The overall objectives of this proposal are to determine the abuse liability of phencyclidine (PCP) and selected PCP analogues and to develop profiles of their pharmacologic effects which can be correlated with their abuse potential. Structure activity relationships (SAR's) will be determined for analogues selected on the basis of substitutions on the three functional groups of the phenylcyclohexylamine nucleus of PCP. Specificically, we will investigate the abuse liability of PCP and PCP analogues in rats trained to respond during a self-administration paradigm. Drugs will be substituted for cocaine and once the reinforcing doses are identified, the relative reinforcing efficacy will be determined using a progressive ratio procedure. Electroencephalographic (EEG) correlates (using power spectral analysis techniques) of these analogues will be obtained in an attempt to identify significant features present in the EEG which may relate to the reinforcing properties of these drugs. Assessment of the other pharmacologic effects of PCP and PCP analogues including analgesic potency, anesthetic potency, effects on overt behavior, locomotor activity and forced motor performance will be obtained and correlated with the results of assessment of reinforcing potency and efficacy and effects on the EEG power psectrum. These assays will be quantified using the hotplate method, the loss of righting reflex, rating on a behavioral inventory, the annular activity cage, and the rotorod apparatus, respectively. The data from this study will be important with respect to defining those PCP analogues which may have a high abuse potential and to defining possible electrophysiological and behavioral determinants of their abuse potential. Additionally, through these studies we will establish a model in the rat for future investigations of the electrophysiological and behavioral consequences of long-term self-administration of PCP and PCP analogues. After refining and validating the model, we will utilize it in future investigations of other drugs of abuse such as sedatives and hypnotics, CNS stimulants, and opioids in order to better understand the relationship between chemical structure, pharmacologic action, and abuse potential of a drug.
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