In order to determine whether chronic exposure to delta9tetrahydrocannabinol (THC) alters brain structure in rats, we conducted extensive quantitative light and electron microscopic analyses of a strictly defined region of hippocampal field CA1 during the preceding phase of this project. We found that 5 x weekly administration (s.c.) of THC for 8 months to youngmature rats resulted in reduced neuronal density and increased astroglial reactivity. The doses of THC used did not induce toxicity or strongly affect behavoir. These effects of THC on brain structure appear highly similar to those that occur spontaneouly during normal aging in rats, or that occur in young rats treated with high doses of glucocorticoids. It therefore seemed of interest that we also confirmed prior reports that THC increases the release of adrenal corticosteroids. Based on these results, it is proposed in this application to use a higher, but still tolerated, dose of THC, in order to determine whether the brain aging-like patterns that THC induces in young rats can be accentuated, particularly at the ultrastructural level, as a means of examining underlying mechanisms of synaptic degeneration and remodeling. It is also proposed to further test the view (suggested by your prior results) that THC may accelerate normal brain aging processes, by chronically treating young rats with THC, allowing them to age in our colony for an additional 12 months after cessation of THC treatments, and then quantitatively comparing the degree of brain aging pathology to sameage vehicle controls. It is also proposed to examine the view that THC acts on the brain by corticoid-like effects (either directly, or by increasing endogenous steroid release) by studying the brain morphological effects of THC in chronically adrenalectomized animals, by correlating plasma hormone and THC levels with brain effects, and by studying THC interactions with specific brain glucocorticoid receptors.
