Our studies have succeeded in establishing an EEG and behavioral model in the rat whereby the abuse liability and pharmacologic profile of phencyclidine could be compared and contrasted qualitatively and quantitatively with various PCP analogues. Prominent behavioral effects of PCP in rodents are the mixed behavioral activation (stereotypy & locomotion) and ataxia. We have shown that these behavioral effects are dose-dependent and directly associated with characteristic shifts in the EEG power spectra. This EEG and behavioral profile in the rat is characteristic of drugs with psychotomimetic action in humans. The relevance of our EEG and behavioral model is supported by the fact that the cerebral cortex and hippocampus, which contribute mainly to the EEG effects of PCP in the rat and which are thought to be important in mediating many of the behavioral effects of PCP, contain high concentrations of PCP recep- tors. Moreover, the potency of analogues in this model corresponds to their potency and reinforcing efficacy in our rodent self-administration studies. Furthermore, distinctive effects on EEG spectral quantities were defined during self-administration of PCP and two analogues. Additional biological correlates were obtained of effects of self-administered PCP on regional brain 14C-2-deoxyglucose uptake in dopaminergic regions thought to mediate drug reinforcement. Subsequently, in preliminary studies haloperidol attenuated PCP self-administration. The objectives of this continuation proposal are to combine these behavioral, electrophysiologic and self-administration techniques to investigate the consequences of long-term administration of PCP, and to determine pharmacologic treatments which may attenuate PCP self-administration in the rat. We will characterize the development and expression of PCP tolerance and dependence; define receptor/neurotransmitter systems involved in development of tolerance, dependence and maintenance of PCP self-administration; and investigate possible pharmacologic interventions in PCP self-administration and relapse. These studies will, therefore, focus on the hallmarks of chronic drug abuse; tolerance, dependence, maintenance of drug seeking behavior and relapse. A clear definition of these phenomena and an understanding of the neuroanatomical, neurochemical and neurobehavioral bases will ultimately lead to improved methods of treatment and prevention of PCP abuse.
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