Environmental Enrichment Increases Alcohol Reward Via Modulation of The Oxitocinergic System

Abstract

Environmental enrichment (EE; model of “eustress”) has been hypothesized to prevent and reverse drug addiction‐related behaviors. Our group has already shown a protective effect of EE on ethanol sensitization and alcohol consumption. However, the mechanisms underlying these effects are not known. The aim of this study was to evaluate the effect of EE on alcohol reward. Swiss male mice (PDN=70) were distributed in control (reared in standard cages) and EE (kept in large cages with objects and a running wheel) groups, during 21 days. We first behaviorally characterized the effects of EE on alcohol (2.0 g/Kg, i.p) conditioned‐place preference (CPP). Since one of the main pillars of EE is increased social interaction, we accessed the effects of EE on the OT peptide and OT receptor (OTR), via ELISA and autoradiography, respectively. Although all mice showed ethanol CPP, EE group exhibited higher ethanol preference, suggesting a sensitization of the reward system induced by EE. EE animals had higher OT levels in the hypothalamus and lower OTR binding in the olfactory nuclei, frontal and piriform cortices, brains regions involved in social information processing. Taken together, these results indicate that EE can modulate the OT system by increasing OT synthesis in the brain, leading to OTR downregulation in specific brain regions. To assess the functional role of the OT neurotransmission in the observed EE‐induced enhancement of ethanol CPP, we studied the effects the OT analogue, carbetocin (CBT) (6.4 mg/kg/day, i.p) and the OTR antagonist, L,369–899 (OTR‐A) (5 mg/kg/day, i.p) in that paradigm. CBT administration, similar to EE, enhanced alcohol CPP in control animals. Conversely, treatment with the OTR‐A during the EE exposure blocked this enhancement in ethanol CPP. These findings suggest that EE enhances ethanol rewarding effects via a direct modulation of the OT system. In conclusion, we demonstrated that EE and OT treatment may constitute a risk factor that may predispose to alcohol use. Therefore, OT‐based therapies regarding alcohol addiction should be considered cautiously, particularly in the early stages of alcohol use.All the animal studies were conducted in accordance with Ethical Committee for Animal Use (CEUA) of the University of São Paulo, registered under protocol nº 132, page 110, book 02.Support or Funding InformationSupported by CAPES, CNPq, FAPESP and SantanderThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.