Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

• Published in: Psychopharmacology Vol. 232; no. 18; pp. 3417 - 3430
• Main Authors: Faccidomo, Sara, Salling, Michael C., Galunas, Christina, Hodge, Clyde W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2015; Springer; Springer Nature B.V
• Subjects: Aminoacetonitrile - analogs & derivatives; Aminoacetonitrile - pharmacology; Amygdala - drug effects; Amygdala - metabolism; Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - metabolism; Central Nervous System Depressants - administration & dosage; Central Nervous System Depressants - pharmacology; Conditioning, Operant; Ethanol; Ethanol - administration & dosage; Ethanol - pharmacology; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Health aspects; House mouse; Influence; Kinases; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Neurosciences; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Original Investigation; Pharmacology/Toxicology; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Protease Inhibitors - pharmacology; Protein kinases; Proteins; Psychiatry; Reinforcement (Psychology); Reward; Self Administration; Studies; Operant conditioning; Accumbens; Addiction; Amygdala; Motor activity; Reinforcement; Alcohol; Prefrontal cortex; MAPK; ERK
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-015-3993-z

Rationale
Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown.
Objective
This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2).
Methods
Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9 % ethanol + 2 % sucrose (ethanol) or 2 % sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC, or AMY prior to self-administration.
Results
pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg = 1.21 g/kg; BAC = 54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions.
Conclusions
Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.