Cannabinoids and the hippocampal glucocorticoid receptor: recent findings and possible significance

It has long been recognized that cannahinoids, including Δ⁹-tetrahydrocannabinol (THC), the major psychoactive substance of marijuana, hear structural similarities to steroid hormones. The hippocampal region of the brain is particularly rich in glucocorticoid receptors (GCRs), and the reffion also displays dense autoradiographic binding by synthetic cannabinoids. The present report summarises studies conducted on cannabinoid interaction with hippocampal GCRs, both in vivo und in vitro. Young rats treated for 8 months with THC displayed anatomic and cellular changes in the hippocampus similar to those seen in older, untreated rats. or in rats treated with hiffh levels of glucocorticoids. Binding of [³H]dexamethasone in cytosol prepared from adrenalectomized rat hippocampus was reduced in the presence of 100-fold molar excess of unlabeled THC. However, further increases of THC concentration, to 20,000-fold excess, could displace no more than 50% of radiolabeled dexamethasone. Scatchard analysis of the binding produced a parallel competition plot for THC, versus the plot for dexamethasone. which may reflect a noncompetitive or allosteric interaction with hippocampal GCR. Cannabidiol, a nonpsychoactive cannabinoid, displayed less competition than THC in all parameters. Treatment of adrenalectomized rats for 14 days with 10 mg/kg THC produced down-regulation of hippocampal GCR binding in a manner also reported following high glucocorticoid administration. Although an initial oral administration of THC to intact rats stimulated release of plasma corticosterone, daily repetition of treatment for 7 and 14 days failed to elicit further corticosterone secretion. Taken together, the results indicate that THC may possess some agonist-like properties of glucocorticoids at the hippocampal GCR site. However, results also suggest that cannabinoids may he weak, noncompetitive inhibitors of glucocorticoid binding in the brain.