Effects of systemic glycine on accumbal glycine and dopamine levels and ethanol intake in male Wistar rats

Yasmin Olsson,Bo Söderpalm,Mia Ericson,Klara Danielsson,Helga Höifödt Lidö

doi:10.1007/s00702-020-02284-x

Abstract

Approved medications for alcohol use disorder (AUD) display modest effect sizes. Pharmacotherapy aimed at the mechanism(s) by which ethanol activates the dopamine reward pathway may offer improved outcomes. Basal and ethanol-induced accumbal dopamine release in the rat involve glycine receptors (GlyR) in the nucleus accumbens (nAc). Glycine transporter 1 (GlyT-1) inhibitors, which raise extracellular glycine levels, have repeatedly been shown to decrease ethanol intake in the rat. To further explore the rational for elevating glycine levels in the treatment of AUD, this study examined accumbal extracellular glycine and dopamine levels and voluntary ethanol intake and preference in the rat, after systemic treatment with glycine. The effects of three different doses of glycine i.p. on accumbal glycine and dopamine levels were examined using in vivo microdialysis in Wistar rats. In addition, the effects of the intermediate dose of glycine on voluntary ethanol intake and preference were examined in a limited access two-bottle ethanol/water model in the rat. Systemic glycine treatment increased accumbal glycine levels in a dose-related manner, whereas accumbal dopamine levels were elevated in a subpopulation of animals, defined as dopamine responders. Ethanol intake and preference decreased after systemic glycine treatment. These results give further support to the concept of elevating central glycine levels to reduce ethanol intake and indicate that targeting the glycinergic system may represent a pharmacologic treatment principle for AUD.

Highlights

Ethanol consumption contributes substantially to the global burden of disease (WHO 2018), and individuals with alcohol use disorder (AUD) are especially prone to high ethanol consumption
Accumbal dopamine levels were mildly elevated after treatment with systemic glycine, two-way-ANOVAt=0–120; treatment effect F(3, 33) = 1.92, p = 0.145, time effect F(6,198) = 10.02, p < 0.001, interaction term F(18, 198) = 1.54, p = 0.080 (Fig. 3a)
Comparisons of the area under the curve (AUC) did not reveal any significant alterations of accumbal dopamine levels (Fig. 3b)

Summary

Introduction

Ethanol consumption contributes substantially to the global burden of disease (WHO 2018), and individuals with alcohol use disorder (AUD) are especially prone to high ethanol consumption. AUD generates enormous socioeconomic costs encompassing both healthcare expenses and social harm (Rehm et al 2009). One way of combating AUD is Yasmin Olsson and Helga Höifödt Lidö contributed to this paper. In similarity to other drugs of abuse, ethanol’s reinforcing properties involve enhanced dopamine activity in the nucleus accumbens (nAc), an important part of the mesolimbic dopamine system (Di Chiara and Imperato 1988; Gonzales et al 2004; Spanagel 2009). A large body of evidence suggests that transition from recreational to compulsive drinking, characteristic of AUD, involves neuroadaptations in the mesolimbic reward system (Gonzales et al 2004; Koob and Volkow 2010). Pharmacotherapies tailored to act directly on the mechanism(s) by which ethanol interferes with the reward system could offer an improved treatment

Methods

Results

Conclusion