CANNABINOIDS MODULATE VOLTAGE-SENSITIVE POTASSIUM A-CURRENT IN HIPPOCAMPAL-NEURONS VIA A CAMP-DEPENDENT PROCESS

Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (I-A) in cultured hippocampal c ells. Because cannabinoid receptors inhibit adenylate cyclase, the pre sent study explored whether cAMP played a role in mediating this effec t on I-A. The specific issue of whether cannabinoid receptor modulatio n of voltage-dependent I-A acts via a cAMP-dependent process was inves tigated. The cAMP analog, 8-bromo-cAMP, as well as the adenylate cycla se stimulant forskolin, produced concentration-dependent shifts in I-A that were opposite those produced by cannabinoid receptor ligands. Mo reover, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine al so produced a marked negative shift in the steady-state voltage depend ence of I-A and increased the effect of forskolin on I-A. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased I-A v ia a decrease in steady-state voltage-dependent inactivation of I-A. W IN 55,212-2 also reversed the effects of forskolin on I-A. The electro physiological studies were paralleled by direct assays of cAMP in thes e cells, where cannabinoids inhibited forskolin-stimulated cAMP by 50% in a pertussis toxin-sensitive manner. The results confirmed that per tussis toxin-sensitive cannabinoid receptor-mediated changes in I-A we re probably the result of inhibition of adenylate cyclase. The finding s are discussed in terms of modulation of I-A conductance properties v ia cannabinoid receptor-mediated inhibition of cAMP levels within the cell.