The experiments in this project propose to examine the development of the positively reinforcing properties of abused drugs. Two paradigms that are well established in the adult literature and are believed to assess drug abuse potential will be used. These are the conditioned place preference and intracranial electrical self-stimulation paradigms (ICSS). Because of the large literature suggestive of a critical role of the mesolimbic dopamine system in drug abuse and in these two paradigms, the proposed experiments concentrate on the ventral tegmental area of the midbrain (VTA). The effects of morphine and cocaine will be tested in these two paradigms: we will test that ability of these drugs to enhance ICSS responding to stimulation by a VTA located electrode and to support place preference conditioning when injected directly into the VTA. These experiments will determine the development of the reinforcing properties of these two abused drugs and will provide a developmental time frame for in vivo dialysis studies of the effects of these drugs on mesolimbic dopamine function. In a second series of experiments, the effects of early postnatal exposure to morphine and cocaine will be tested in three models of drug abuse vulnerability. The first two are the conditioned place preference and ICSS as described above and the third is self-administration of abused drugs.. Rats dosed chronically during infancy will be tested in these three models; in addition, subjects treated both in infancy and adulthood will be tested. These experiments are unique in that there are no data that speak to the issue of the long term consequences of early perinatal exposure to drugs, despite the large and growing numbers of human infants who have been so exposed. In addition, these treatments serve as independent variables for testing the hypothesis that the action of abused drugs is mediated through the mesolimbic dopamine system. Biochemical studies of in vivo dopamine release and opioid and dopamine receptor autoradiography will pinpoint neurochemical differences caused by the neonatal drug exposure that do or do not correlate with the increased drug abuse vulnerability. The studies therefore provide new and important information about the development of the reinforcing properties of morphine and cocaine, the long term consequences for brain reward mechanisms due to exposure to these drugs, and the neural mechanisms by which these.drugs produce their potent effects on neural systems related to reinforcement.
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