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Martí-Prats L, Campos-Jurado Y, Bahilo A, Cano-Cebrián MJ, Polache A, Granero L, Zornoza T, Hipolito L

Universitat de València, Department of Farmàcia i Tecnologia Farmacèutica, Burjassot, Valencia (Spain).

Despite decades of research, the specific mechanism by which ethanol induces its motivational properties has not been determined yet. In this sense, the endogenous opioid system has been demonstrated to be crucial for mediating ethanol-activating effects. A large body of literature has shown that ethanol could activate the opioid system, and concretely the mu-opioid receptors (MORs). Because of this interaction, acute administration of ethanol would cause the activation of the posterior ventral tegmental area (pVTA) dopamine (DA) neurons. Nevertheless, the mechanisms by which ethanol interacts with MORs remain poorly understood. Our and others recent published data show that acetaldehyde (ACD) or its derivative, salsolinol (SAL), could be key components of the ethanol effects. Concretely SAL, an ethanol derivative formed by condensation of ACD with DA, has structural similarities to morphine and is able to bind to MORs to produce opioid-like effects. Therefore, SAL could be the final responsible for the ethanol-derived MORs activation, which will cause the excitation of pVTA DA neurons. In the present study, our aim is to further investigate ethanol motivational properties by analyzing the acquisition, extinction and reinstatement of conditioned place preference (CPP), focusing on SAL and MORs role. For this reason, we have analyzed the previously unreported ability of ethanol to induce CPP when administered directly into the pVTA. Furthermore, the involvement of local MORs in the behavior observed has been studied by their selective blockade with the antagonist β-Funaltrexamine (β-FNA). Lastly, we have evaluated the capability of SAL to reinstate the ethanol induced-CPP. Results showed, for the first time, that intra-pVTA ethanol induces CPP in a dose-dependent manner. Moreover, the blockade of pVTA MORs appears to impact the acquisition and expression of ethanol-induced CPP. Interestingly, after extinction of ethanol-induced CPP, a single dose of SAL was able to induce cross-reinstatement of the preference observed. These data support the relevant role of SAL as mediator of the motivational and activating properties of ethanol, including learned associations of the context with the ethanol effects.