Effects of Cagemate Gender and the Cagemate's access to ethanol on ethanol and water intake of the proximal male or the proximal female CD-1 mouse

Alcohol 48 (2014) 73e82

Contents lists available at ScienceDirect

Alcohol journal homepage: http://www.alcoholjournal.org/

Effects of Cagemate Gender and the Cagemate’s access to ethanol on ethanol and water intake of the proximal male or the proximal female CD-1 mouse Arthur Tomie a, b, *, Alyssa A. DeFuria b, Heather A. Jones b, Sara D. Edwards b, Lei Yu a, c a

Center of Alcohol Studies, Rutgers e The State University of New Jersey, 607 Allison Road, Piscataway, NJ 08854-8001, USA Department of Psychology, Rutgers e The State University of New Jersey, 607 Allison Road, Piscataway, NJ 08854-8001, USA c Department of Genetics, Rutgers e The State University of New Jersey, 607 Allison Road, Piscataway, NJ 08854-8001, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 3 June 2013 Received in revised form 23 September 2013 Accepted 17 October 2013

The effects of social stimulation on ethanol drinking in humans may depend on the gender of the drinker, the gender of the social stimulus, and the availability of ethanol provided to the social stimulus. The present study employed the Proximal Cagemate Drinking (PCD) Procedures to evaluate the effects of the gender of the social stimulus Cagemate mouse and the effects of providing ethanol to the Cagemate mouse on the drinking of ethanol and water by the male or female CD-1 Drinker mouse. Twelve groups of subjects were arranged in a 3
2
2 factorial design with 3 levels of Cagemate Gender (Male vs. Female vs. None), 2 levels of Drinker Gender (Male vs. Female), and 2 levels of Cagemate Ethanol (Ethanol vs. No Ethanol). In the 8 groups assigned to social housing conditions, each Drinker mouse was housed with a Cagemate mouse on opposite sides of a clear plastic shoebox cage equipped with a clear plastic barrier that divided the cage lengthwise into 2 equal compartments. Six groups of Drinkers and 4 groups of Cagemates were provided with continuous access to 2 bottles (ethanol vs. water), while the 4 groups of Cagemates in the No Ethanol condition were provided with 2 bottles containing water. Results revealed that providing the Cagemate with ethanol elevated ethanol intake and ethanol preference but reduced water intake in Drinkers in Other-Gender Pairings (Male Drinker-Female Cagemate or Female Drinker-Male Cagemate) relative to Drinkers in Same-Gender Pairings (Male Drinker-Male Cagemate or Female Drinker-Female Cagemate). In contrast, when the Cagemate was not provided with access to ethanol, the opposite effects were observed. These novel PCD procedures reveal that the gender of the Cagemate and the Cagemate’s access to ethanol influenced ethanol drinking in proximal-housed CD-1 Drinker mice. Ó 2014 Elsevier Inc. All rights reserved.

Keywords: Ethanol Gender Mice Modeling Social Water

Introduction There is considerable experimental evidence that human beings engaging in social interactions drink more ethanol than control subjects in similar situations but without the opportunity to engage in social interactions (Abrams & Niarura, 1987; Caudill & Kong, 2001; Caudill & Lipscomb, 1980; Caudill & Marlatt, 1975; Maisto, Carey, & Bradizza, 1999) The effects of social stimulation in rodent models of ethanol drinking are also well-documented (Advani, Hensler, & Koek, 2007; Anacker, Loftis, Kaur, & Ryabinin, 2011; Anacker & Ryabinin, 2010; Caldwell & Riccio, 2010; Croft, Brooks, Cole, & Little, 2005; de Almeida, Rowlett, Cook, Yin, & Miczek, 2004; Funk, Harding, Juzytsch, & Lê, 2005; Hall, Huang, Fong, Pert, & Linnoila, * Corresponding author. Center of Alcohol Studies, Rutgers e The State University of New Jersey, 607 Allison Road, Piscataway, NJ 08854-8001, USA. Tel.: þ1 732 445 3593; fax: þ1 732 445 3500. E-mail addresses: [email protected], [email protected] (A. Tomie). 0741-8329/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.alcohol.2013.10.006

1998; Hunt & Hallmark, 2001; Maldonado, Finkbeiner, & Kirstein, 2008; McCool & Chappell, 2009; Randall & Lester, 1975; Tomie, Burger, Di Poce, & Pohorecky, 2004; Tomie, Gittleman, Dranoff, & Pohorecky, 2005; Tomie et al., 2006; Tomie, Lewis, Curiotto, & Pohorecky, 2007; Tomie, Uveges, Burger, Patterson-Buckendahl, & Pohorecky, 2004; Wolffgramm, 1990; Wolffgramm & Heyne, 1991; Yanai & Ginsburg, 1976). Studies of modeling of ethanol drinking in humans reveal that the stimulating effect of social interaction is enhanced when ethanol is made available to the confederate (Caudill & Kong, 2001; Caudill & Marlatt, 1975; Collins, Parks, & Marlatt, 1985; Larsen, Engels, Souren, Granic, & Overbeek, 2010; Larsen, Overbeek, Granic, & Engels, 2010; Larsen, Overbeek, Granic, & Engels, 2012). For example, high-drinking confederates induced elevated ethanol drinking relative to low-drinking confederates or relative to confederates drinking non-alcoholic beverages (Larsen, Engels, Granic, & Overbeek, 2009; Larsen, Engels, et al., 2010; Larsen, Engels, Wiers, Granic, & Spijkerman, 2012). In humans, there is no evidence of an

