Despite the fact that marihuana is one of the major drugs of abuse, relatively little is known regarding the mechanism by which its principal psychoactive constituent, delta 9- tetrahydrocannabinol (THC), produces its subjective effects. It is hypothesized that the behavioral effects of delta 9-THC represent a composite of effects that arise from the actions of cannabinoids produce these behavioral effects. The emphasis will be directed toward determining whether behavioral effects of delta 9-THC are mediated either through a specific cannabinoid receptor or through membrane perturbation. Therefore, a major objective will be to determine whether the pharmacological profile of cannabinoids can be separated into individual behavioral components by evaluating synthetic analogs for their ability to produce motor hypoactivity, hypothermia, catalepsy and antinociception in mice, stimulus generalization to delta 9-THC in delta 9-THC trained rats and monkeys and behavioral effects (static ataxia) in dogs. Partition coefficients of the analogs will be determined as well as the degree to which the analogs cause membrane perturbation. A correlation between the pharmacological profile of the analogs and their actions on these biochemical systems should provide insight into their mechanism of action. In addition, efforts will be made to determine whether or not specific cannabinoid receptor exists. Attempts will be made to establish an in vitro binding assay by synthesizing radiolabeled ligands that regain behavioral activity but are less lipophilic than delta 9-THC. These radiolabeled ligands will include potential photoaffinity labels (azido compounds) as well as nitrogen mustards. Efforts will also be made to isolate specific binding sites by affinity chromatography. In addition, attempts will be made to develop a specific cannabinoid antagonist. The analogs that exhibit little or no agonistic activity will be evaluated in the above mentioned behavioral tests as potential antagonists of delta 9-THC. The results of these experiments will provide important insights into the mechanism by which cannabinoids produce their central effects. Identification of the neurochemical processes involved in the subjective effects of cannabinoids will lead to a better understanding of the etiology of recreational use of marihuana and may lead to the development of an effective deterrent. In addition, identification of the biochemical events associated with cannabinoid behavioral effects may provide insights into the processes involved in mental abberations.
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