Dopamine signaling in the dorsomedial striatum promotes compulsive behavior

Compulsive behavior is a defining feature of disorders such as substance use disorders. Current evidence
suggests that corticostriatal circuits control the expression of established compulsions, but little is known
about the mechanisms regulating the development of compulsions. We hypothesized that dopamine, a critical modulator of striatal synaptic plasticity, could control alterations in corticostriatal circuits leading to the
development of compulsions (defined here as continued reward seeking in the face of punishment). We used
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. Amplifying this dopamine signal accelerated
animals’ transitions to compulsion, whereas inhibition delayed it. 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.