74

A. Tomie et al. / Alcohol 48 (2014) 73e82

effect of the gender of the confederate on ethanol drinking of either the male or the female experimental subject. That is, the ethanol drinking of the confederate of either gender induced similar levels of ethanol drinking in Same-Gender Pairing arrangements as in Other-Gender Pairing arrangements (Larsen, Engels, et al., 2012; Larsen, Overbeek, et al., 2010). In studies of ethanol drinking in animals, the gender of the social stimulus relative to the gender of the drinker (i.e., gender-pairing arrangement) and, in addition, providing ethanol access to the social stimulus, have been shown to influence ethanol drinking of the experimental subject. For example, in prairie voles, Same-Gender Pairs (maleemale and femaleefemale) separated by a wire-mesh barrier in the home cage drank more ethanol than did isolationhoused controls (Anacker, Loftis, Kaur, et al., 2011). However, in another study, Other-Gender Pairing (maleefemale) did not induce more ethanol drinking relative to isolation-housed controls (Hostetler, Anacker, Loftis, & Ryabinin, 2012), suggesting that in prairie voles, the proximal social presence of the same gender may be more effective than the proximal social presence of the other gender in stimulating ethanol drinking. This effect of the genderpairing arrangement on modeling of ethanol drinking was also observed in the coordination of drinking within pairs. In SameGender Pairing arrangements, pairing with a higher-drinking prairie vole induced more ethanol drinking, as compared to pairing with a lower-drinking prairie vole (Anacker, Loftis, Kaur, et al., 2011; Anacker, Loftis, & Ryabinin, 2011; Hostetler et al., 2012), but this positive correlation effect was not observed in Other-Gender Pairing arrangements (Hostetler et al., 2012). Studies by Pamela Hunt and her colleagues (Hallmark & Hunt, 2004; Hunt, Holloway, & Scordalakes, 2001; Hunt, Lant, & Carroll, 2000) reported a modeling-like effect on ethanol drinking in rats. These investigators evaluated the effects of interacting with an intoxicated Same-Gender sibling “demonstrator” rat on the subsequent ethanol intake of an “observer” rat. It should be noted that intoxication was induced by pre-session intraperitoneal ethanol injection rather than ethanol drinking, and these studies employed only pairs of siblings of the same gender. They found that an observer animal increased its intake of ethanol following a brief interaction with an intoxicated sibling, relative to following interaction with a non-intoxicated sibling. In other studies from the Hunt laboratory, littermates were randomly assigned to conditions as demonstrators or as observers, thereby allowing for Other-Gender Pairings, but the effects of gender pairing on ethanol drinking of the observer were not reported (Hallmark & Hunt, 2004; Hunt & Hallmark, 2001). Therefore, injection-induced intoxication of the proximal social stimulus may induce elevated ethanol drinking in rats, but this effect has been documented only in Same-Gender littermates. Tomie et al. (2006) reported that in male rats, an Other-Gender Pairing arrangement relative to a Same-Gender Pairing arrangement induced elevated ethanol drinking. In that study the female social stimulus rat, relative to the male social stimulus rat, induced more ethanol intake in the male experimental rat, but this effect was not observed with water, indicating that the effect was specific to ethanol (Tomie et al., 2006). It should be noted that the experimental design employed by Tomie et al. was incomplete in that the effects of the proximal presence of a male rat or a female rat on the ethanol or water drinking of the experimental female rat were not evaluated. In addition, they employed single-bottle drinking procedures, which did not allow for assessment of the effects of gender pairing on ethanol preference. The current study employed a novel technique, the Proximal Cagemate Drinking (PCD) procedures, to evaluate the effects of the gender of the social stimulus (Cagemate) mouse on the ethanol drinking of the experimental (Drinker) mouse. The PCD procedures

allowed the Cagemate mouse to be placed in close proximity to the Drinker mouse such that the Cagemate mouse was physically isolated from the Drinker mouse by a plastic barrier drilled with holes to allow ventilation between the 2 sides of the plastic shoebox cage. In addition, the PCD procedures provided the Drinker mouse with continuous and unrestrained access to the ethanol and water sippers during the entire duration of the drinking session. Thus, the PCD procedures allowed for the assessment of the effects of the presence of the proximal social stimulation provided by the Cagemate mouse on the fluid (ethanol and water) intake of the Drinker mouse, and did so under conditions where the fluid intake of the Drinker was unencumbered by the effects of direct physical contact with the Cagemate. This is an important consideration, because allowing direct physical contact between Drinker and Cagemate would likely alter drinking behavior in ways that would differ depending upon the gender-pairing arrangement. For example, procedures allowing direct physical contact between the Male Drinker and Male Cagemate would likely produce aggressive behaviors (van Erp & Miczek, 2000, 2001), whereas procedures allowing direct physical contact between the Male Drinker and Female Cagemate would likely produce sexual responses (Firman & Simmons, 2008; Sawrey & Dewsbury, 1981). Aggressive or sexual responses would interfere with drinking behavior, leaving unclear the effects on drinking of the mere proximal presence per se, of the gender of the Cagemate. The PCD procedures are similar to “contact” cagemate procedures employed by Wolffgramm (1990) in studies of ethanol drinking in rats and by Ryabinin and his associates in studies of ethanol drinking in prairie voles (Anacker, Loftis, Kaur, et al. 2011; Anacker, Loftis, & Ryabinin, 2011; Hostetler et al., 2012). Wolffgramm used a wire mesh to separate the male Drinker rat from the male Cagemate rat and found patterns of ethanol preference of the contact-cagemate group to be intermediate between those of isolation-housed and group-housed rats. The study by Wolffgramm did not vary the availability of ethanol for the contactcagemate nor did that study employ female rats, as either Drinkers or as Cagemates. The studies by Ryabinin and his associates of prairie voles did not directly compare the effects of Same-Gender vs. Other-Gender Pairings, nor did their studies evaluate the effects of providing only one member of the pair with access to ethanol on the ethanol drinking of the other member of the pair (Anacker, Loftis, Kaur, et al., 2011; Anacker, Loftis, & Ryabinin, 2011; Hostetler et al., 2012). Thus, while investigators of social stimulation of ethanol drinking have reported effects of gender-pairing arrangements, and other investigators have reported effects of modeling of the ethanol drinking of the social stimulus, there are no published studies employing the factorial combination of these factors, leaving the nature of the interaction between these 2 factors unclear. This is an important consideration because the literature suggests that the effects of the ethanol drinking of the social stimulus may depend on the gender-pairing arrangement. Materials and methods Animals The study employed 832 CD-1 mice obtained from Charles River (Kingston, NY). The outbred CD-1 mice were employed as experimental subjects because, like humans, they are genetically diverse, known to provide substantial between-subjects variability in ethanol drinking, while also providing stable and modest mean levels of intake of moderate concentrations of ethanol. At the beginning of the study, the CD-1 mice were approximately 49 days old, and mean body weights were 32.2 g and 26.2 g, for males and

