The anxious amygdala: CREB signaling and predisposition to anxiety and alcoholism

Abstract

The amygdala is believed to play a key role in assigning emotional significance to specific sensory input, and conditions such as anxiety, autism, stress, and phobias are thought to be linked to its abnormal function. Growing evidence has also implicated the amygdala in mediation of the stress-dampening properties of alcohol. In this issue of the JCI, Pandey and colleagues identify a central amygdaloid signaling pathway involved in anxiety-like and alcohol-drinking behaviors in rats (see the related article beginning on page 2762). They report that decreased phosphorylation of cAMP responsive element-binding protein (CREB) resulted in decreased neuropeptide Y (NPY) expression in the central amygdala of alcohol-preferring rats, causing high anxiety-like behavior. Alcohol intake by these animals was shown to increase PKA-dependent CREB phosphorylation and thereby NPY expression, subsequently ameliorating anxiety-like behavior. These provocative data suggest that a CREBdependent neuromechanism underlies high anxiety-like and excessive alcohol-drinking behavior.

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…Increases in the release of norepinephrine, which stimulates cAMP formation in the brain (Bettahi et al, 1998;Quesada and Etgen, 2000), produce anxiogenic-like behavior in animals (Tanaka et al, 2000). Although there is no evidence showing a high expression of PDE4B in the mouse amygdala, significantly decreased activity of PDE4 in PDE4BÀ/À mice indicates that PDE4B most likely is the predominant PDE4 subtype in this region, which is important in anxiety (Wand, 2005). Loss of PDE4B leads to increases in cAMP in these brain regions and results in anxiogenic-like behavior.…”

The role of GABAA receptors in the development of alcoholism

“…Alcohol may be consumed in excess as a coping mechanism for stress and the altered homeostasis subsequent to addiction can result in stress upon withdrawal (Thomas et al, 2003;Wand, 2005). GABAergic neurotransmission is likely to be important in addictionassociated stress because GABA modulates emotion and response to stress.…”

“…PKA regulation of GABAactivated currents occurs through phosphorylation at highly conserved sites in the intracellular domain of β subunits, the effect depending on the particular β subunit isoform (McDonald et al, 1998). PKA has been implicated in anxiety and drinking behavior (Wand, 2005). A range of proteins that associate with individual GABA A subunits and play important roles in regulation have recently been found and are described elsewhere (reviewed in Chen and Olsen, 2007).…”

Effects of a stressor and corticotrophin releasing factor on ethanol deprivation-induced ethanol intake and anxiety-like behavior in alcohol-preferring P rats

“…Brain regions implicated in CRF-induced and ethanol withdrawal-induced anxiety-like behavior are the amygdala (Amyg) (Huang et al 2010;Knapp et al 2007;Koob 2003Koob , 2008Lack et al 2008;Overstreet et al 2006;Rassnick et al 1993;Wand 2005;Silberman et al 2009) and the dorsal raphe nucleus (DRN) (Huang et al 2010;Overstreet et al 2006). The basolateral amygdala and dorsal bed nucleus of the stria terminalis were also implicated in withdrawalinduced anxiety-like behavior following repeated CRF and stressor presentations prior to exposure to chronic ethanolcontaining diets (Huang et al 2010).…”