U-69593 prevents cocaine sensitization by normalizing basal accumbens dopamine.

Repeated intermittent administration of cocaine (20 mg kg-1, i.p.) for 3 days dramatically increased basal dopamine (DA) overflow in the nucleus accumbens (ACB) 48 h after the final daily injection. This cocaine pretreatment also produced a significant increase in stereotypy in response to a subsequent cocaine challenge. However, when the selective kappa-opioid receptor agonist U-69593 was administered in combination with cocaine for 3 days, these cocaine-induced biochemical and behavioral effects were abolished. It is suggested that the responsiveness of mesolimbic DA neurons to cocaine is intimately related to basal DA concentrations within the ACB and that U-69593, by normalizing cocaine-induced increases in basal DA overflow, may prevent the development of behavioral sensitization to cocaine.