A. Tomie et al. / Alcohol 48 (2014) 73e82

females, respectively. Mice were randomly assigned to conditions, as either Drinkers or Cagemates. Drinkers were 448 CD-1 mice (224 males and 224 females), and Cagemates were 384 CD-1 mice (192 males and 192 females). All mice were housed individually in plastic shoebox cages in a colony room with a 12-h light, 12-h dark cycle (lights on at 0600 h) where they were provided with unrestricted access to water and food (Lab Diet, 5001 Rodent Diet, PMI Nutrition International, Brentwood, MO, USA). All Male Drinkers paired either with a Male Cagemate or with no Cagemate were housed in a male-only colony room and all Female Drinkers paired either with a Female Cagemate or with no Cagemate were housed in a female-only colony room. All Drinkers paired with a Cagemate of the Other Gender were housed in a mixed-gender colony room. There was no direct ventilation between the 3 colony rooms. All mice were allowed to habituate to their colony rooms for 1 week prior to the beginning of the experiment. All procedures were performed in accordance with the guidelines of the Institutional Care and Use Committee of the National Institute on Drug Abuse, National Institute of Health, and the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources Commission on Life Sciences, National Research Council, 1996), and approved by the IACUC at Rutgers University. Apparatus Each Drinker mouse was housed with a Cagemate mouse in a standard clear plastic shoebox cage equipped with a clear plastic barrier that divided the shoebox cage lengthwise into 2 equal compartments. The plastic barrier was the height of the shoebox cage and was drilled with 20 quarter-inch diameter circular holes to allow ventilation between the 2 compartments. The Drinker mouse was placed on one side of the plastic barrier, while the Cagemate mouse was placed on the opposite side of the plastic barrier. Both mice were provided with free access to food and to 2 stainless steel sippers. For each Drinker mouse, one sipper was inserted in the rubber stopper of a glass tube containing ethanol while the other sipper was inserted in the rubber stopper of a glass tube containing water, and this arrangement of drinking tubes was also employed for each Cagemate mouse provided with access to ethanol. For the Cagemate mouse without ethanol access, both sippers were inserted in glass tubes containing only water. In the Isolation condition, on the other side of the plastic barrier, opposite to the Drinker mouse, there was no Cagemate mouse, but there were 2 tubes, one containing ethanol and the other containing water (Ethanol on Cagemate side) or 2 tubes, both containing water (No Ethanol on Cagemate side). Drugs Bulk ethanol (95%) was obtained from Rutgers University Chemical Stores. Ethanol was diluted in tap water to produce the concentrations (volume to volume, vol/vol) employed in the study. Ethanol drinking procedures Subjects were unsystematically assigned to 12 groups. Eight groups of subjects (48 Drinkers per group and 48 Cagemates per group) were assigned to Social Housing conditions, while 4 groups of subjects (16 Drinkers per group and zero Cagemates per group) were assigned to Isolation Housing conditions. The 12 groups were arranged in a 3
2
2 factorial design based on all combinations of Cagemate Gender (Male vs. Female vs. None), Drinker Gender (Male vs. Female), and Cagemate Ethanol condition (Ethanol on Cagemate Side vs. No Ethanol on Cagemate Side). The PCD procedures were employed during each daily 23-h drinking session,

75

with 1-h time set aside for mouse weighing, liquid consumption recording, and refilling of drinking tubes. During each of the 12 daily drinking sessions, each Drinker mouse was weighed at approximately 1000 h. All 12 groups of Drinker mice and the 6 groups of Cagemate mice in the Ethanol on Cagemate Side condition were provided with 2 tubes, one containing ethanol and the other containing water. The 6 groups in the No Ethanol on Cagemate Side condition were also provided with 2 tubes on the Cagemate side, but both tubes contained water. During experimental days 1e5, for the Drinker mice and for the Cagemate mice provided with access to ethanol, the vol/vol concentration of ethanol in the sipper was increased daily in 2% increments from 2% to 10%, and then maintained at 10% for the remaining 7 days of the study (experimental days 6e12). This schedule of ascending ethanol concentrations, with a maximum ethanol concentration of 10%, was similar to the schedule of ethanol concentrations employed in earlier investigations of intergender effects in rats (Tomie et al., 2006) and in prairie voles (Hostetler et al., 2012). For the Drinker mice, fluid bottles were weighed, emptied, refilled, and re-weighed during the 1-h set-aside time, to allow determination of the amount of fluid removed from each bottle during each 23-h drinking session. For the Cagemate mice, fluid bottles were emptied and refilled, but not weighed or re-weighed during the 1-h set-aside time; therefore, daily levels of drinking of ethanol and water of the Cagemate mice were not determined. The positions of the ethanol bottle and the water bottle in each cage were randomized across days for Drinker mice and for Cagemate mice with access to ethanol. Data analysis For each Drinker mouse, for each daily session, ethanol fluid consumed (g) and water fluid consumed (g) and body weight (g) were measured. For each Drinker mouse, grams of ethanol consumed per kg of body weight (g/kg ethanol intake), grams of water consumed per kg of body weight (g/kg water intake) and percent ethanol preference (grams of ethanol fluid consumed divided by the sum of grams of ethanol fluid consumed plus grams of water consumed) were derived. For each subject, the mean for each measure (g/kg ethanol intake, g/kg water intake, % ethanol preference) of the last 5 daily sessions of training with the 10% ethanol solution (sessions 8e12) was derived, and each of these 5-day means provided the data subjected to statistical analysis. For the 12 groups, the effects of Cagemate Gender (Male vs. Female vs. None), Drinker Gender (Male vs. Female), Cagemate Ethanol condition (Ethanol on Cagemate Side vs. No Ethanol on Cagemate Side), and their interaction effects were assessed by 3-way 3
2
2 univariate analysis of variance (ANOVA) using General Linear Model (Systat Statistical Software, Richmond, CA, USA), with a 2-tailed alpha level of 0.05. Note that a significant 2-way interaction between Drinker Gender and Cagemate Gender is revealed by a significant main effect of Gender-Pairing Arrangement (Same-Gender Pairing vs. Other-Gender Pairing). A significant 3-way interaction was followed by 2
2 ANOVA using Gender-Pairing Arrangement (Same-Gender Pairing vs. OtherGender Pairing) and Cagemate Ethanol condition as factors. For each Drinker Gender, a 3
2 ANOVA evaluated the effects of Cagemate Gender and Cagemate Ethanol. Planned comparisons evaluated the effects of Cagemate Gender under each Cagemate Ethanol condition. Planned comparisons also evaluated the effects of isolation housing for each Drinker Gender under each Cagemate Ethanol condition by comparing isolation housing (i.e., No Cagemate) relative to the effect of the Same-Gender Cagemate and relative to the effect of the Other-Gender Cagemate, as assessed by 1-way ANOVAs.

76

A. Tomie et al. / Alcohol 48 (2014) 73e82

Results Ethanol intake (g/kg) Ethanol intake data of Drinkers (see Fig. 1) were evaluated using 3-way 3
2
2 ANOVA. This analysis revealed a significant 3-way interaction (F[2, 431] ¼ 9.74, p < 0.01). Two-way 2
2 ANOVA evaluating effects of Gender Pairing and Cagemate Ethanol revealed a highly significant interaction (F[1375] ¼ 16.77, p < 0.01). Providing the Cagemate with access to ethanol induced elevated ethanol intake in Drinkers in Other-Gender Pairing arrangements relative to Drinkers in Same-Gender Pairing arrangements (F[1186] ¼ 11.17, p < 0.01). The opposite result was observed when the Cagemate was not provided with access to ethanol, with ethanol intake for Drinkers in Same-Gender Pairing arrangements significantly elevated relative to ethanol intake of Drinkers in Other-Gender Pairing arrangements (F[1189] ¼ 5.69, p < 0.02). Thus, the ethanol-drinking Cagemate significantly elevated ethanol intake of Drinkers in Other-Gender Pairings, but the sober Cagemate induced more elevated ethanol intake of Drinkers in Same-Gender Pairings.

