Effect of ethanol-derived acetaldehyde on extracellular signal Regulated Kinase in the rat nucleus accumbens and extended amygdala. Immunohistochemical and place conditioning study

The activation of Extracellular signal-Regulated Kinase (ERK) in the nucleus accumbens (Acb), bed nucleus of stria terminalis lateralis (BSTL) and central amygdala (CeA) has been linked to the acute effects of addictive drugs and suggested to act as intracellular integrator between acute actions of drugs and gene expression. Aim of this study was to determine the effects of ethanol (EtOH), acetaldehyde (ACD) and EtOH-derived ACD on ERK phosphorylation in the Acb, BSTL and CeA and the role of dopamine D1 receptors (D1R) on ERK activation in these brain regions. To this end we administered by gavage EtOH (0.5, 1 and 2 g/kg) and ACD (10 and 20 mg/kg) and determined ERK activation by immunohistochemistry. Both EtOH and ACD, dose-dependently, elicited ERK phosphorylation in Acb, BSTL and CeA. To assess the role of EtOH-derived ACD in the effects of EtOH on ERK phosphorylation we administered the alcohol dehydrogenase inhibitor, 4-methyl pyrazole (4MP) (90 mg/kg). Pre-treatment with 4MP fully prevented the effect of EtOH on ERK phosphorylation in Acb, BSTL and CeA. Pre-treatment with the D1R antagonist, SCH 39166 (50 µg/kg), also fully prevented the activation of ERK elicited by EtOH (1 g/kg) and ACD (20 mg/kg) in all brain regions studied. Furthermore, in order to assess the role of D1R in the motivational properties of EtOH and ACD we studied their effects on conditioned place preference: EtOH (1 g/kg) and ACD (20 mg/kg) produced a significant side preference shift and pre-treatment with SCH 39166 (50 µg/kg) prevented acquisition of both EtOH- and ACD-elicited place preference. Finally, to assess the role of ERK in ACD-elicited place preference we also studied the effect of intracerebroventricular administration of PD 98059, a MEK inhibitor that prevents ERK activation, and found that it prevents, dose and time dependently, the acquisition of ACD-elicited place preference. These results indicate that ACD, metabolically derived from EtOH, is responsible of its activation of ERK signalling and that blockade of D1R prevents the activation of ERK in Acb, BSTL and CeA, by EtOH, ACD and EtOH-derived ACD as well as EtOH and ACD conditioned place preference. These results also indicate that ERK activation plays a critical role in the acquisition of ACD-elicited place preference and overall these results underscore the importance of the D1R/ERK pathway in the primary reinforcing mechanism of action of ACD and Ethanol.