Phencyclidine (PCP) is a significant drug of abuse. Among the factors which may determine the abuse liability of PCP, genetically determined predisposition to PCP effects may play a significant role. The proposed experiments will test the hypothesis that genetic determinants of behavioral responsiveness to PCP is linked to and therefore predictive of neurochemical responsiveness to PCP in genetically defined mice. Genetically defined mice will be used to isolate the PCP responsiveness trait using changes in locomotor activity and motor ataxia as the behavioral endpoints. This approach has been used successfully to analyze determinants of responsiveness to other psychoactive drugs (e.g., stimulants and sedatives). To date, there have been relatively few studies published which examine the genetic determinants of PCP responsiveness. There appears to be more than one mechanism of PCP's behavioral effects. If these mechanisms are determined by different genes, then it should be possible using classical genetic analysis to isolate responsiveness to specific mechanisms of PCP's behavioral effects. The projects proposed are designed to isolate locomotor activity responsiveness to PCP and determine if this behavioral effect is associated with PCP-induced changes in the component processes of dopamine (DA) neuron function in specific brain regions from the progenitor strains and their classical crosses (F1, F2 and backcross generations). The component processes which will be characterized include endogenous DA release and DA metabolism, DA autoreceptor modulation of DA release, [3H]DA uptake, binding to the recognition site associated with the DA transporter and monoamine oxidase activity. Inherent differences in the parameters that describe each of the neurochemical measures will be characterized, and subsequently inherent differences in the effect of PCP determined. Among the drugs of abuse which affect DA systems, in this study we will compare inherent differences in PCP and cocaine responsiveness. The generality of the correlation between PCP-induced effects on locomotor activity and specific regional changes in DA function will begin to be determined in the progenitor strains using PCP receptor agonists (TCP, MK801 and ketamine) and drugs (cocaine, GBR 12909 and BTCP) which act at the DA transporter complex. We will test the hypothesis that PCP responsiveness is inherited as a single dominant gene. Future studies will use classical genetic analysis to determine if PCP behavioral and neurochemical responsiveness co-segregates with behavioral and neurochemical responsiveness to these drugs.
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