significantly suppress ethanol intake of Male Drinkers relative to the effect of the isolation housing (F[1,62] ¼ 14.73, p < 0.01). This pattern of results was not observed when the Cagemate side did not contain an ethanol tube. Planned comparisons revealed that ethanol intake for Male Drinkers with No Cagemate did not differ significantly from ethanol intake of Male Drinkers paired with a Male Cagemate or paired with a Female Cagemate (both p’s > 0.10). Female Drinkers The 3
2 ANOVA for the 6 groups composed of a Female Drinker (see Fig. 1, right panel) revealed no significant main effects or interaction effects (all p’s > 0.10). Planned comparisons revealed that in the No Cagemate Ethanol condition, Female Cagemates stimulated more ethanol intake than did Male Cagemates (F[1,94] ¼ 4.91, p < 0.05). Planned comparisons revealed that mean ethanol intakes of Female Drinkers with No Cagemate did not differ significantly from mean ethanol intakes of Female Drinkers paired with a Female Cagemate or paired with a Male Cagemate, and this was the case regardless of the presence of an ethanol tube on the Cagemate side (all p’s > 0.10).

Male Drinkers Water intake (g/kg) The 3
2 ANOVA for the 6 groups composed of a Male Drinker (see Fig. 1, left panel) revealed a significant main effect of Cagemate Gender (F[2213] ¼ 5.69, p < 0.01), no significant main effect of Cagemate Ethanol (F[1213] ¼ 2.12, p > 0.10), and a significant interaction between Cagemate Gender and Cagemate Ethanol (F[2213] ¼ 11.00, p < 0.01). Analysis revealed that for the Female Cagemate the elevating effect of Cagemate Ethanol was significant (F[1,89] ¼ 17.50, p < 0.01), but the effect of providing the Male Cagemate with access to ethanol was to suppress ethanol intake of the Male Drinker (F[1,94] ¼ 3.98, p < 0.05). When provided with access to ethanol, the Female Cagemate significantly elevated ethanol intake of Male Drinkers relative to the effect of the Male Cagemate (F[1,90] ¼ 24.07, p < 0.01), and relative to the effect of No Cagemate (F[1,62] ¼ 6.49, p < 0.05). The effect of providing the Male Cagemate with access to ethanol, on the other hand, was to

Analysis of water intake revealed results complementary to ethanol intake (see Fig. 2). Groups that drank more water were those that drank less ethanol, indicating that the effects on ethanol intake of Gender Pairing and Cagemate Ethanol were not attributable to non-specific factors, such as general arousal or adjunctive polydipsia. The 3-way 3
2
2 ANOVA revealed a significant 3-way interaction (F[2431] ¼ 16.16, p < 0.01), but the pattern was the opposite of that for ethanol intake. For example, 2-way 2
2 ANOVA with 2 levels of Gender Pairing and 2 levels of Cagemate Ethanol revealed a highly significant interaction (F[1375] ¼ 29.69, p < 0.01), revealing that the ethanol-drinking Cagemate induced elevated water intake in Drinkers in Same-Gender Pairing arrangements relative to Drinkers in Other-Gender Pairing arrangements (F[1186] ¼ 11.09, p < 0.01), but, in contrast, the sober

Fig. 1. Mean grams of ethanol consumed per kilogram of body weight for Male Drinkers (left panel) and for Female Drinkers (right panel) as a function of Cagemate (None vs. Male Cagemate vs. Female Cagemate) and Cagemate Ethanol (No Ethanol vs. Ethanol). The vertical bars represent the standard error of the mean. The single asterisk (*) indicates that the groups differ (p < 0.05). The double asterisk (**) indicates that the groups differ (p < 0.01).

A. Tomie et al. / Alcohol 48 (2014) 73e82

77

Fig. 2. Mean grams of water consumed per kilogram of body weight for Male Drinkers (left panel) and for Female Drinkers (right panel) as a function of Cagemate (None vs. Male Cagemate vs. Female Cagemate) and Cagemate Ethanol (No Ethanol vs. Ethanol). The vertical bars represent the standard error of the mean. The single asterisk (*) indicates that the groups differ (p < 0.05). The double asterisk (**) indicates that the groups differ (p < 0.01).

Cagemate induced elevated water intake in Drinkers in SameGender Pairing arrangements relative to Drinkers in Other-Gender Pairing arrangements, (F[1189] ¼ 19.46, p < 0.01). Thus, the effect of Gender Pairing depended upon the Cagemate Ethanol procedure.

differ from water intake of Female Drinkers paired with a Female Cagemate or paired with a Male Cagemate (both p’s > 0.10).

Male Drinkers

Ethanol preference results (see Fig. 3) closely approximated ethanol intake results, indicating that those factors that stimulated ethanol intake also tended to elevate the relative preference for drinking ethanol over drinking water. The 3-way 3
2
2 ANOVA revealed a significant 3-way interaction (F[2431] ¼ 12.71, p < 0.01). The interaction between Gender Pairing and Cagemate Ethanol was significant (F[1375] ¼ 21.78, p < 0.01). The ethanol-drinking Cagemate elevated ethanol preference of the Drinker in Other-Gender Pairing arrangements relative to the Drinker in Same-Gender Pairing arrangements (F[1186] ¼ 13.05, p < 0.01). In contrast, the sober Cagemate elevated ethanol preference of the Drinker in Same-Gender Pairing arrangements relative to the Drinker in Other-Gender Pairing arrangements (F[1189] ¼ 9.00, p < 0.01). Thus, the effect of Gender Pairing depended upon the Cagemate Ethanol procedure.

The 3
2 ANOVA for the 6 groups composed of a Male Drinker (see Fig. 2, left panel) revealed no significant main effect of Cagemate Gender (p > 0.10), a significant main effect of Cagemate Ethanol (F[1213] ¼ 4.92, p < 0.05), and a significant interaction between Cagemate Gender and Cagemate Ethanol (F[2213] ¼ 13.04, p < 0.01). Analysis revealed no effect of Cagemate Ethanol when paired with a Female Cagemate (p > 0.20), but there was a significant elevating effect of Cagemate Ethanol when paired with a Male Cagemate (F[1,94] ¼ 37.52, p < 0.01). The elevating effect of providing the Male Cagemate with access to ethanol was also significant relative to pairing with a Female Cagemate (F[1,90] ¼ 18.36, p < 0.01), and relative to the effect of No Cagemate (F[1,62] ¼ 11.86, p < 0.01). The sober Female Cagemate induced significantly elevated water intake in Male Drinkers relative to the effect of the sober Male Cagemate (F[1,93] ¼ 6.36, p < 0.02). Female Drinkers The 3
2 ANOVA for the 6 groups composed of Female Drinkers (see Fig. 2, right panel) revealed a significant main effect of Cagemate Gender (F[2218] ¼ 3.70, p < 0.05), no significant main effect of Cagemate Ethanol (F < 1), and a significant interaction between Cagemate Gender and Cagemate Ethanol (F[2218] ¼ 5.74, p < 0.01). Analysis revealed that the sober Female Cagemate suppressed water intake relative to the ethanol-drinking Female Cagemate (F[1,94] ¼ 6.26, p < 0.02), relative to the sober Male Cagemate (F[1,94] ¼ 13.93, p < 0.01), and relative to the effect of No Cagemate (F[1,62] ¼ 7.55, p < 0.01). These trends were opposite to those observed in ethanol intake. With Ethanol on the Cagemate Side, water intake of isolation-housed Female Drinkers did not

