The histone deacetylase inhibitor valproic acid reduces ethanol consumption and ethanol-conditioned place preference in rats

Abstract

Introduction: Recent evidence suggests that epigenetic mechanisms, such as chromatin modification (specifically histone acetylation), may play a crucial role in the development of addictive behaviour. However, little is known about the role of epigenetic modifications in the rewarding properties of ethanol. Objectives: To investigate the effect of systemic injection of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on ethanol consumption and ethanol-elicited conditioned place preference (CPP). Materials and methods: The effect of VPA (300mg/kg) on voluntary ethanol intake and preference was assessed using continuous two-bottle choice procedure with escalating concentrations of alcohol (2.5– 20% v/v escalating over 4 weeks). Taste sensitivity was studied using saccharin (sweet; 0.03% and 0.06%) and quinine (bitter; 20mM and 40mM) tastants solutions. Ethanol conditioned reward was investigated using an unbiased CPP model. Blood ethanol concentration (BEC) was also measured. Results: Compared with vehicle, VPA-injected rats displayed significantly lower preference and consumption of ethanol in a two-bottle choice paradigm, with no significant difference observed with saccharin and quinine. More importantly, 0.5g/kg ethanol-induced-CPP acquisition was blocked following VPA administration. Finally, vehicle- and VPA-treated mice had similar BECs. Conclusions: Taken together, our results implicated HDAC inhibition in the behavioural and reinforcement-related effects of alcohol and raised the question of whether specific drugs that target HDAC could potentially help to tackle alcoholism in humans. Acknowledgements: The authors would like to acknowledge Mr Mohamed Elwasila and Mr Mohamed Shafiullah for their technical assistance and Dr Mahmoud Hag Ali from the Central Animal Facility for his advice on veterinary care.