Activation of Adenosine A1 Receptors Reduces Anxiety-Like Behavior During Acute Ethanol Withdrawal (Hangover) in Mice

Abstract

Elevated signs of anxiety are observed in both humans and rodents during withdrawal from chronic as well as acute ethanol exposure, and it represents an important motivational factor for ethanol relapse. Several reports have suggested the involvement of brain adenosine receptors in different actions produced by ethanol such as motor incoordination and hypnotic effects. In addition, we have recently demonstrated that adenosine A 1 receptors modulate the anxiolytic-like effect induced by ethanol in mice. In the present study, we evaluated the potential of adenosine A 1 and A 2A receptor agonists in reducing the anxiety-like behavior during acute ethanol withdrawal (hangover) in mice. Animals received a single intraperitoneal administration of saline or ethanol (4 g/kg) and were tested in the elevated plus maze after an interval of 0.5-24 h. The results indicated that hangover-induced anxiety was most pronounced between 12 and 18 h after ethanol administration, as indicated by a significant reduction in the exploration of the open arms of the maze. At this time interval, ethanol was completely cleared. The acute administration of 'nonanxiolytic' doses of adenosine and the selective adenosine A 1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), but not the adenosine A 2A receptor agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), at the onset of peak withdrawal (18 h), reduced this anxiogenic-like response. In addition, the effect of CCPA on the anxiety-like behavior of ethanol hangover was reversed by pretreatment with the selective adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). These results reinforce the notion of the involvement of adenosine receptors in the anxiety-like responses and indicate the potential of adenosine A 1 receptor agonists to reduce the anxiogenic effects during ethanol withdrawal.

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

“…For example, withdrawal from alcohol liquid diet, chronic injections, vapor exposure, or consumption from a single drinking bottle increase anxiety-like behavior in mice that persists for up to 48 h after alcohol exposure (Costall et al, 1988;Joshi et al, 2005;Kliethermes et al, 2004;Prediger et al, 2006;Sparta et al, 2007). Similar results have been obtained in rat models showing increased anxiety-like behavior during acute and early withdrawal from an alcohol liquid diet (Baldwin et al, 1991;Moy et al, 1997;Pandey et al, 1999;Rassnick et al, 1993).…”

Ethanol Interference on Adenosine System

“…High amount of experimental studies, involving ethanol administration, use a chronic treatment as methodology protocol; but subchronic and acute treatments are also well used (Soares et al, 2009;Prediger et al, 2006). While acute treatment simulates hangover, chronic treatment usually refers to the withdrawal symptoms and body's adaptive responses to prolonged consumption of ethanol.…”

“…Prediger et al (2006) designed an experimental study of acute ethanol withdrawal (hangover) in mice, in which a timedependent development of anxiety-like behavior after an intraperitoneal administration of a single dose of ethanol (4 g/kg) in mice was assessed, and the potential of adenosine A 1 and A 2A receptor agonists in reducing this behavior was evaluated. They presented evidence that acute administration of 'nonanxiolytic' doses of adenosine (5-10 mg/kg, i.p.)…”

“…In addition, there is strong evidence of an involvement of the adenosinergic system on ethanol effects, including the extracellular increase of adenosine after acute exposure to ethanol (Krauss et al, 1993;Nagy et al, 1990), the accentuation or blockade of ethanolinduced motor incoordination provided by adenosine receptor agonists or antagonists, respectively (Dar, 2001;Soares et al, 2009), and the reduction of anxiogenic-like behavior in acute ethanol withdrawal (Prediger et al, 2006). Adenosine antagonists, like caffeine, are implicated in alcohol tolerance (Fillmore, 2003), and retrograde memory impairment caused by ethanol (Spinetta et al, 2008).…”

“…Moreover, another pathway that is rising on researches about ethanol effects is the adenosinergic system (Prediger et al, 2006;Thorsell et al, 2007).…”