Relationship between the subcellular distribution of delta-9-tetrahydrocannabinol and its metabolites in rat brain and the duration of the effect on motor activity

Abstract

Female rats were injected intraperitoneally with 10 mg/kg of unlabelled delta-9-tetrahydrocannabinol ( Δ 9-THC) and their locomotor activity was recorded every 15 minutes for 12 hours. The maximum depressant effect was observed between the first and fourth hour and had completely disappeared by the eighth hour of treatment. In parallel experiments rats were injected with 10 mg/kg of 3H-delta-9-THC and decapitated either one, four or twelve hours later. The concentrations of unchanged delta-9-THC and metabolites in brain subcellular fractions were determined using thin layer chromatographic methods. There were no substantial differences in the relative specific activities of delta-9-THC or 11-OH-delta-9-THC between all fractions except cytosol, indicating no preferential site of accumulation. However, when the synaptosomal fraction was osmotically shocked, the concentration of delta-9-THC in nerve-ending membranes was markedly higher than that in vesicles or soluble fraction. Our results in vivo showed a marked decline, over twelve hours, in the relative specific activities of delta-9-THC and 11-OH-delta-9-THC with a concomitant increase in the concentration of highly polar, non-extractable metabolites in all subfractions. It is suggested that the diminution of the depressant effect on motor activity may be related to the formation of highly polar, pharmacologically inactive metabolites of delta-9-THC and/or 11-OH-delta-9-THC inside the brain which do not easily migrate out of the cells.