Chronic cocaine exposure alters D1 medium spiny neuron activity to promote relapse

Learned associations between environmental cues and experience are the basis of decision‐making and allow organisms to guide behavior towards advantageous outcomes. Dysfunction in the processes that regulate these associations, especially in the nucleus accumbens, is a critical factor in the underlying pathology of addiction. The nucleus accumbens is a heterogeneous region composed of both D1 and D2 medium spiny projection neurons (MSNs), and understanding the cell‐type specific signals that mediate learning processes has far reaching implications for treatment. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in the brain that encodes drug associations. Chronic cocaine exposure dysregulates the temporally specific D1 signals that encode contextual information to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Further, manipulating the D1 signal using designer receptors exclusively activated by designer drugs (DREADD), even after associations have been formed, can eliminate these associations indefinitely. Together, these data elucidate the underlying neural processes that control associative learning and how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse following abstinence. Further, these processes have been localized to a single cell population in the nucleus accumbens that can be manipulated to attenuate the strength of these associations and prevent relapse. Support or Funding Information This work was supported by grants from the National Institute on Drug Abuse and Brain & Behavior Research Foundation.