Because acute ethanol increases dynorphin release in CeA (Lam et al., 2008), we hypothesize that ethanol consumption by non-dependent animals stimulates dynorphin release that functions as a brake to limit ethanol-induced enhancement of GABAergic transmission in CeA, thereby preventing disinhibition of downstream targets of CeA. Indeed, dynorphin activation suppresses drug reward and drug self-administration in non-dependent animals (Shippenberg et al., 2007) including alcohol (Nestby et al., 1999), suggesting that its physiological role is to limit excessive drug seeking (Shippenberg et al., 2007). It is reasonable to hypothesize that KOR effects on GABAergic transmission would be substantially altered in the CeA of an alcohol-dependent rat. The transition to alcohol and drug dependence produces hyperactivation of brain KOR systems that promote negative affect and subsequent seeking of alcohol and drugs for their negative reinforcing effects (Koob, 2008; Wee and Koob, 2010). Indeed, recent data from our group shows that pharmacological manipulations of KORs produces opposite effects on GABAergic transmission in CeA of rats with in vivo history of long-access versus short-access to cocaine (Kallupi et al., 2013), suggesting the same may be true for other drugs of abuse, including alcohol.
