model of alcoholic beer seeking. First, two major AcbSh projections, to lateral hypothalamus (LH) and to ventral tegmental area (VTA), were shown to arise from distinct populations of neurons. The AcbSh to VTA projection was found to be critical for promoting relapse, specifically context-induced reinstatement and reacquisition. This was independent of any role in drug self-administration, locomotor activity, or motivation. The effect on relapse was recapitulated by activation of VTAGad1 neurons, suggesting that AcbSh exerts inhibitory control over this population to control relapse. It was then shown that AcbSh to LH projection is important for the suppression of drug seeking following extinction. This was also independent of any role in locomotor activity or self-administration. This role did, however, depend on the presence of a contextual memory of self-administration. The effect on extinction was recapitulated by activation of LHGad1 neurons. Consistent with a role in promoting extinction, stimulation of AcbSh to LH pathway prevented relapse, although this was not mediated by LHGad1 neurons. Taken together, these results show that distinct AcbSh output pathways promote abstinence versus relapse to alcohol seeking. Both projections emerge from AcbSh medium spiny neurons and interact with Gad1 neuronal populations in their downstream projection targets. These common circuit motifs have important implications for pharmacological approaches to treatment of substance use disorders, as current therapeutics lack the target specificity that would be required to distinguish between these two projections.