Previous studies have shown that the development of neuropathology in the hippocampus of aging rats appear to be dependent in part on glucocorticoid actions on the hippocampus. In addition, recent studies have shown that long-term exposure to delta-9-tetrahydrocannabinol (THC) can induce a similar aging-like pattern of hippocampal neuropathology in young rats. Because of a resemblance between the molecular structure of cannabinoids and adrenal steroids (CORT), it has been proposed that an important (although not necessarily exclusive) target site for cannabinoids may be the brain CORT receptor system. Very recent data are consistent with this hypothesis, since it was found that THC is able to compete for binding to CORT receptors in hippocampal cytosol and that it can down-regulate CORT receptors in vivo. The present application is an offshoot of this earlier work, and it is proposed here to intensify the study of these new and potentially important clues on a possible target system for cannabinoids. The studies would attempt to resolve 3 key issues: (1) the nature of THC binding to CORT receptors (competitive or allosteric, affinity, topographic distribution, etc.); (2) the functional impact (agonist or antagonist) of THC binding on a wide range of CORT receptor-dependent molecular and physiological responses (receptor plasticity and translocation, protein synthesis, ACTH suppression, etc.); and (3) whether long-term changes in CORT receptor systems quantitatively correlate with THC-induced neuronal loss in hippocampus. In addition, new CORT receptor blocking drugs will be tested throughout the studies to determine if either short- or long-term consequences of THC exposure can be inhibited or diminished. Thus, although it seems clear that THC binds to brain CORT receptors, at concentrations relevant to psychoactivity (sub-200 nM), and that long-term THC exposure can induce hippocampal neuropathology, it still remains to be determined whether these events are linked. The present experiments would test the hypothesis of this linkage more directly, would clarify many aspects of the nature and consequences of the cannabinoid-CORT receptor interaction, and would assess the anti-THC effectiveness of new steroid antagonist drugs.
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