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 g of dexmedetomidine into the LC (an effective hypnotic dose for 95% of animals) was tested. Other groups of rats were pre-treated 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 g. kg1 ip rolipram, a cAMP-specific phosphodiesterase inhibitor, and the hypnotic response to 7 g 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 Rpadenosine-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.

Most of the amine and peptide neuroreceptors possess at least one receptor subtype that either stimulates or inhibits adenylate cyclase activity, making it the archetypal enzyme effector mechanism for signal transduction in the central nervous system(see Schramm and Selinger, 1984). A biochemical feature common to all atpha2 adrenergic receptors is the ability, when activated, to inhibit adenylate cyclase(see Limbird,