Inhibition of extracellular signal-regulated kinase (ERK) activity with SL327 does not prevent acquisition, expression, and extinction of ethanol-seeking behavior in mice

Abstract

Although extracellular signal-regulated kinase (ERK) activity is essential for the acquisition of a variety of associative learning tasks, its involvement in the acquisition and extinction of ethanol (EtOH)-induced conditioned place preference (CPP) remains unknown. Therefore, in these experiments we examined the effects of the ERK-kinase (MEK)-inhibitor SL327 on acquisition and expression of EtOH-CPP as well as the dose-and time-dependent effects of SL327 on CPP extinction. The parametric findings of Experiment 1 showed that three 30-min (but not 15-or 5-min) non-reinforced trials were required to completely extinguish EtOH-CPP in male, DBA/2J mice. In Experiments 2 & 3, SL327 (30 and 50 mg/kg), administered 30 or 90 min prior to extinction trials, was unable to impair EtOH-CPP extinction. Experiment 4 showed that SL327 (50 mg/kg) had no effect on acquisition of EtOH-CPP or the development of EtOH-induced sensitization during conditioning. When administered prior to testing in Experiments 5 & 6, SL327 did not alter expression of EtOH-CPP but did reduce test activity. Importantly, SL327 significantly reduced pERK protein levels when assessed in the dorsal striatum and motor cortex (Experiment 7). Together, these data suggest that EtOH-related learning and EtOH reward in mice, as assessed with CPP, are not impaired by the systemically administered MEK-inhibitor SL327.

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

“…In the CPP model, the alcohol metabolite ACD-CPP is dependent on D1-R activation and the development of ACD-CPP can be attenuated by the MEK inhibitor, PD98059 253 . In contrast, a previous study has indicated that the systemic SL327 administration in the ERK-independent learning mechanism in EtOH-CPP did not affect the acquisition, expression and extinction of EtOH-CPP (2g/kg) as well as pERK after acute EtOH administration (2.5g/kg) 254 . However, EtOH-CPP has been shown to be established by the lower dose of EtOH (1g/kg) in D1-R dependent manner 253 , which is sufficient to induce pERK induction as described above.…”

Activation and role of the medial prefrontal cortex (mPFC) in extinction of ethanol-induced associative learning in mice

“…Extinction consisted of AM and PM sessions during which animals received four, 30-min non-reinforced exposures to each of the CS+ and CS- cues separately as previously described ( see Groblewski et al, 2011). Specifically, for the AM session, animals were weighed, injected with saline, and immediately placed on the CS- cue for 30 mins.…”

“…Extinction was defined a priori as a significant reduction in place preference that was determined by Bonferroni-adjusted within-subject comparisons of preferences on Test 1 and 2 (paired t-tests) for each group following an initial two-way ANOVA (Group x Test) (Groblewski et al, 2011). Additional between-group analyses of the time spent on the Grid floor were performed including the Conditioning Subgroup (G+ and G−) as a third factor (Cunningham et al, 2003) and these data are reported in Table 1 for both experiments.…”

Decrease of phosphorylated CREB and ERK in nucleus accumbens is associated with the incubation of heroin seeking induced by cues after withdrawal

“…Chronic morphine and spontaneous withdrawal (24 h) is not associated with alterations in the content of phosphorylated MEK1/2 in the brain [1]. EtOH-related learning and EtOH reward in mice are not impaired by the systemically administered MEK-inhibitor SL327 [7]. However, central amygdala ERK signaling pathway is critical to incubation of cocaine or opiate craving [10,13].…”