Intra-amygdala inhibition of ERK(1/2) potentiates the discriminative stimulus effects of alcohol.
Extracellular signal-regulated kinase (ERK(1/2)) 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 ERK(1/2) 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 ERK(1/2) (pERK(1/2)) immunoreactivity (IR) was significantly elevated in the amygdala, but not the nucleus accumbens. Therefore, we hypothesized that intra-amygdala inhibition of ERK(1/2) would disrupt expression of the discriminative stimulus effects of alcohol. However, intra-amygdala or accumbens administration of the MEK/ERK(1/2) 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 pERK(1/2) in each brain region was confirmed. Therefore, the increase in pERK(1/2) 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 ERK(1/2). These findings show that activity of the ERK signaling pathway in the amygdala can influence the discriminative stimulus effects of alcohol.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. jbesheer@med.unc.edu
Joyce
J
Besheer
Kristen R
KR
Fisher
Reginald
R
Cannady
Julie J M
JJ
Grondin
Clyde W
CW
Hodge
D000438:Alcohols / Q000008:administration & dosage*; D000679:Amygdala / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D008845:Microinjections; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D018709:Statistics, Nonparametric
D000438:Alcohols; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3