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The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

Role of cAMP Response Element-Binding Protein in the Rat Locus Ceruleus: Regulation of Neuronal Activity and Opiate Withdrawal Behaviors