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

Abstract

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 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.

Extracellular Signal-Regulated Kinase in Nucleus Accumbens Mediates Propofol Self-Administration in Rats

“…In the present study, we found that propofol, as a positive reinforcer, maintained the intravenous self-administration, and increased the expression of p-ERK in the NAc. These results are consistent with several previous studies showing increased p-ERK expression in the NAc following cocaine and ethanol self-administration [16,20,29]. Thus, the data indicated that activation of ERK transduction pathways in the NAc is involved in propofol self-administration.…”

Molecular mechanisms underlying alcohol-drinking behaviours

“…In line with the possible role of ERK1/2 as stop-pathway molecules, systemic inhibition of MKK, the upstream activator of ERK1/2 (Fig. 2), increases moderate and excessive alcohol intake in mice (AS-OSA and 20%LA models) 105, 106, 107 , suggesting that alcohol-induced activation of ERK1/2 is required for keeping consumption under control.…”

Using In Vitro Electrophysiology to Screen Medications

“…Moreover, pretreatment with an inhibitor of ALK, TAE684 (Galkin et al, 2007), prevents the ethanol-induced activation of ERK. As ERK has been shown by several groups to modulate ethanol-related behaviors (Agoglia et al, 2015; Faccidomo, Besheer, Stanford, & Hodge, 2009; Faccidomo, Salling, Galunas, & Hodge, 2015), these latest findings point toward a possible biochemical mechanism for ALK’s influence on ethanol consumption.…”