Inhibition of adenylate cyclase in the locus coeruleus 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 alpha 2 agonist, resides in the locus coeruleus (LC) of the rat. Candidates for the effector mechanism of this alpha 2 adrenoceptor-mediated hypnotic response include inhibition of adenylate cyclase, which has been shown to be pivotal to the cellular response of alpha 2 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 micrograms 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 micrograms.kg-1 i.p. rolipram, a cAMP-specific phosphodiesterase inhibitor, and the hypnotic response to 7 micrograms 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Correa-Sales
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Department of Anesthesiology, Stanford University, Palo Alto, California.
Nacif-Coelho
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Reid
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Maze
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M
D000067956:Adenylyl Cyclase Inhibitors; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000201:enzymology*; D008297:Male; D020926:Medetomidine; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram
D000067956:Adenylyl Cyclase Inhibitors; D000316:Adrenergic alpha-Agonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011760:Pyrrolidinones; D003994:Bucladesine; D020889:Rolipram; D020926:Medetomidine