Ethanol-Induced Social Facilitation in Adolescent Rats: Role of Endogenous Activity at Mu Opioid Receptors

Ethanol consumption is considerably elevated during adolescence. According to the 2007 Monitoring the Future National Survey, 8% of eighth graders, 19% of tenth graders, and 30% of twelfth graders were reported being drunk within the past 30 days, with approximately 11% of eighth graders, 22% of tenth graders, and 25% of high school seniors reported to show binge pattern of drinking (i.e., consumption of five or more drinks per occasion) in the last 2 weeks (Johnston et al., 2007). Given the importance of interactions with peers during adolescence (see Spear, 2000 for references and review), it is not surprising that human adolescents often drink with peers, with heavy drinkers, and problem drinkers expecting alcohol to make them more sociable and relaxed (Brown et al., 1987). Therefore, attractiveness of ethanol for human adolescents seems to be based, in part, on its ability to facilitate social interactions (Beck and Treiman, 1996; Beck et al.,1993). Adolescence is a developmental transition during which an immature and dependent youth is gradually transformed into a mature and relatively independent adult. A similar developmental transition from immaturity toward maturity can be identified across different mammalian species. In humans, adolescence is commonly defined as the second decade of life (Petersen et al., 1996), with females generally maturing more rapidly than males (e.g., Buchanan et al., 1992). A conservative interval during which rats of both sexes and most breeding stock exhibit adolescent-typical neurobehavioral features is the range between postnatal day (P) 28 and P42 (Spear, 2000), with this age range being sometimes subdivided into three developmental phases, namely, early (around P28), mid (around P35), and late (around P42) adolescence (Adriani et al., 2002). Human adolescents and adolescents of other mammalian species demonstrate substantial commonalities in developmental history, age-typical behavioral predispositions, neural characteristics, and changing hormonal milieu (see Spear, 2007, for review). These across-species similarities provide sufficient face and construct validity to support elaboration of animal models of adolescence. The use of a model of adolescence in the rat has demonstrated that the propensity for elevated ethanol intake and ethanol-induced social facilitation is not restricted to human adolescents. Adolescent rats likewise demonstrated greater voluntary ethanol intake than their adult counterparts under various circumstances (Brunell and Spear, 2005; Doremus et al., 2005; Lancaster et al., 1996; Vetter et al., 2007; although see also Yoshimoto et al., 2002). Moreover, acute exposure to relatively low experimental doses of ethanol (0.5 to 0.75 g/kg) administered intraperioneally (i.p.) has been shown to facilitate social interactions in adolescent rats tested under familiar, nonanxiogenic circumstances (Varlinskaya and Spear, 2002, 2006). These doses produce blood ethanol concentrations (BECs) from approximately 40 to 80 mg/dl—BECs that are within the moderate to heavy consumption range in humans (see Eckardt et al., 1998, for references and review). Ethanol-induced social facilitation is seen in both male and female adolescent rats and is predominantly characterized by an increase in play fighting—an adolescent-characteristic form of social interactions in rats (Vanderschuren et al., 1997). This social facilitation is most pronounced early in adolescence and declines gradually across the adolescent period to be no longer evident in late adolescents and adults (Varlinskaya and Spear, 2002, 2006). Adolescents develop tolerance to the social consequences of ethanol following repeated exposure, with ethanol-induced social facilitation emerging at higher ethanol doses in these tolerant animals (Varlinskaya and Spear, 2007). Although sex differences in ethanol consumption, pharmacokinetics, and some ethanol-induced effects have been reported for adult rats (Blanchard and Glick, 1995; Blanchard et al., 1993; Brasser and Spear, 2002; Cailhol and Mormede, 2001; Doremus et al, 2005; Lancaster et al., 1996; Silveri and Spear, 1999; Varlinskaya and Spear, 2004; Webb et al., 2002), in sufficiently powered experiments, we have not observed significant sex differences in responsiveness to ethanol-induced social facilitation among adolescent animals (Varlinskaya and Spear, 2002, 2006). Likewise, although sex differences in social interactions with same sex peers have been reported in adult rats, as well as in some experiments with adolescent rats (Johnston and File, 1991; Pellis and Pellis, 1990; Pellis et al., 1997; Thor and Holloway, 1986), sex differences in baseline social activity have not emerged in group-housed adolescents in our studies (Varlinskaya and Spear, 2008). Variations across studies in the incidence of sex differences in social behavior may, in part, be strain-dependent. For instance, sex differences in play fighting have been observed in adolescent Long–Evans hooded but not Sprague–Dawley rats (Pellis et al., 1997). Given the reliable ethanol-induced social facilitation seen under our testing circumstances in adolescent animals regardless of sex (Varlinskaya and Spear, 2002, 2006), both male and female adolescent rats were used in the present study to explore the role of endogenous activity at opioid receptors in ethanol-induced social facilitation. Although multiple neurochemical brain systems have been implicated in the behavioral and reinforcing effects of ethanol (see Eckardt et al., 1998, for references and review), the current project focused on the role of endogenous opioid systems, as activation of μ-opioid receptors contributes to the positive reinforcing and stimulatory effects of ethanol. Ethanol has been shown to induce the release of endogenous ligands (including β-endorphin) for these receptors in the hypothalamus, nucleus accumbens, and ventral tegmental area (Boyadjieva and Sarkar, 1997; De Waele and Gianoulakis, 1993; De Waele et al., 1992; Olive et al., 2001; Rasmussen et al., 1998). The consequent interaction of these endogenous ligands with μ-opioid receptors located within the mesolimbic reward system is viewed as a central event underlying the euphoric, positively reinforcing effects of ethanol (Froehlich and Li, 1994; Gianoulakis, 1996; Herz, 1997; Oswald and Wand, 2004). Likewise, μ-opioid agonists (Beatty and Costello, 1982; Niesink and Van Ree, 1989; Vanderschuren et al., 1995) join ethanol, alpha-2 adrenoreceptor antagonists (Siviy and Baliko, 2000; Siviy et al., 1994), indirect cannabinoid agonists (Trezza and Vanderschuren, 2008a,b), and N-methyl-D-aspartate (NMDA) antagonists (Siviy et al., 1995) in being among the few pharmacological manipulations effective in precipitating play fighting in young adolescent animals. Together, such data support the hypothesis that the facilitation of play fighting in adolescent animals may be mediated, in part, via ethanol-induced release of endogenous ligands for the μ-opioid receptor or ethanol-associated enhancement of sensitivity of μ-opioid receptors to their endogenous ligands. Therefore, the present study used an animal model of peer-directed social behavior to investigate the possible roles of endogenous opioid systems in the facilitation of social interactions by low doses of ethanol during early adolescence. Specifically, Experiment 1 assessed the effects of a nonselective opioid antagonist naloxone on ethanol-induced social facilitation in rats challenged with 0.5 g/kg ethanol, whereas Experiment 2 examined whether naloxone-induced blockade of the stimulatory effects of ethanol on social behavior reflected an overall shift in the dose–response curve for ethanol or pharmacokinetic factors. Finally, Experiment 3 investigated whether selective blockade of μ-opioid receptors was effective in attenuating ethanol-induced social facilitation during early adolescence.