GENETIC FACTORS IN DRUG SELF-ADMINISTRATION

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Molecular genetic manipulations in mice provide some of the most sophisticated means for investigating the neurobiology, psychophysiology and psychopharmacology of abused drugs. Our laboratory is specifically interesting in the integration of molecular biology, behavior genetics and behavior pharmacology. To date, our laboratory has examined intravenous opioid self-administration behavior in two inbred (C57, BALB), two recombinant inbred (mu-deficient CXBK, opiate-rich CXBH) and transgenic lines of mice (overexpressing superoxide-dismutase, overexpressing mu-opiate receptor). These mice are some of the most divergent lines available in terms of CNS opiate receptor concentration. CXBK mice have 25-40% fewer mu-opiate receptors than C57 mice while insertion of the Cu/Zn-superoxide dismutase (SOD) or rat mu-opiate receptor transgene results in 17-60% region-specific increase in CNS mu- opiate receptors. The goal of these experiments are to use the genotype x region variation in mu-opiate receptor concentration to provide a means to identify neural regions significantly associated with the efficacy of morphine as a reinforcer using a non-invasive technique. As a preliminary step in this process, multivariate analysis of the relationship between neuroanatomical region and self-administration behavior was performed by correlating the mean genotypic value for the dependent variable obtained in the PR self-administration project with a mean 'set' of mu-opiate receptor binding values obtained in each genotype using 125I-DAMGO autoradiographic techniques. Preliminary results of these studies demonstrate that 1) The genotype of the subject significantly affects the efficacy of morphine as a reinforcer, 2) Genotype significantly affects the concentration and regional distribution of mu-opiate receptors, 3) No one region can account for the genetic variance seen in morphine self-administration behavior and 4) Consideration of the relative concentration of mu-opiate receptors in the ventral tegmental area, shell of the nucleus accumbens and amygdala may account for a significant portion of the genetically based variance seen in behavior maintained by morphine injections.