CHRONIC MORPHINE ADMINISTRATION CAUSES REGION-SPECIFIC INCREASE OF BRAIN-TYPE-VIII ADENYLYL-CYCLASE MESSENGER-RNA

The up-regulation of the cyclic AMP system and enhanced phosphorylatio n of protein substrates after either sudden interruption of chronic op ioid treatment or antagonist administration has been proposed to accou nt for the various behavioral responses observed during withdrawal. Us ing in situ hybridization histochemistry, we show here for the first t ime that type VIII adenylyl cyclase mRNA is selectively increased, as early as 12 h after morphine treatment in the locus coeruleus and the amygdala, two brain regions suggested to be important in morphine depe ndence expression. Moreover, the time course of morphine-induced chang es in type VIII adenylyl cyclase mRNA in locus coeruleus is related to the incidence of jumping, the most important sign of morphine withdra wal in mice. In addition, the overexpression of type VIII adenylyl cyc lase mRNA in thalamic nuclei could add to morphine tolerance. These fi ndings offer a strong support, at the molecular level, for an altered regulation of the cyclic AMP system in opiate tolerance and dependence . The present measure relates only to type VIII adenylyl cyclase mRNA and similar tests with other cyclases are needed to explore fully this relationship.