Effects of Caffeine on Alcohol Consumption and Nicotine Self‐Administration in Rats

CAFFEINE, ALCOHOL AND NICOTINE are three of the most widely used psychoactive drugs in the world. Although these drugs are often used together, the influence of caffeine on consumption of alcohol and nicotine is not fully explored. The aim of the current study was to investigate the effect of caffeine on alcohol consumption in selectively-bred alcohol preferring rats and on intravenous (i.v.) nicotine self-administration in Sprague-Dawley rats. There is considerable evidence indicating an interaction between alcohol and the adenosine system in the brain. Alcohol blocks re-uptake of adenosine resulting in an increase in extracellular adenosine (Nagy et al., 1990) which leads to the activation of adenosine receptors (Yao et al., 2002). Activation of adenosine A2A receptors inhibits dopamine transmission and blockade of these receptors by adenosine receptor antagonists such as caffeine enhances dopamine release (Shook and Jackson, 2011). Thus, adenosine can play a significant role in the reinforcing effects of alcohol and other drugs of abuse by modulating dopamine which has been implicated in drug seeking behavior (Dohrman et al., 1997; Koob, 2003; Mailliard and Diamond, 2004; Ruby et al., 2010). Adenosine has also been shown to be involved in alcohol-induced ataxia (Dar, 2001). The caffeine molecule is structurally similar to adenosine and acts as competitive non-selective antagonist for adenosine receptors including adenosine A1 and A2A receptors which suppress several neurotransmitters including monoaminergic transmitters and acetylcholine (Basheer et al., 2004; Fisone et al., 2004; Fredholm et al., 1999; Shook and Jackson, 2011; Tanda and Goldberg, 2000). Caffeine by blocking adenosine receptors enhances dopamine transmission in the dopaminergic terminals (Ferre et al., 2008; Shook and Jackson, 2011). Thus, considering the role of the dopaminergic systems in both alcohol and nicotine self-administration (Di Chiara, 2000; Koob, 2003; McBride et al., 2003) it is expected to see a change in alcohol and nicotine intake as a result of caffeine or other adenosine receptor antagonists administration. It has been shown that administration of adenosine A2 receptor antagonist 3,7-dimethyl-propargylxanthine significantly decreases lever pressing for alcohol in a dose-dependent manner in Wistar rats (Thorsell et al., 2007). It has also been demonstrated that the administration of the selective adenosine A2A receptor antagonist, SCH 58261 or the selective A1 receptor antagonist DPCPX, reduces fixed ratio responding for alcohol in inbred alcohol preferring iP rats (Adams et al., 2008) and systemic administration of adenosine A2 receptor antagonist, DMPX, significantly reduces alcohol intake in Long Evans rats (Arolfo et al., 2004) suggesting an important role for adenosine A2 receptors in the regulation of alcohol intake. However, adenosine receptor antagonist 8-cyclopentyl-1,3,dimethylxanthine (CPT) was not found to have a significant effect on alcohol intake in male Long-Evans rats (Gatch et al., 1999) and pretreatment with an A2A receptor antagonist (ANR 94) increased alcohol intake while A2A agonists (VT 7 and CGS 21680) reduced alcohol intake using a limited access paradigm in a selectively-bred alcohol preferring rats (msP) (Micioni Di Bonaventura et al., 2012). Acute systemic IP administration of caffeine at a dose of 5 mg/kg has been shown to increase alcohol intake, while doses of 2.5 and 10 mg/kg showed no effects on alcohol intake in outbred Wistar rats using a limited 1-hr access paradigm (Kunin et al., 2000). Thus, it seems that there is an inconsistency in the literature regarding the effects of adenosine agonist and antagonist on alcohol intake. There are several reasons for this inconsistency. In all of these experiments a limited (1-2 hr) access to alcohol was provided and the animals did not drink long enough to become dependent on alcohol. The other reason might be related to the dose of the drug used. In one study only one dose was used (Gatch et al., 1999). Another reason might be related to the genetic background of these animals. Furthermore, in these studies the effects of these drugs on alcohol intake at different time points after the drug administration were not measured. Considering these issues, we systematically investigated the effect of different doses of caffeine given both acutely and chronically in chronically drinking alcohol preferring (P) rats. Furthermore, we studied the effects of caffeine on alcohol intake following a period of alcohol deprivation in P rats. Interaction of caffeine and nicotine has been also reported (Tanda and Goldberg, 2000). It has been shown that pretreatment with caffeine markedly potentiates the discriminative-stimulus effects of nicotine in rats without affecting the pharmacokinetics of nicotine (Gasior et al., 2002). Furthermore, chronic oral exposure to caffeine has been shown to facilitate acquisition of self-administration and discrimination of nicotine in rats (Gasior et al., 1999; Shoaib et al., 1999). These findings support previous results from other laboratories that showed chronic caffeine exposure potentiates the reinforcing properties of nicotine in non-human primates (Yaser et al., 1997). Altogether, these findings suggest that caffeine can significantly potentiate the reinforcing properties of nicotine. This may explain the positive correlation that has been reported in several studies between coffee drinking and smoking in humans. Both anecdotal and clinical reports suggest that heavy smokers tend to drink more coffee than non-smokers and smokers smoke more while drinking coffee (Brown and Benowitz, 1989; Emurian et al., 1982; Istvan and Matarazzo, 1984; Tanda and Goldberg, 2000). However, it should be noted that there are some epidemiological and clinical data suggesting no causal correlation between smoking and coffee drinking (Bundey et al., 1993; Istvan and Matarazzo, 1984; Swanson et al., 1994). Since caffeine is so widely consumed, it is important to know the effect of caffeine on consumption of other potentially addictive drugs such as alcohol and nicotine. Given the fact that these three drugs are often used together, the present study was designed to determine whether caffeine would alter consumption of alcohol or nicotine. It was hypothesized that caffeine administration would reduce alcohol intake, but would increase nicotine self-administration.