INHIBITION OF ADENYLATE-CYCLASE IN THE LOCUS-CERULEUS MEDIATES THE HYPNOTIC RESPONSE TO AN ALPHA(2)-AGONIST IN THE RAT

Recently, we determined that the transduction mechanism for the hypnotic response to dexmedetomidine, a highly selective alpha2 agonist, resides in the locus coeruleus (LC) of the rat. Candidates for the effector mechanism of this alpha2 adrenoceptor-mediated hypnotic response include inhibition of adenylate cyclase, which has been shown to be pivotal to the cellular response of alpha2 agonists in some, but not in all, cases. The LC of rats were stereotaxically cannulated with an indwelling catheter, and after the 2nd day, the hypnotic response to 7 mug of dexmedetomidine into the LC (an effective hypnotic dose for 95% of animals) was tested. Other groups of rats were pretreated with the permeable nonhydrolyzable cyclic AMP (cAMP) analog, dibutyryl cAMP (dB cAMP), at a dose of 0.2 to 1.2 ng into the LC, or 2.75 to 275 mug.kg-1 i.p. rolipram, a cAMP-specific phosphodiesterase inhibitor, and the hypnotic response to 7 mug of dexmedetomidine into the LC was tested. Both dB cAMP and rolipram reversed the hypnotic response to dexmedetomidine. To test for the specificity of these hypnotic-reversing perturbations, rats were pretreated with Rp-adenosine-3',5'-cyclic phosphorothioate, a cAMP-dependent protein kinase inhibitor, and the experiments were repeated. The hypnotic-reversing property of either dB cAMP or rolipram could be prevented by blocking cAMP-dependent protein kinase (''A'' kinase) activity with Rp-adenosine-3',5'-cyclic phosphorothioate. Thus, perturbations designed to sustain the intracellular cAMP content block the hypnotic action of dexmedetomidine and establish a pivotal role for inhibition of adenylate cyclase in the transduction of the hypnotic response to an alpha2 agonist in the LC of the rat.