It is proposed to conduct detailed quantitative analyses of the effects of long-term administration of delta-9-tetrahydrocannabinol (THC) on brain structure in a mammalian species (rats). Both electron and light microscopic variables will be measured. In addition, it is proposed to determine whether long-term effects on brain ultrastructure are correlated with residual behavioral effects, as assessed on a maze reversal learning task one month after THC treatment is stopped. There have apparently been no systematic animal studies on the brain structural effects of long-term exposure (e.g., 15-30% of the life span) to a psychoactive component of marijuana, although chronic use of marijuana is increasingly common in our society. Further, there have been no tests of the possibility that residual behavioral effects of chronic exposure are correlated with brain structural changes. It is therefore proposed to study brain morphologic changes in a well defined region of a limbic system structure (hippocampus) in rats given several dosages of delta-9-THC 5 x weekly for 8 mo. (e.g., for about 30% of the life span). The paradigms and quantitative approaches used are similar to those we previously developed for examining long-term effects of steroids on the ultrastructure of rat hippocampus. It will also be determined: 1) whether adolescent rats are more susceptible than older rats to chronic THC effects on the brain; 2) whether a shorter period of treatment (4 mo. or about 15% of the life span) is sufficient to induce brain structural change; and 3) whether any observed long-term effects of THC on brain structure are reversible. Since the methods we propose to use appear to be highly sensitive and reliable, these studies seem likely to yield a definitive answer to the question of whether brain structural effects result from chronic exposure to an active component of marijuana. Moreover, these studies should provide important information on relations of brain morphology to behavior, and on the nature of mechanisms that normally modulate long-term brain structural remodeling.
