| The upsurge of marijuana use in the 1960's rekindled interest in the pharmacology of the cannabinoids. Although research efforts have focused on both the psychological manifestations and the therapeutic benefits of marijuana use, until recently the mechanism by which marijuana produces its effects in vivo was not readily apparent. To test the hypothesis that THC acts by way of a specific receptor-mediated mechanism, the effect of THC on the in vitro binding of selective radioligands in various neurotransmitter systems was examined. THC was found to have no effect on dopamine, muscarinic cholinergic, GABAergic or benzodiazepine receptors, whereas, mu- and delta-opioid receptor binding was found to be inhibited in a dose-dependent manner. The effect of in vivo acute and chronic THC treatment on the binding properties of mu-opiod receptors was also examined. High dose THC (10 mg/kg) treatment significantly decreased binding density of mu-receptors relative to 1.0 mg/kg THC and vehicle treatment. To evaluate the effect of THC on developing opioid receptors in vivo, the binding properties of mu-opioid receptors following perinatal THC treatment were examined. Both binding affinity and density were affected in THC-treated offspring suggesting that maternal THC administration has a dramatic regionally selective effect on the development of fetal brain opioid receptors. These combined results suggest that there is a regionally-selective, noncompetitive interaction between THC and mu-opioid receptors in rat brain. In the final study, the effect of acute THC administration on regional brain metabolism was examined. THC altered 2- ({dollar}sp3{dollar}H) deoxy-D-glucose uptake in a biphasic, dose-dependent manner in most limbic and cortical structures. Similar results were obtained in a subsequent 2- ({dollar}sp{lcub}14{rcub}{dollar}C) DG study of the effect of CP 55,940, a potent synthetic cannabinoid. Maximal effects of these studies were observed in brain regions known to contain high densities of cannabinoid receptors. Therefore, the finding that both THC and CP 55,940 affect metabolic activity in a biphasic, dose-dependent manner in the same brain regions suggests that these compounds act at the same site. Thus, these results support the notion that THC acts by way of a receptor-mediated mechanism. |
