Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism

Abstract

We investigated the role of cAMP-responsive element-binding protein (CREB) in genetic predisposition to anxiety and alcohol-drinking behaviors using alcohol-preferring (P) and -nonpreferring (NP) rats. The levels of CREB, phosphorylated CREB, and neuropeptide Y (NPY) were innately lower in the central amygdala (CeA) and medial amygdala (MeA), but not in the basolateral amygdala (BLA), of P rats compared with NP rats. P rats displayed higher baseline anxiety-like behaviors and consumed higher amounts of alcohol compared with NP rats. Ethanol injection or voluntary intake reduced the higher anxiety levels in P rats. Ethanol also increased CREB function in the CeA and MeA, but not in the BLA, of P rats. Infusion of the PKA activator Sp-cAMP or NPY into the CeA decreased the alcohol intake and anxiety-like behaviors of P rats. PKA activator infusion also increased CREB function in the CeA of P rats. On the other hand, ethanol injection or voluntary intake did not produce any changes either in anxiety levels or on CREB function in the amygdaloid structures of NP rats. Interestingly, infusion of the PKA inhibitor Rp-cAMP into the CeA provoked anxiety-like behaviors and increased alcohol intake in NP rats. PKA inhibitor decreased CREB function in the CeA of NP rats. These novel results provide the first evidence to our knowledge that decreased CREB function in the CeA may be operative in maintaining the high anxiety and excessive alcohol-drinking behaviors of P rats.

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

“…Although the findings reported by Pandey and coworkers (13) are important, cautious interpretation is appropriate. While animal models employed to study alcohol-use disorders have been extremely helpful, they have limitations.…”

“…A provocative implication of these findings (13) is that decreased CREB function in the CeA may be operative in maintaining high anxiety levels and alcohol-drinking behaviors of P rats. These data need to be replicated and then placed in context with 2 other very important neurotransmitter systems in the amygdala: corticotropin-releasing factormediated (CRF-mediated) and GABA-mediated signaling.…”

“…With these caveats, the findings of Pandey and coworkers (13) are noteworthy. Their data inform us that we cannot limit our investigational focus to the mesolimbic DA system; the amygdala must be included when formulating models for alcohol abuse and dependence.…”

“…In this issue of the JCI, Pandey and colleagues suggest that the neural substrate underlying the stress-dampening properties of alcohol is not the nucleus accumbens, but is probably the extended amygdala (13). The extended amygdala plays a crucial role not only in anxiety behaviors, but also in promoting alcohol intake (14).…”

“…The P rats generally drink greater than 5 grams of alcohol per kilogram body weight per day, whereas the NP line drinks less that 1.5 g/kg/d. In this issue of the JCI, Pandey and coworkers used these rats to investigate the role of cAMP/PKA signaling in the central amygdala (CeA) as it relates to alcohol consumption and anxiety (13). The CeA is a major component of the extended amygdala.…”