The ancient dialogue between brain and body.

The statistics on alcohol use disorder (AUD) in the United States clearly indicate the severity of this public health problem. According to the National Institute on Alcohol Use and Alcoholism (), about 10% (about 12% males/ 8% females) of the United States population (28 million people) have alcohol use disorder (AUD); worldwide percentages for AUD occurrence are similar. Despite the prevalence of this disease, less than 10% of individuals with AUD receive any treatment, and only about 2.5% received medication-assisted treatment (). The existing FDA-approved medications for the treatment of AUD (naltrexone, acamprosate, and disulfram) can be effective in some patients, but additional medications are needed. Other drugs approved for use in AUD treatment by other entities (Veterans Administration/Department of Defense, for example) include topiramate and gabapentin, but these have side effects or reduced efficacy in significant patient populations (e.g., heavy drinkers) (), further supporting the need for investigations into other drugs for AUD treatment. Craving and other symptoms of AUD are associated with brain neuroadaptation; epigenetic modifications () induced by chronic alcohol use produce changes in gene expression and neurotransmission, and ultimately result in symptoms such as increased stress responses (). Stress is associated with withdrawal and can be a trigger for relapse, making the amelioration of stress one of the keys to effective treatment of AUD (). The amygdala is a key brain area associated with emotion and stress, so study of the actions of chronic alcohol on the amygdala are useful in determining cellular mechanisms (); the central amygdala (CeA) projects to numerous brain regions to produce behavioral and autonomic responses associated with emotion, and receives inputs from numerous brain regions, including the basolateral amygdala (BLA). Furthermore, the noradrenergic system of the brain is closely associated with stress responses, and noradrenergic systems interact throughout the extended amygdala with other neurotransmitter systems such as corticotropin releasing factor; these interactions are important for neuroadaptation associated with AUD (). Changes in central noradrenergic systems are linked to alcohol exposure and withdrawal in AUD patients as well as in animal models (, ). What is needed is a coherent understanding of the roles of each class of noradrenergic receptor in AUD to promote the development of selective agents that can counteract those neuroadaptations that increase craving or trigger relapse. With this background in mind, the article by Anjos-Santos, et al. () is a timely investigation of the actions of noradrenergic modulation of GABA neurotransmission in the CeA. Following their important work in male rats (), the authors examined how the alcohol dependence in female rats affected the modulation of GABA transmission in the CeA by noradrenergic agents. Briefly, in naïve female rat CeA neurons, norepinephrine (NE), acting presynaptically, increased the frequency of GABA release (as measured by spontaneous inhibitory postsynaptic potentials (IPSPs)) onto half of the neurons, and decreased frequency of GABA release onto a third of the neurons but overall decreased GABA transmission frequency (especially as measured by miniature IPSPs or mIPSPs); postsynaptically, NE decreased the amplitude of GABA responses regardless of the presynaptic effect. After induction of alcohol dependence, the responses to NE were significantly blunted; amplitude of GABA responses of CeA neurons and mIPSP frequency of dependent rats were no longer reduced by NE. After a two-week withdrawal, NE-induced reductions of the amplitude and frequency of postsynaptic GABA responses were generally restored to the alcohol-naïve state. GABA neurotransmission in the CeA was sensitive to both α- and β-adrenergic antagonists; α1 antagonist prazosin alone reduced the amplitude and frequency of GABA transmission in dependent and withdrawal groups, and β antagonist propranolol alone reduced frequency of GABA release. In the presence of prazosin, NE decreased the frequency GABA release only from dependent rats and propranolol blocked the NE-induced alteration of frequency of release in all groups. Furthermore, hybridization experiments showed that both β2 and α1A noradrenergic receptor mRNA increased in CeA cells during dependence, possibly as a compensatory mechanism for the disruption in GABA signaling (). Overall, the results demonstrate a dependence-induced dysfunction and reduction of modulation of GABA neurotransmission by NE. While a two-week withdrawal period is useful to determine whether dependence-induced effects on neuron physiology recover with time, additional studies would be helpful to elucidate the state of NE regulation of GABA in the CeA at shorter withdrawal periods (24–72 hours); these additional studies may provide crucial insight into the time course of neuroadaptation to alcohol ex