Delta 9-Tetrahydrocannabinol and Brain Metabolism

Hammer, Ronald

Abstract

Delta-9-tetrahydrocannabinol (THC), the active constituent of marijuana, is a prevalent psychoactive substance of abuse. Although we do know that it is active in the central nervous system, its mechanism of action and the means by which it produces behavioral alteration are unknown. The experiments proposed in this application will examine the metabolic effects of acute THC administration in the rat brain. A range of THC doses, from low (2mg/kg, 4mg/kg) to moderate (8mg/kg) and high (16 mg/kg, 30mg/kg) will be intravenously administered. Tritiated 2-deoxy-D-glucose (2DG), a high resolution marker for autoradiographic localization of brain metabolism, will be given 30 min after the THC dose and the brain will be sectioned and prepared for autoradiography using (3H)sensitive X-ray film. Autoradiographs will be densitometrically analysed using an image processing system; at least 56 brain regions will be individually outlined on Nissl-stained brain sections and their optical densities will be measured from the corresponding autoradiographs. Ratios of this regional optical density to that of a white matter region in the same section will be calculated. These regional optical density ratios will be statistically compared between THC-treated and control groups and between high and low THC-treated groups to assess the THC-induced changes in regional glucose uptake. Drug-induced alterations in glucose uptake have been used to assess the effect of the drug on regional brain metabolism: specifically, on neuronal or synaptic activity in the region. THC-induced changes in 2DG labeling will help elucidate the mechanism of THC action on the central nervous system. These results will suggest brain loci for further investigations into acute THC mechanisms, putative differences between acute and chronic mechanisms, and regional co-localization of THC receptors and brain metabolism.