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Opioid peptides play a key role in ethanol reinforcement and may also represent important determinants in brain sensitivity to ethanol through modulation of nigrostriatal dopaminergic activity. Regulation of opioid levels by peptidase-degrading enzymes could be relevant in ethanol's actions. The aim of this work was to study the acute ethanol (2.5 g/kg) effects on the activity and mRNA expression of enkephalinase (NEP) and aminopeptidase N (APN) in the rat substantia nigra (SN) and the anterior-medial (amCP) and medial-posterior (mpCP) regions of the caudate-putamen (CP). Enzymatic activities were measured by fluorometric assays and mRNA expression by reverse transcriptase polymerase chain reaction. Acute ethanol administration differentially altered peptidase activities and mRNA expression with different kinetics. Ethanol increased and decreased NEP mRNA levels in the SN and amCP, respectively, but produced biphasic effects in the mpCP. APN mRNA levels were increased by ethanol in all brain regions. Ethanol induced a transient and long-lasting increase in NEP (mpCP) and APN (amCP) activities, respectively. Peptidase activities were not changed by ethanol in the SN. Our results indicate that striatal NEP and APN are important ethanol targets. Ethanol-induced changes in these neuropeptidases in the CP could contribute to the mechanisms involved in brain sensitivity to ethanol.

Opioid peptides play a key role in ethanol reinforcement and alcohol drinking behavior. However, regulation of opioid levels by peptidase-degrading activities in ethanol's actions in brain is still unclear. The aim of this work was to study the acute effects of ethanol (2.5 g/kg) on enkephalinase (NEP) and aminopeptidase N (APN) activities and expression in regions of the mesocorticolimbic system, as well as on corticosterone levels in serum for up to 24 h after administration. Enzymatic activities were measured by fluorometric assays, mRNA's expression by reverse transcriptase polymerase chain reaction (RT-PCR) and corticosterone levels by radioimmunoassay. Acute ethanol administration modified peptidase activity and expression with different kinetics. Ethanol induced a transitory increase and decrease in NEP and APN activities in the frontal cortex (FC) and ventral tegmental area (VTA), whereas only increases in these activities were observed in the nucleus accumbens (NAcc). Ethanol induced an increase in NEP mRNA in the FC and decreases in APN mRNA in the FC and NAcc. In contrast, ethanol produced biphasic effects on both enzymes expression in the VTA. Corticosterone levels were not changed by ethanol. Our results suggest that NEP and APN could play a main role in ethanol reinforcement through regulation of opioid levels in mesolimbic areas.