Ethanol preference (%)

Male Drinkers The 3
2 ANOVA for the 6 groups composed of a Male Drinker (see Fig. 3, left panel) revealed a significant main effect of Cagemate Gender (F[2213] ¼ 3.34, p < 0.05), no significant main effect of Cagemate Ethanol (F < 1), and a significant interaction between Cagemate Gender and Cagemate Ethanol (F[2213] ¼ 11.15, p < 0.01). Analysis revealed that the ethanol-drinking Female Cagemate induced elevated ethanol preference relative to the sober Female Cagemate (F[1,89] ¼ 12.90, p < 0.01), but the ethanoldrinking Male Cagemate, relative to the sober Male Cagemate, suppressed ethanol preference of the Male Drinker (F[1,94] ¼ 7.43, p < 0.01). The ethanol-drinking Female Cagemate significantly elevated ethanol preference of Male Drinkers relative to the effect of the ethanol-drinking Male Cagemate (F[1,90] ¼ 21.86, p < 0.01), and relative to the effect of No Cagemate (F[1,62] ¼ 5.98, p < 0.05).

78

A. Tomie et al. / Alcohol 48 (2014) 73e82

Fig. 3. Mean percent ethanol preference for Male Drinkers (left panel) and for Female Drinkers (right panel) as a function of Cagemate (None vs. Male Cagemate vs. Female Cagemate) and Cagemate Ethanol (No Ethanol vs. Ethanol). The vertical bars represent the standard error of the mean. The double asterisk (**) indicates that the groups differ (p < 0.01).

The ethanol-drinking Male Cagemate, on the other hand, significantly suppressed ethanol preference of Male Drinkers relative to the effect of isolation housing (F[1,62] ¼ 12.12, p < 0.01). This pattern of results was not observed when the Cagemate side did not contain an ethanol tube. Ethanol preference for Male Drinkers with No Cagemate did not differ significantly from ethanol preference of Male Drinkers paired with a Male Cagemate or paired with a Female Cagemate (both p’s > 0.10). Female Drinkers The 3
2 ANOVA for the 6 groups composed of a Female Drinker (see Fig. 3, right panel) revealed no significant main effect of Cagemate Gender (p > 0.05), no significant main effect of Cagemate Ethanol (p > 0.70), and a significant interaction between Cagemate Gender and Cagemate Ethanol (F[2218] ¼ 3.14, p < 0.05). Analysis revealed that the sober Female Cagemate was significantly more effective in inducing elevated ethanol preference in the Female Drinker than was the sober Male Cagemate (F[1,94] ¼ 7.04, p < 0.01). Planned comparisons revealed that ethanol preference of Female Drinkers with No Cagemate did not differ significantly from ethanol preferences of Female Drinkers paired with a Female Cagemate or paired with a Male Cagemate, and this was the case regardless of the presence of an ethanol tube on the Cagemate side (all p’s > 0.10). Discussion The present study employed Proximal Cagemate Drinking (PCD) procedures to assess intergender effects on ethanol intake in mice. The results revealed that the ethanol intake of the Drinker was significantly influenced by the gender of the Cagemate, and that this Gender-Pairing effect depended on the presence, on the Cagemate side, of an ethanol drinking tube. The Drinker in SameGender Pairings showed significantly elevated ethanol intake relative to the Drinker in Other-Gender Pairings, but these effects were only observed when the Cagemate did not have access to

ethanol. Providing ethanol to the Cagemate completely reversed the effects of Gender Pairing, such that the Same-Gender Pairing arrangement significantly reduced the ethanol intake of the Drinker relative to the Drinker in Other-Gender Pairing arrangements. The effect in Other-Gender Pairings when the Cagemate was provided with access to ethanol was primarily due to the Male Drinker, whose ethanol intake was significantly elevated when paired with a Female Cagemate relative to when paired with a Male Cagemate. On the other hand, the effect in Same-Gender Pairings when the Cagemate did not have access to ethanol was primarily due to the Female Drinker, whose ethanol intake was significantly elevated when paired with a Female Cagemate relative to pairing with a Male Cagemate. These PCD procedures allow for the evaluation in mice of the effects of Gender Pairing and the effects of Cagemate Ethanol on ethanol intake of the Drinker, and the interaction between these factors are reported here for the first time. The effects of Gender Pairing and Cagemate Ethanol on ethanol intake cannot be attributed to nonspecific factors such as arousalinduced drinking (Badiani, Jakob, Rodaros, & Stewart, 1996; Smith, Gannon, & Tierney, 1984) or adjunctive polydipsia (Falk, 1969, 1971; Porter & Bryant, 1978), because analysis of water intake revealed results complementary to ethanol intake. That is, groups that provided higher levels of ethanol intake tended to provide lower levels of water intake. The complementary relationship between ethanol intake and water intake, moreover, contributed to the substantial congruence between the patterns of ethanol intake and percent ethanol preference. These data add to the literature indicating an effect of the gender of the social stimulus on ethanol intake of the experimental subject. The initial report of an intergender effect on ethanol drinking employed procedures that did not provide the social stimulus with access to ethanol (Tomie et al., 2006). In that study, the experimental subject, a male rat, consumed more ethanol when provided with social stimulation by a female rat as compared to trials when provided with social stimulation by a male rat, but this outcome was not observed in the present study. The discrepant results may be due to differences in the manner in which the studies were

