Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens

Chronic exposure to cocaine causes long-lasting behavioral changes associat ed with cocaine reinforcement and addiction. An important neural substrate for cocaine addiction is the nucleus accurnbens (NAc), which receives dopam inergic input from the ventral tegmental area. Although the neural circuit of the NAc is controlled by several other neurotransmitters, their involvem ent in cocaine addiction remains elusive. In this investigation, we ablated cholinergic interneurons from the adult NAc with immunotoxin-mediated cell targeting and examined the role of acetylcholine transmitter in adaptive b ehavioral changes associated with cocaine reinforcement and addiction. Acut e exposure to cocaine induced abnormal rotation in unilaterally cholinergic cell-eliminated mice, This abnormal turning was enhanced by repeated ex su re of cocaine. In bilaterally cholinergic cell-eliminated mice, chronic coc aine administration induced a prominent and progressive increase in locomot or activity. Moreover, these mice showed robust conditioned place preferenc e with a lower dose of cocaine, compared with wild-type littermates. This i nvestigation demonstrates that acetylcholine in the NAc plays a key role in both acute and chronic actions of cocaine.