ADAPTATIONS IN THE MESOACCUMBENS DOPAMINE SYSTEM RESULTING FROM REPEATED ADMINISTRATION OF DOPAMINE D-1 AND D-2 RECEPTOR-SELECTIVE AGONISTS- RELEVANCE TO COCAINE SENSITIZATION

The mesoaccumbens dopamine (DA) system is intricately involved in sens itization to the locomotor stimulant effects of cocaine. Among the ada ptations implicated in cocaine sensitization are transient subsensitiv ity of impulse-regulating DA D-2 autoreceptors on ventral tegmental ar ea (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA p athway, and persistently enhanced DA D-1 receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of t hese adaptations are necessary to produce cocaine sensitization. We in jected rats twice daily for 2 weeks with the selective DA D-1 class re ceptor agonist SKF 38393, the DA D-2 class receptor agonist quinpirole , or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D-1 re ceptor sensitivity at three withdrawal times: 1 day, 1 week and 1 mont h. We also tested whether these treatments produced cross-sensitizatio n to cocaine at each withdrawal time, Repeated quinpirole treatment pr oduced a reduction in VTA autoreceptor sensitivity and cross-sensitiza tion to cocaine, but these effects lasted for less than 1 week. Repeat ed SKF 38393 treatment produced enhanced NAc D-1 responses which laste d for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination o f the two agonists transiently down-regulated autoreceptor sensitivity , enhanced and prolonged D-1 receptor supersensitivity (lasting 1 mont h), and produced enduring cross-sensitization to cocaine. These result s suggest that neuroadaptations within both the VTA and NAc may be nec essary for the induction of enduring cocaine sensitization.