A. Tomie et al. / Alcohol 48 (2014) 73e82

conducted, including the species of the experimental subjects (rats vs. mice), the duration of the ethanol drinking session (1 h vs. 23 h), the duration of social interaction opportunity (15 s vs. 23 h), the drinking environment (home cage vs. test chamber), or the drinking procedure (2-bottle vs. 1-bottle). While the study by Tomie et al. reported an intergender effect on ethanol drinking in rats, their study did not assess ethanol drinking in female rats or the effects of ethanol drinking by the social stimulus rat; therefore, in rats, the interaction between these factors remains unclear. Studies of ethanol drinking in prairie voles provide evidence suggestive of an intergender effect (Hostetler et al., 2012). These investigators found that Same-Gender Pairings induced elevated ethanol drinking relative to isolation controls, but, in a separate study employing Other-Gender Pairings, this effect was not observed (Hostetler et al., 2012). Their data suggest that there is less of a stimulating effect on ethanol drinking (i.e., less of a modeling or peer pressure effect) in Other-Gender Pairings. It should be noted that this difference was not observed in the present study, where the Other-Gender Cagemate provided with ethanol was more effective in stimulating ethanol intake than was the Same-Gender Cagemate, and this was especially true for the Male Drinker. These studies employing prairie voles did not assess the effects of not providing the Cagemate with access to ethanol; therefore, the effects of Cagemate Ethanol and the interaction between Gender Pairing and Cagemate Ethanol were not evaluated. They did, on the other hand, record the ethanol drinking of the Cagemate, and found in Same-Gender Pairings a positive correlation between the ethanol drinking of the Cagemate and the ethanol drinking of the Drinker (Anacker, Loftis, Kaur, et al., 2011; Anacker, Loftis, & Ryabinin, 2011; Hostetler et al., 2012), but this positive correlation effect was not observed in Other-Gender Pairing arrangements (Hostetler et al., 2012). Other studies have also reported coordination of ethanol drinking between members of a Same-Gender pair while utilizing a more complex multi-stage experimental design wherein they evaluated large numbers of prairie voles for baseline ethanol drinking, and then paired the high drinkers with either high or low drinkers. They found decreased ethanol drinking in the latter condition (Anacker, Loftis, & Ryabinin, 2011; Hostetler et al., 2012), but this effect was not observed in Other-Gender Pairing arrangements (Hostetler et al., 2012). Their data provide evidence of a modeling or peer pressure effect in Same-Gender pairs of prairie voles, but ethanol drinking appears to be much less coordinated in OtherGender Pairs (Hostetler et al., 2012). A modeling-like effect has also been reported in rats (Hallmark & Hunt, 2004; Hunt & Hallmark, 2001; Hunt et al., 2001; Hunt et al., 2000). In their studies, the Same-Gender social stimulus or “demonstrator” rats did not have the opportunity to drink ethanol, but rather, were administered a pre-session injection of ethanol. The presumably intoxicated “demonstrator” rats induced elevated ethanol drinking in experimental “observer” rats following a brief interaction with an intoxicated sibling, relative to following interaction with a non-intoxicated sibling (Hallmark & Hunt, 2004; Hunt & Hallmark, 2001; Hunt et al., 2001; Hunt et al., 2000). Their data indicate that the effects of modeling are not due to observing ethanol drinking per se but rather are due to ethanol’s pharmacological effect on the social stimulus. Nevertheless, this type of an effect of ethanol on the social stimulus was not observed in the present study, where Cagemate Ethanol in the Same-Gender Pairing arrangement reduced ethanol intake of the Drinker, and particularly in the Male Drinker. The discrepant results may be due to differences in species (rats vs. mice) or route of ethanol administration to the social stimulus (injection vs. drinking) or the timing of the assessment of ethanol drinking in the experimental subject (following brief social interaction vs. during 23-h social interaction). It should be noted that the studies by Hunt and her associates

79

did not evaluate effects of the intoxicated demonstrator when the observer was a sibling of the Other-Gender subject; consequently, their studies do not address the interaction between Gender Pairing and Cagemate Ethanol. The results of the present study reveal that this interaction effect is significant, with modeling observed in Other-Gender Pairings, but not in Same-Gender Pairings, where the ethanol drinking of the Cagemate reduced ethanol intake of the Drinker. Studies of modeling in humans reveal that in a bar-like setting a confederate drinking an alcoholic beverage, as compared to drinking a non-alcoholic beverage, induced elevated ethanol drinking in experimental subjects (Caudill & Kong, 2001; Caudill & Marlatt, 1975; Collins et al., 1985; Larsen, Engels, et al., 2010; Larsen, Overbeek, et al., 2010; Larsen, Overbeek, et al., 2012). On the other hand, it should be noted that modeling was not observed in Males when paired with a Female confederate or in Females when paired with a Male confederate (Larsen, Overbeek, et al., 2010; Larsen, Overbeek, et al., 2012), indicating that modeling effects are less robust in Other-Gender Pairing as compared to SameGender Pairing arrangements. The finding of modeling in humans, but only in Same-Gender Pairings, resembles the pattern of results reported in studies of prairie voles by Ryabinin and her associates (Anacker, Loftis, Kaur, et al., 2011; Anacker, Loftis, & Ryabinin, 2011; Hostetler et al., 2012). The present study, however, found the opposite pattern of results, with stronger evidence of modeling in mice observed in Other-Gender Pairing arrangements. The results of the present experiment provide the first report of modeling in mice, and this, in turn, leads to the expectation that coordination of drinking within a pair may also be observed. The present study did not include data on ethanol drinking by the Cagemate; therefore, the coordination of ethanol drinking within pairs was not evaluated. The results of the present experiment did reveal that the ethanol-drinking Cagemate did induce elevated ethanol intake in the Drinker, and this is consistent with the modeling hypothesis, but this effect was only observed when a Male Drinker was paired with a Female Cagemate. Nevertheless, the elevating effect of Cagemate Ethanol on ethanol intake of the Drinker provides the basis for the expectation that under some conditions, coordination of ethanol intake will be observed in mice. In previous studies, it was those groups providing elevated group mean ethanol intakes that exhibited coordinated ethanol drinking. Our data, therefore, suggest that the ethanol intake of the Female Cagemate, but not the Male Cagemate, may stimulate elevated ethanol intake in the paired Male Drinker, but this coordination effect may not be observed in the Female Drinker, regardless of the gender of the Cagemate. To evaluate coordination effects in mice in future studies employing PCD procedures, the ethanol intake of the Cagemate will be recorded and regressed to the ethanol intake of the Drinker, to assess the coordination in ethanol drinking within the pair. The present study provides the first systematic investigation of Gender-Pairing effects on ethanol intake as a function of allowing the Cagemate access to an ethanol tube. Though the amount of ethanol fluid consumed by a Cagemate each day was not recorded, there was consistent evidence of displacement of fluid from the ethanol tubes provided to the Cagemates, indicating that the Cagemates were drinking from the ethanol tube. The data reveal that the effect of a Cagemate, who presumably had consumed ethanol, was not the same as the effect of a Cagemate who had not, and the effect of the ethanol drinking of the Cagemate was more pronounced in Male Drinkers. The data reveal that the ethanoldrinking Male Cagemate significantly reduced ethanol intake of the Male Drinker, relative to the effect of the sober Male Cagemate, but the effect of the ethanol-drinking Female Cagemate was to significantly increase ethanol intake of the Male Drinker, relative to

