REGULATION OF ADENYLATE-CYCLASE BY CHRONIC EXPOSURE TO CANNABIMIMETIC DRUGS

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  • 1 March 1988
    • journal article
    • research article
    • Vol. 244  (3) , 1157-1163
Abstract
Previous studies in this laboratory have demonstrated that a cloned neuroblastoma cell line (N18TG2) responds to .DELTA.9-tetrahydrocannabinol (THC), the major psychoactive product of marihuana, with an attenuation of cyclic AMP accumulation that results from an inhibition of adenylate cyclase. The requirement for the G1 regulatory protein, stereoselectivity, pharmacologic specificity and cell selectivity of this response suggest that a receptor for cannabimimetic compounds may be associated with adenylate cyclase in the neuroblastoma cell. Presented here is a comprehensive investigation of cellular effects of chronic exposure to cannabimimetic agents. Short-term exposure to either .DELTA.9-THC or the more potent nantradol analog, desacetyllevonantradol (DALN), at doses up to 100 .mu.M did not compromise the plating efficiency of the cells. Cells that were exposed to 1 .mu.M .DELTA.9-THC (maximally effective for inhibiting cyclic AMP production) for 24 hr in a serum-free medium were shown to accumulate the drug but not to metabolize it. Exposure to 10 .mu.M .DELTA.9-THC or DALN for up to 48 hr failed to significantly affect cell growth rate or protein content per cell. The gross morphology of cannabinoid-treated cells was not altered at the light or the electron microscope level. The cellular organelles and membranes appeared intact, with no remarkable differences from control cells. The inhibition of cyclic AMP accumulation in response to cannabimimetic drugs was diminished in cells treated with .DELTA.9-THC or DALN for 24 hr. This desensitization was homologous because both .DELTA.9-THC and DALN responses were attenuated after exposure to either cannabimimetic drug. In contrast, the inhibition of cyclic AMP accumulation in response to carbachol via the muscarinic receptor was unaltered by previous exposure of the cells to cannabimimetic agents. For DALN, the desensitization could be observed as early as 4 hr and was dose-dependent. These studies demonstrate that desensitization of the cannabimimetic regulation of adenylate cyclase can occur in the absence of cytotoxicity.