Intra-amygdala inhibition of ERK1/2 potentiates the discriminative stimulus effects of alcohol

Abstract

Extracellular signal-regulated kinase (ERK1/2) has been implicated in modulating drug seeking behavior and is a target of alcohol and other drugs of abuse. Given that the discriminative stimulus (subjective/interoceptive) effects of drugs are determinants of abuse liability and can influence drug seeking behavior, we examined the role of ERK1/2 in modulating the discriminative stimulus effects of alcohol. Using drug discrimination procedures, rats were trained to discriminate a moderate intragastric (IG) alcohol dose (1g/kg) versus water (IG). Following an alcohol (1g/kg) discrimination session phosphorylated ERK1/2 (pERK1/2) immunoreactivity (IR) was significantly elevated in the amygdala, but not the nucleus accumbens. Therefore, we hypothesized that intra-amygdala inhibition of ERK1/2 would disrupt expression of the discriminative stimulus effects of alcohol. However, intra-amygdala or accumbens administration of the MEK/ERK1/2 inhibitor U0126 (1 and 3μg) had no effect on the discriminative stimulus effects of the training dose of alcohol (1g/kg). Contrary to our hypothesis, intra-amygdala infusion of U0126 (3μg) potentiated the discriminative stimulus effects of a low alcohol dose (0.5g/kg) and had no effect following nucleus accumbens infusion. Importantly, site-specific inhibition of pERK1/2 in each brain region was confirmed. Therefore, the increase in pERK1/2 IR in the amygdala following systemic alcohol administration may be reflective of the widespread effects of alcohol on the brain (activation/inhibition of brain circuits), whereas the site specific microinjection studies confirmed functional involvement of intra-amygdala ERK1/2. These findings show that activity of the ERK signaling pathway in the amygdala can influence the discriminative stimulus effects of alcohol.