80

A. Tomie et al. / Alcohol 48 (2014) 73e82

the effect of the sober Female Cagemate. While a similar pattern was observed with Female Drinkers, these effects were less robust and did not achieve statistical significance. Thus, overall, the Male Drinker, compared to the Female Drinker, was more influenced by the gender of the Cagemate and by the ethanol drinking of the Cagemate. The present results reveal that the ethanol drinking of the Cagemate was particularly effective in stimulating ethanol drinking in the Drinker of the Other Gender. The basis of this effect may be due to the exaggeration of ethanol’s rewarding effects due to the pairing of ethanol with the positive emotional states induced in the Drinker by the Other-Gender Cagemate. For example, there is evidence that the proximal presence of the Other-Gender Cagemate may be more rewarding or more positively reinforcing than the proximal presence of the Same-Gender Cagemate. Male rats (Dahlgren, Matuszczyk, & Hård, 1991; Kruijver et al., 1993; Vega Matuszczyk & Larsson, 1993) and male mice (Watabe & Endo, 1994) preferentially chose female partners over male partners, while female rats (Brand & Slob, 1991; de Jonge, Muntjewerff, Louwerse, & van de Poll, 1988; de Jonge & van de Poll, 1986) preferentially chose male partners over female partners. This preference for choosing Other-Gender Pairing partners may be exaggerated by the pairing of the exteroceptive stimulus properties of ethanol (i.e., odor, taste) with the Other-Gender Cagemate. That is, while interacting with the ethanol-drinking Cagemate, the Drinker may detect the presence of ethanol, which may lead to the development of an association between ethanol and the OtherGender Cagemate. Under these conditions, the more highly rewarding Other-Gender Cagemate would condition secondary rewarding effects to ethanol (Mackintosh, 1974; Rashotte, 1981; Robinson & Flagel, 2009) and more so than the less rewarding Same-Gender Cagemate. The secondary rewarding effects accrued to ethanol may, in turn, result in more drinking of the more positively rewarding ethanol by the Drinkers in the Other-Gender Pairing arrangements. Alternative interpretations of the differential effects of the ethanol-drinking Cagemate in Gender-Pairing arrangements warrant consideration. It is possible, for example, that behaviors induced by the pharmacological effects of ethanol in the Female Cagemate, relative to those induced in the Male Cagemate, are more effective in stimulating corticosterone release in the Male Drinker (Retana-Márquez et al., 2003; Taylor, Weiss, & Rupich, 1987). There is evidence that the release of corticosterone will stimulate ethanol intake (Blanchard, Steindorf, Wang, & Glick, 1993; Hansen, Fahlke, Söderpalm, & Hård, 1995; Hatton & Vieth, 1974; Núñez et al., 2002; Opsahl & Hatton, 1972; Prasad & Prasad, 1995). The stimulation of testosterone release may also play a role. It is also possible that the Female Cagemate provided with ethanol, relative to the Male Cagemate provided with ethanol, will more effectively induce the Male Drinker to release testosterone (Amstislavskaya & Popova, 2004; Kavaliers, Choleris, & Colwell, 2001; Macrides, Bartke, & Dalterio, 1975), and this effect may induce elevated sexual arousal which contributes to the reward value of drinking ethanol (Abrahamson, 2004; Friedman, McCarthy, Förster, & Denzler, 2005; Wilson, 1981). It should be noted that an intergender study reported elevated ethanol intake, elevated corticosterone, and elevated testosterone in male rats, as a result of social interaction opportunity with a female rat, relative to social interaction opportunity with a male rat (Tomie et al., 2006). Further experimentation with PCD procedures that include measures of levels of corticosterone and testosterone are needed to clarify the underlying neuroendocrine correlates associated with the elevated ethanol intake observed in the Male Drinker paired with a Female Cagemate. A number of investigators have reported that, in rats and mice, isolation-housed females provide elevated ethanol intake relative

to isolation-housed males (Almeida et al., 1998; Juárez & Barrios de Tomasi, 1999; Lancaster & Spiegel, 1992; Piano, Carrigan, & Schwertz, 2005; Tambour, Brown, & Crabbe, 2008; VetterO’Hagen, Varlinskaya, & Spear, 2009). In addition, there is evidence that isolation-housed female rats maintain elevated ethanol preference relative to isolation-housed male rats (Almeida et al., 1998). In the present study, there was no evidence of a difference in either ethanol intake or ethanol preference between groups of isolation-housed males or females, and this is consistent with several reports that in rats and mice, ethanol intakes and ethanol preferences in males and females did not differ (He, Overstreet, & Crews, 2009; Wiren et al., 2006). In rodents, isolation housing induces more ethanol intake than does social housing (Advani et al., 2007; Ehlers, Walker, Pian, Roth, & Slawecki, 2007; Hall et al., 1998; McCool & Chappell, 2009; Wolffgramm & Heyne, 1991; Yanai & Ginsburg, 1976; Hostetler et al., 2012). In PCD procedures, the condition of group housing is most closely approximated by the Same-Gender Pairing arrangement with ethanol available to the Cagemate. The results of the present study are consistent with the literature in that isolationhoused Male Drinkers showed significantly elevated ethanol intake and significantly elevated ethanol intake and significantly elevated ethanol preference relative to Male Drinkers housed with a Male Cagemate who was provided with access to ethanol. On the other hand, these PCD procedures reveal that there are conditions under which social housing facilitated rather than reduced ethanol drinking in Males. The Male Drinker housed in proximity to the ethanol-drinking Female Cagemate drank significantly more ethanol than the isolation-housed Male. Finally, it should be noted that Female Drinkers housed in isolation did not differ in ethanol intake or in ethanol preference relative to Female Drinkers housed with a Cagemate, and this was the case regardless of the Gender of the Cagemate and regardless of whether ethanol was available to the Cagemate. The use of CD-1 mice in the present study warrants discussion. The CD-1 strain is outbred and exhibits a high degree of genetic diversity relative to the inbred strains of mice and rats that are widely employed in studies of ethanol drinking. The outbred CD-1 mice, therefore, more closely approximate the degree of genetic diversity of humans, and this broader range of genetic diversity might be valuable for examining the genetic determinants of individual variation in alcohol drinking. The large number of subjects in each of our groups of CD-1 mice and the range of individual differences in ethanol drinking within these groups provide conditions conducive to the evaluation of the relationships between individual differences in gene expression profiling and individual differences in ethanol drinking. It should also be noted that CD-1 mice are known for behavioral traits associated with vulnerability to relapse into alcohol abuse. For example, CD-1 mice are notably aggressive (Nevison, Barnard, & Hurst, 2003; Van Loo et al., 2003), which, in humans, is a trait that confers vulnerability to alcohol abuse (Molina, Donovan, & Belendiuk, 2010) and the tendency for males to relapse into alcoholism (Baars, Müller, Gallhofer, & Netter, 2013). Moreover, CD-1 mice are risk-takers (Michalikova, van Rensburg, Chazot, & Ennaceur, 2010), which is also a trait that confers vulnerability to relapse into alcohol abuse in humans (Bowden-Jones, McPhillips, & Joyce, 2006; Bowden-Jones, McPhillips, Rogers, Hutton, & Joyce, 2005; Zuckerman, 1984). The PCD procedures employed in the present study reveal that the ethanol drinking of the Cagemate mouse may influence the ethanol intake of the Drinker mouse, and this outcome is consistent with the modeling or peer pressure hypothesis. On the other hand, studies of modeling in humans are conducted away from the home environment, typically in bar-like settings. These data suggest that modeling effects may also be observed in the home environment

