How an Understanding of the Function of the Locus Coeruleus Led to Use of Dexmedetomidine to Treat Agitation in Bipolar Disorder: Example of Rational Development of Psychiatric Medications.

This column reviews >50 years of research on the functions subsumed by the locus coeruleus (LC) (also called the central adrenergic system). A major role of the LC is monitoring acid-base balance in the brain and responding by regulating blood-brain permeability to water and other small molecules and cerebral blood flow. The LC, through its downward projections, also regulates and coordinates respiratory and cardiac functions. Through its effect regionally or more globally depending on the stimulus and its magnitude, the LC can regulate the extracellular space in the brain, which in turn can alter ionic concentrations and thus the sensitivity of neurons to signaling. As a result of these far-reaching effects, the LC has been implicated in brain functions ranging from sleep and wakefulness to psychiatric conditions such as hyperarousal/hypervigilance, fear, agitation, anxiety, and panic attacks. This understanding of the brain functions subsumed by the LC has, in turn, led to the most recent development in the use of dexmedetomidine, an alpha-2 adrenergic agonist, to treat agitation in patients with bipolar disorder. This column also illustrates a theme discussed in a series of previous columns concerning the successful development of novel psychiatric/central nervous system drugs on the basis of an understanding of relatively simple circuits or mechanisms that underlie pathologic behavior.