Molecular control of locus coeruleus neurotransmission

The locus coeruleus (LC) is the major noradrenergic nucleus in the brain and innervates large segments of the neuraxis. LC neurons are thought to regulate states of attention and vigilance as well as activity of the sympathetic nervous system. These neurons also have been implicated in the actions of stress, antidepressants, and opiates on the brain. Aided in part by the fact that the LC is relatively homogeneous, it has been possible to understand some of the cellular and molecular mechanisms that control their functional state. This review focuses on the role played by the cAMP pathway in regulation of LC neurons, particularly after chronic perturbations. Thus, several components of this intracellular signaling pathway are upregulated in the LC after chronic stress or chronic opiate treatment, but downregulated after chronic antidepressant treatment. LC neurons exhibit a pacemaker activity, which appears to be mediated, at least in part, by a nonspecific cation current that is activated by protein kinase A. As a result, stimuli that upregulate the cAMP pathway after chronic administration (e.g., stress or opiates) increase the excitability of LC neurons, whereas stimuli that downregulate the cAMP pathway (e.g., antidepressants) exert the opposite effect. Such molecular adaptations could contribute to the behavioral plasticity that is associated with these various conditions.