Young investigators stress alcohol-induced neuroadaptations in extended amygdala.

Excessive alcohol use, alcohol abuse, and relapse to heavy drinking are all characteristic of alcohol use disorders. Brain circuits controlling reward, appetitive behavior, decision making and habit formation have been implicated in these aspects of alcohol seeking and intake in a variety of animals. A number of studies over the past 10–15 years have also generated evidence that brain circuits implicated in stress responsiveness also regulate alcohol drinking behavior (reviewed in Breese, Sinha, & Heilig, 2011; Heinz, Beck, Grusser, Grace, & Wrase, 2009; Koob, 2009; Silberman et al., 2009; Vengeliene, Bilbao, Molander, & Spanagel, 2008). The extended amygdala, a series of interconnected limbic brain nuclei that includes (among other regions) the nucleus accumbens, central amygdala and bed nucleus of the stria terminalis (BNST) has emerged as a circuit key to the interface of stress- and alcohol-related behaviors. Interactions of these brain regions with “limbic” cortical areas provide influences from brain circuitry involved in context recognition, affective control and decision making. Thus, the extended amygdala is poised to integrate an array of environmental information that can influence alcohol-related behaviors. In addition, evidence of direct alcohol effects on this circuitry has emerged from studies using animal models. Overall, this circuit is most strongly linked to alcohol intake driven by the need to relieve negative outcomes of abstinence/withdrawal following a history of alcohol consumption. Withdrawal itself is stressful, and can also be impacted by stressful environmental events. Studies in several laboratories are now focusing on how stress, past drinking history and the extended amygdala circuitry contribute to relapse to drinking in rodent models. The review articles in this issue of Alcohol, written by Young Investigator Awardees from the 2011 meeting entitled Alcoholism and Stress: A Framework for Future Treatment Strategies, provide summaries of some of the latest research performed in laboratory animals on stress, alcohol and the extended amygdala. Presentations focus on alcohol-induced changes in molecular expression, neuronal function and synaptic plasticity, as well as alcohol-related behaviors involving the BNST, central amygdala, nucleus accumbens and prefrontal cortex, all key parts of this circuitry. One theme that emerges from these reviews is that acute and chronic ethanol exposure alter the actions of a number of neurotransmitters and neuromodulators, including γ-aminobutyric acid (GABA), glutamate, dopamine, serotonin and neuropeptides such as dynorphin, corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY) in extended amydala circuitry. Indeed, the roles of these different neurotransmitters in alcohol-related behaviors were a consistent theme of the entire meeting. Ethanol effects on neuronal excitability and ion channel function within extended amygdala subregions are also prominent topics explored by these young investigators. Roles for the extracellular matrix and synaptic remodeling are also discussed. Experiments using state-of-the-art neurobiological and behavioral procedures were described in the talks presented by the young investigators at the meeting itself, and are discussed in the articles they have written for this issue. The extended amygdala circuitry is strongly affected by environmental stressors, and stress effects on circuit function and drinking are also covered in some of the reviews. Examination of stress–alcohol interactions that affect alcohol seeking and drinking is an area poised for rapid expansion within this overall line of research. The studies reviewed in these articles represent the beginnings of a concerted effort in several laboratories and research consortia aimed at understanding how extended amygdala circuitry is altered by ethanol exposure and contributes to heavy drinking and relapse. There is clearly much left to learn, including which molecular and physiological changes contribute to drinking/relapse and stress effects, and how different neurotransmitters work in concert within a given brain region and across brain regions to affect alcohol-related behaviors. Future studies will also need to determine how activity within the different extended amygdala areas is coordinated during alcohol intoxication, drinking, withdrawal and relapse. Ultimately it will be important to determine what molecules can be targeted to produce treatments effective in reducing relapse and stress effects on drinking. The enthusiastic effort and new neurobiological approaches brought to bear on this question by these young investigators indicates that a wealth of information on this topic will be forthcoming in the near future.