The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry

Abstract

The commonalities between different phases of stress and alcohol use as well as the high comorbidity between alcohol use disorders (AUDs) and anxiety disorders suggest common underlying cellular mechanisms governing the rewarding and aversive aspects of these related conditions. As an integrative center that assigns emotional salience to a wide variety of internal and external stimuli, the amygdala complex plays a major role in how alcohol and stress influence cellular physiology to produce disordered behavior. Previous work has illustrated the broad role of the amygdala in alcohol, stress, and anxiety. However, the challenge of current and future studies is to identify the specific dysregulations that occur within distinct amygdala circuits and subpopulations and the commonalities between these alterations in each disorder, with the long-term goal of identifying potential targets for therapeutic intervention. Specific intra-amygdala circuits and cell type-specific subpopulations are emerging as critical targets for stress- and alcohol-induced plasticity, chief among them the corticotropin releasing factor (CRF) and CRF receptor 1 (CRF1) system. CRF and CRF1 have been implicated in the effects of alcohol in several amygdala nuclei, including the basolateral (BLA) and central amygdala (CeA); however, the precise circuitry involved in these effects and the role of these circuits in stress and anxiety are only beginning to be understood.

Alcohol Drinking Exacerbates Neural and Behavioral Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

“…Moreover, cue-specific fear suggests altered AMY function (Phillips and LeDoux, 1992) and is consistent with known effects of alcohol and amygdala-based fear responses (Agoglia and Herman, 2018;McCool et al, 2010). The AMY also regulates positive reinforcing effects of alcohol (Besheer et al, 2003;Besheer et al, 2012;Cannady et al, 2017;Salling et al, 2016;Schroeder et al, 2003) and cue-induced relapse to alcohol-seeking behavior (Cannady et al, 2011;Salling et al, 2017;Schroeder et al, 2008), which suggests common neuroanatomical mechanisms of AD and alcohol addiction.…”

New viral‐genetic mapping uncovers an enrichment of corticotropin‐releasing hormone‐expressing neuronal inputs to the nucleus accumbens from stress‐related brain regions

“…As apparent from the overview in Figure , there afferent projections to the NAc were limited to relatively few brain regions. Importantly, the regions contributing richly to CRH + projections to the NAc are mainly the regions involved in the processing and integration of salient and context‐dependent signals (Agoglia & Herman, ; Do‐Monte, Quiñones‐Laracuente, & Quirk, ; Liberzon & Abelson, ; Zhu et al, ), where activation of endogenous CRH‐expressing cells in these regions is typically induced by adverse emotional or physical events (e.g., Gunn et al, ; Marcinkiewcz et al, ).…”

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies

“…Chronic alcohol exposure increases hypothalamic and extrahypothalamic CRF gene expression immediately after consumption. However, during withdrawal hypothalamic CRF and CRFR1 expression is reduced, with subsequent blunting of the HPA response, whereas extrahypothalamic CRF release is increased within the CeA and BNST (see Agoglia and Herman, , Roberto et al, and Schreiber and Gilpin, for review). It has been hypothesized that upregulation of CRF signaling may contribute to negative affect during withdrawal that motivates escalation of alcohol drinking (Zorrilla et al, ).…”

“…Likewise, CRFR1 antagonists reduced binge‐like EtOH drinking, drinking in dependent animals, and drinking in nondependent animals that consume large amounts of alcohol. CRF signaling in the CeA has been thought to play a critical role in this effect, given that antagonism of CRFR1 in the CeA, but not BNST or NAc, reduced alcohol self‐administration in dependent rats (Agoglia and Herman, ; Schreiber and Gilpin, ; Zorrilla et al, ).…”