Dopaminergic Circuits for Compulsion: The Dorsomedial Striatum in Punishment-Resistant Reward-Seeking

Compulsive behavior is a defining feature of disorders such as substance use disorder and obsessive-compulsive disorder. Current evidence suggests that corticostriatal circuits control the expression of established compulsions, but little is known about the mechanisms regulating the development of compulsions. This work hypothesized that dopamine, a critical modulator of striatal synaptic plasticity, could control alterations in corticostriatal circuits leading to the development of compulsions (defined as continued reward-seeking in the face of punishment). The first aim utilized dual-site fiber photometry to measure dopamine axon activity in the dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) as compulsions emerged. Individual variability in the speed with which compulsions emerged was predicted by DMS dopamine axon activity. In the second aim, we manipulated the activity of DMS and DLS dopamine terminals using excitatory and inhibitory optogenetics. Amplifying the DMS dopamine signal accelerated animals’ transitions to compulsion, whereas inhibition led to learning delays. In contrast, amplifying DLS dopamine signaling had no effect on the emergence of compulsions. These results establish DMS dopamine signaling as a key controller of the development of compulsive reward-seeking.