The central amygdala as an integrative hub for anxiety and alcohol use disorders

Abstract

The central amygdala (CeA) plays a central role in physiologic and behavioral responses to fearful stimuli, stressful stimuli, and drug-related stimuli. The CeA receives dense inputs from cortical regions, is the major output region of the amygdala, is primarily GABAergic (inhibitory), and expresses high levels of prostress and antistress peptides. The CeA is also a constituent region of a conceptual macrostructure called the extended amygdala that is recruited during the transition to alcohol dependence. We discuss neurotransmission in the CeA as a potential integrative hub between anxiety disorders and alcohol use disorder, which are commonly co-occurring in humans. Imaging studies in humans and multidisciplinary work in animals collectively suggest that CeA structure and function are altered in individuals with anxiety disorders and alcohol use disorder, the end result of which may be disinhibition of downstream "effector" regions that regulate anxiety-related and alcohol-related behaviors.

Keywords: Anxiety disorder; CRF; Extended amygdala; GABA; NPY; Posttraumatic stress disorder.

Figure 1

(A) Schematic of amygdala circuitry showing inter- and intranuclear connectivity. Abbreviations: BLA- basolateral amygdala; CeA_M- medial central amygdala, CeA_L- lateral central amygdala; IN- main intercalated cell cluster; LA-lateral amygdala; mITC intercalated cell cluster. B. Microcircuitry of the CeA_M illustrating excitatory transmission by glutamatergic afferents (green) and phasic and tonic inhibitory transmission by GABAergic afferents (dark red) and local interneurons (light red).

Figure 2

Schematic illustrating location of neuropeptides and their receptors in the medial CeA synapse, and their proposed roles in stress, anxiety, and alcohol effects. Here and in the text, we focus on pro-stress pro-alcohol-drinking CRF and anti-stress anti-alcohol-drinking NPY systems, intended to provide a snapshot of what may be (or is) occurring with other stress peptides in CeA in response to stress and alcohol. Abbreviations: CeA_M- medial central amygdala, CRF1- corticotropin-releasing factor receptor 1, NPY- neuropeptide Y, Y₁ NPY Y₁ receptor, Y₂ - NPY Y₂ receptor.