Dopamine in the Nucleus Accumbens Shell Mediates Acute Opiate Withdrawal

Abstract

The onset of withdrawal after cessation of drug use is one of the defining characteristics of opiate addiction. Addiction is in part driven by negative reinforcement in an attempt to alleviate negative emotional states during withdrawal. Evidence suggests that opiate withdrawal is characterized by diminished neurotransmission in the mesolimbic dopamine system. However, it is not known where dopamine’s actions may play a role during withdrawal. We hypothesized that acute withdrawal occurs when dopamine levels diminish after the initial morphine-induced surge. We microinfused a non-specific dopamine receptor agonist into three structures downstream of the ventral tegmental area, where morphine exerts its primary effects. Using the withdrawal-potentiated startle (WPS) paradigm to measure anxiety-like symptoms of withdrawal, we found that apomorphine, a dopamine receptor agonist, attenuates withdrawal symptoms when administered into the nucleus accumbens (NAc) shell. Our results demonstrate the involvement of dopamine receptor activity in morphine withdrawal, and suggest that withdrawal is brought on by declining levels of dopamine in the NAc. This finding is one of the first to show that dopamine modulates the rewarding as well as aversive properties of morphine, implicating a possible mechanism for the transition from early opiate use to dependence.