Extinction of Cocaine Self-Administration Induces Metaplasticity in Nucleus Accumbens

Cocaine addiction remains a significant problem and is thought to be a disorder of pathologically strong associations between environmental stimuli, motivated action, and drug reward. Behavioral exposure therapies that repeatedly present the addicted patient with cues but not drug could theoretically break this pathological association and enable addicts to refrain from drug seeking. The neurobiological basis for the learned association between environmental stimuli and drug seeking has been well characterized, especially regarding its involvement of glutamatergic synaptic plasticity in the nucleus accumbens. The learning that ultimately countermands the motivational value of the learned drug associations and leads to patients refraining from drug seeking may likewise rely on glutamatergic synaptic plasticity in nucleus accumbens. This therapeutic learning to inhibit drug seeking can be modeled in animals by extinction training, in which an operant response (e.g. lever press) that previously delivered drug fails to deliver a drug reinforcement, and animals gradually learn to refrain from emitting the operant response. In the experiments contained in this thesis, I demonstrate that extinction training induces a form of metaplasticity in D2 dopamine receptor-­‐expressing medium spiny neurons (D2-­‐MSNs). This enables D2-­‐MSNs to undergo transient synaptic potentiation (tSP) when an animal is given the opportunity to seek drug, and the D2-­‐MSN potentiation suppresses drug seeking. In contrast, D1-­‐MSN tSP underlies drug seeking and is not altered by extinction training. Finally, tSP during refraining is distinct from tSP during reinstatement in its cellular expression profile, anatomical locus, and signaling mechanisms. Overall, these findings suggest that mechanisms supporting synaptic potentiation of D2-­‐MSNs may present therapeutic targets for the treatment of cocaine addiction