Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh Caffeine modulates voluntary alcohol intake in mice depending on the access conditions: Involvement of adenosine receptors and the role of individual differences N. SanMiguel a , L. López-Cruz a,1 , C.E. Müller b , J.D. Salamone c , M. Correa a,c, ⁎ a Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, Castelló, Spain b Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Universität Bonn, Bonn, Germany c Department of Psychology, University of Connecticut, Storrs, CT, USA ARTICLE INFO Keywords: Ethanol Adenosine-antagonists Caffeine Energy-drinks Self-administration Reinstatement ABSTRACT Caffeine is the most consumed psychoactive stimulant and the main active ingredient of energy drinks. Epidemiology studies have shown a positive correlation between the consumption of energy drinks and that of ethanol. The popular belief is that caffeine antagonizes the intoxicating effects of alcohol. Both drugs act on the adenosine system but have opposite effects. Caffeine is a methylxanthine that acts as a nonselective adenosine receptor antagonist, binding to A 1 and A 2A receptor subtypes. In contrast, ethanol increases extracellular ade- nosinergic tone. The purpose of this study was to examine the impact of a broad range of doses of caffeine and of selective adenosine A 1 and A 2A receptor antagonists on voluntary ethanol intake under different ethanol access conditions. C57BL/6 J male mice had access to ethanol (10% w/v) under different conditions: restricted (2 h in the dark), unrestricted (24 h access), or after 4 days of alcohol removal following several periods of unrestricted access. Mice reduced ethanol intake in the restricted access condition after receiving caffeine (20.0 mg/kg), or theophylline (20.0 mg/kg), another methylxanthine. Selective A 1 and A 2A adenosine receptor antagonists, or their combination, did not have any effect. However, under unrestricted access conditions caffeine and the adenosine A 2A receptor antagonist increased ethanol intake. After splitting animals into high, moderate and low ethanol consumers, caffeine (2.5–20.0 mg/kg) significantly increased ethanol consumption in moderate con- sumers with no effect on low or high consumers. In addition, after reintroducing ethanol access, caffeine (5.0 mg/kg) decreased ethanol consumption among moderate consumers. Thus, caffeine produced different effects on ethanol intake depending on the access condition and the baseline consumption of ethanol. 1. Introduction Caffeine and alcohol are the two most consumed psychoactive substances in the world (Temple et al., 2017; Kalinowski and Humphreys, 2016). Interest in caffeine abuse has grown ever since the introduction to the market of so-called “energy drinks”. Although en- ergy drinks contain several components with clear psychoactive effects, caffeine is the main active ingredient responsible for the behavioral and cognitive effects associated with these beverages (Giles et al., 2012). The concentration of caffeine in these drinks may range from modest to relatively high levels (50–500 mg caffeine per serving; Reissig et al., 2009; Arria and O'Brien, 2011). A common pattern of alcohol consumption in young people is characterized by repeated bouts of heavy drinking followed by ab- stinence for hours and days. The combined intake of alcohol and “shots” of “energy drinks” is a relatively new phenomenon that is rising among young people. Combining caffeine with ethanol during binge drinking may stem from the popular belief that caffeine antagonizes intoxicating effects of alcohol, and improves social interactions (Weitzman et al., 2003; Reissig et al., 2009; Marczinski, 2011; Correa et al., 2014). Epi- demiologic studies have shown that energy-drink users tend to show increased levels of alcohol consumption. The consumption of alcohol mixed with energy drinks in students is strongly associated with high- risk drinking behavior, including increased binge drinking, and more frequent episodes of weekly drunkenness (O'Brien et al., 2008; Patrick and Maggs, 2013). https://doi.org/10.1016/j.pbb.2019.172789 Received 15 April 2019; Received in revised form 17 August 2019; Accepted 5 September 2019 ⁎ Corresponding author at: Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071 Castelló, Spain. E-mail address: correa@uji.es (M. Correa). 1 Present address: Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK. Pharmacology, Biochemistry and Behavior 186 (2019) 172789 Available online 06 September 2019 0091-3057/ © 2019 Elsevier Inc. All rights reserved. T