Increased operant responding for ethanol in male C57BL/6J mice: specific regulation by the ERK1/2, but not JNK, MAP kinase pathway

Abstract

Rationale Extracellular signal-regulated protein kinase (ERK1/2) is a member of the mitogen-activated protein kinase (MAPK) signaling pathway and a key molecular target for ethanol (EtOH) and other drugs of abuse. Objective The aim of the study was to assess the role of two MAPK pathways, ERK1/2 and c-Jun N-terminal kinase (JNK), on the modulation of EtOH and sucrose self-administration. Materials and methods C57BL/6J mice were trained to lever press on a fixed-ratio 4 schedule with 9% EtOH/2% sucrose, or 2% sucrose, as the reinforcer. In experiments 1 and 2, mice were injected with the MEK1/2 inhibitor SL 327 (0–100 mg/kg) and the JNK inhibitor AS 6012452 (0–56 mg/kg) prior to self-administration. In experiment 3, SL 327 (0–100 mg/kg) was administered prior to performance on a progressive ratio (PR) schedule of EtOH reinforcement. In experiment 4, SL 327 and AS 601245 were injected 2 h before a locomotor test. Results SL 327 (30 mg/kg) significantly increased EtOH self-administration without affecting locomotion. Higher doses of SL 327 and AS 601245 reduced EtOH-reinforced responding and locomotor activity. Reductions of both ligands on sucrose self-administration were due to decreases in motor activity. SL 327 pretreatment had no effect on PR responding. Conclusions ERK1/2 activity is more directly involved in modulating the reinforcing properties of EtOH than JNK activity due to its selective potentiation of EtOH-reinforced responding. The specificity of this effect to EtOH self-administration, rather than sucrose self-administration, suggests that the mechanism by which ERK1/2 increases EtOH-reinforced responding does not generalize to all reinforcing solutions and is not due to increased motivation to consume EtOH.

Alcohol, Cocaine, and Brain Stimulation‐Reward in C57Bl6/J and DBA2/J Mice

“…In humans, reports of euphoria and locomotor stimulation are greater during the rising—rather than in the falling—phases of blood alcohol (Holdstock et al, 2000; Lukas and Mendelson, 1988; Smith et al, 1975). The BAC peaked between 40 and 45 mg/dl, corresponding to the levels achieved by C57 mice during standard 1-hour self-administration sessions (Faccidomo et al, 2009; Fish and Malanga, unpublished data; Middaugh et al, 2003). This suggests that brain reward thresholds may be lowered during the initial phases of a drinking session.…”

Cue-induced reinstatement of alcohol-seeking behavior is associated with increased CaMKII T286 phosphorylation in the reward pathway of mice

“…All subsequent self-administration sessions were 1-h in duration and followed a FR4 schedule of reinforcement. Mice were then trained, during 28 daily 1-h sessions, to self-administer a sweetened alcohol solution (9% EtOH (v/v) + 2% sucrose (w/v)) by using a sucrose fading procedure as previously described (Faccidomo et al, 2009; Salling et al, 2008; Salling et al, 2016). Subsequently the sweetened alcohol solution is referred to as “alcohol.” Self-administration procedures were continued for 28 sessions (7 days per week).…”

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors

“…In this strain of mice, nonsweetened alcoholic solutions offered in operant procedures have marked reinforcing properties in long sessions (lasting 16 to 23 h) (Besheer et al, 2004Hodge et al, 2006;Risinger et al, 1998Risinger et al, , 2001Schroeder et al, 2003) and in foodrestricted mice (Elmer et al, 1986(Elmer et al, , 1988Middaugh et al, 1999;Hayward et al, 2004;Heidbreder et al, 2007). However, studies in ad libitum-fed C57BL/6J mice trained to respond to a plain ethanol solution in water in short sessions have given contrasting results in terms of the amount of ethanol self-administered (ranging from 0.14 to 1.00 g/kg) and in ethanol-maintained operant responding (Faccidomo et al, 2009;Middaugh et al, 2000;Salling et al, 2008).…”