Cannabinoid interactions with glucocorticoid receptors in rat hippocampus.
Previous studies have found that chronic administration of delta9-tetrahydrocannabinol (THC), a psychoactive cannabinoid, can induce brain aging-like degenerative changes in hippocampal structures (e.g., pyramidal cell loss, glial reactivity). Normal aging changes in the hippocampus appear to be partly corticosteroid-dependent. Because THC is similar in molecular structure to corticosteroids (CORT), therefore, we have suggested that THC may act to induce pathology in the hippocampus through CORT receptors. The possibility of THC interactions with CORT receptors was tested more directly in the present studies. Binding of [3H]dexamethasone (DEX) to hippocampal cytosol, in vitro, was inhibited partially, but not completely, by 100-fold excess unlabeled THC and cannabidiol (CBD), a non-psychoactive cannabinoid. Even at 10,000-fold molar excess, moreover, THC could displace only 50% of radiolabeled DEX binding and CBD could inhibit only 22% of tracer binding. Scatchard plot analyses also pointed to a possible non-competitive site for cannabinoid interaction with glucocorticoid receptors. In addition, several studies utilizing the synthetic steroid RU-28362 indicated that THC interacts primarily with the type II class of glucocorticoid receptors. In a separate study, adrenalectomized rats were treated daily for 14 days with 5-10 mg/kg THC or vehicle, and examined 24 h later for [3H]CORT binding in hippocampal cytosol. In THC-treated animals, the Bmax for type II binding was reduced to a degree almost comparable to the down-regulation seen after chronic stress or high corticosteroid administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Eldridge
J C
JC
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27103.
Landfield
P W
PW
D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002185:Cannabidiol / Q000494:pharmacology*; D002499:Centrifugation, Density Gradient; D003600:Cytosol; D003907:Dexamethasone / Q000378:metabolism*; D015536:Down-Regulation; D013759:Dronabinol / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*
D000732:Androstanols; D011965:Receptors, Glucocorticoid; D002185:Cannabidiol; C049154:11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one; D013759:Dronabinol; D003907:Dexamethasone