Cholinergic interneurons and synaptic reorganization within the nucleus accumbens shell and core: potential neural substrates underlying drug addiction

Drug abuse and dependence are among the most challenging public health issues facing America today. The acute treatment of drugs of abuse such as psychostimulants (Trantham-Davidson and Lavin, 2004) and opiates (Harris and Williams, 1991) produce transient changes in cellular activity and synaptic signaling. Repeated drug treatment, however, results in persistent cellular and behavioral changes, such as altered dendritic morphology and behavioral sensitization (Robinson and Kolb, 1999b). Synaptic changes in the brain are posited to underlie a repertoire of drug-induced persistent behaviors, including sensitization, psychosis and relapse. Direct evidence of drug-induced synaptic plasticity, however, has not been demonstrated. The present studies were designed to examine cholinergic neurons and synaptic rewiring as potential neural substrates involved in acute and chronic drug exposure. The proposed studies tested the hypotheses that 1) cholinergic interneurons within the nucleus accumbens (NAcc) are activated by the acute self-administration of cocaine, 2) dopamine (DA) D5 and D2 receptors localized on cholinergic interneurons potentially undergo cocaine-induced neuroadaptation, and 3) repeated administration of cocaine leads to an increase, while repeated administration of morphine leads to a decrease, in the number of synapses within the NAcc, whereas an increase in the number of synapses occurs in the NAcc core of animals exhibiting behavioral sensitization. These studies revealed that accumbal cholinergic interneurons are activated by acute cocaine self-administration and elucidate the specific localization of DA receptor subtypes, D5 and D2, on these cells, suggesting their potential role in mediating druginduced DA changes within the NAcc. The final study provided the first ultrastructural evidence that an increase in the number of excitatory synapses in the NAcc shell occurs following 4-weeks of cocaine and morphine treatment followed by 3 weeks abstinence and that cocaine sensitization is associated with an increase in the number of excitatory synapses in the NAcc core. These findings provide the groundwork for future studies examining the precise cellular and synaptic substrates underlying a repertoire of druginduced behaviors that contribute to the persistence of addiction. Improved pharmacotherapeutic and behavioral treatments can then target the specific cellular and synaptic microcircuitry critically involved in the different stages of drug abuse and dependence.