A. Tomie et al. / Alcohol 48 (2014) 73e82

and that the effect of peer pressure in the home environment will be to induce elevated ethanol drinking, and particularly when the Male is in the presence of the ethanol-drinking Female. Acknowledgments The authors thank Nikyta Sharma, Veronica Tomie, Allison Samuel, and Sunpreet Singh for their technical assistance. This research was supported by NIH grants DA013471 and DA020555 and by funds from Center of Alcohol Studies, Rutgers University. References Abrahamson, M. (2004). Alcohol in courtship contexts: focus-group interviews with young Swedish women and men. Contemporary Drug Problems, 31, 3. Abrams, D. B., & Niarura, R. S. (1987). Social learning theory. In K. E. Leonard, & H. T. Blane (Eds.), Psychological theories of drinking and alcoholism (pp. 131e178). New York: Guilford Press. Advani, T., Hensler, J. G., & Koek, W. (2007). Effect of early rearing conditions on alcohol drinking and 5-HT1A receptor function in C57BL/6J mice. The International Journal of Neuropsychopharmacology, 10, 595e607. Almeida, O. F., Shoaib, M., Deicke, J., Fischer, D., Darwish, M. H., & Patchev, V. K. (1998). Gender differences in ethanol preference and ingestion in rats. The role of the gonadal steroid environment. The Journal of Clinical Investigation, 101, 2677e2685. Amstislavskaya, T. G., & Popova, N. K. (2004). Female-induced sexual arousal in male mice and rats: behavioral and testosterone response. Hormones and Behavior, 46, 544e550. Anacker, A. M., Loftis, J. M., Kaur, S., & Ryabinin, A. E. (2011). Prairie voles as a novel model of socially facilitated excessive drinking. Addiction Biology, 16, 92e107. Anacker, A. M., Loftis, J. M., & Ryabinin, A. E. (2011). Alcohol intake in prairie voles is influenced by the drinking level of a peer. Alcoholism: Clinical and Experimental Research, 35, 1884e1890. Anacker, A. M., & Ryabinin, A. E. (2010). Biological contribution to social influences on alcohol drinking: evidence from animal models. International Journal of Environmental Research and Public Health, 7, 473e493. Baars, M. Y., Müller, M. J., Gallhofer, B., & Netter, P. (2013). Relapse (number of detoxifications) in abstinent male alcohol-dependent patients as related to personality traits and types of tolerance to frustration. Neuropsychobiology, 67, 241e248. Badiani, A., Jakob, A., Rodaros, D., & Stewart, J. (1996). Sensitization of stress-induced feeding in rats repeatedly exposed to brief restraint: the role of corticosterone. Brain Research, 710, 35e44. Blanchard, B., Steindorf, S., Wang, S., & Glick, S. D. (1993). Sex differences in ethanolinduced dopamine release in nucleus accumbens and in ethanol consumption in rats. Alcoholism: Clinical and Experimental Research, 17, 968e973. Bowden-Jones, H., McPhillips, M., & Joyce, E. M. (2006). Neurobehavioural characteristics and relapse in addiction. The British Journal of Psychiatry, 188, 494. Bowden-Jones, H., McPhillips, M., Rogers, R., Hutton, S., & Joyce, E. (2005). Risktaking on tests sensitive to ventromedial prefrontal cortex dysfunction predicts early relapse in alcohol dependency: a pilot study. The Journal of Neuropsychiatry and Clinical Neurosciences, 17, 417e420. Brand, T., & Slob, A. K. (1991). On the organization of partner preference behavior in female Wistar rats. Physiology & Behavior, 49, 549e555. Caldwell, E. E., & Riccio, D. C. (2010). Alcohol self-administration in rats: modulation by temporal parameters related to repeated mild social defeat stress. Alcohol, 44, 265e274. Caudill, B. D., & Kong, F. H. (2001). Social approval and facilitation in predicting modeling effects in alcohol consumption. Journal of Substance Abuse, 13, 425e441. Caudill, B. D., & Lipscomb, T. R. (1980). Modeling influences on alcoholics’ rates of alcohol consumption. Journal of Applied Behavior Analysis, 13, 355e365. Caudill, B. D., & Marlatt, G. A. (1975). Modeling influences in social drinking: an experimental analogue. Journal of Consulting and Clinical Psychology, 43, 405e415. Collins, R. L., Parks, G. A., & Marlatt, G. A. (1985). Social determinants of alcohol consumption: the effects of social interaction and model status on the selfadministration of alcohol. Journal of Consulting and Clinical Psychology, 53, 189e200. Croft, A. P., Brooks, S. P., Cole, J., & Little, H. J. (2005). Social defeat increases alcohol preference of C57BL/10 strain mice; effect prevented by a CCKB antagonist. Psychopharmacology (Berl), 183, 163e170. Dahlgren, I. L., Matuszczyk, J. V., & Hård, E. (1991). Sexual orientation in male rats prenatally exposed to ethanol. Neurotoxicology and Teratology, 13, 267e269. de Almeida, R. M., Rowlett, J. K., Cook, J. M., Yin, W., & Miczek, K. A. (2004). GABAA/ alpha1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice. Psychopharmacology (Berl), 172, 255e263. de Jonge, F. H., Muntjewerff, J.-W., Louwerse, A. L., & van de Poll, N. E. (1988). Sexual behavior and sexual orientation of the female rat after hormonal treatment during various stages of development. Hormones and Behavior, 22, 100e115.

81

de Jonge, F. H., & van de Poll, N. E. (1986). On the involvement of progesterone in sexually rewarded choice behavior of the female rat. Physiology & Behavior, 37, 93e98. Ehlers, C. L., Walker, B. M., Pian, J. P., Roth, J. L., & Slawecki, C. J. (2007). Increased alcohol drinking in isolate-housed alcohol-preferring rats. Behavioral Neuroscience, 121, 111e119. Falk, J. L. (1969). Conditions producing psychogenic polydipsia in animals. Annals of the New York Academy of Sciences, 157, 569e593. Falk, J. L. (1971). The nature and determinants of adjunctive behavior. Physiology & Behavior, 6, 577e588. Firman, R. C., & Simmons, L. W. (2008). The frequency of multiple paternity predicts variation in testes size among island populations of house mice. Journal of Evolutionary Biology, 21, 1524e1533. Friedman, R. S., McCarthy, D. M., Förster, J., & Denzler, M. (2005). Automatic effects of alcohol cues on sexual attraction. Addiction, 100, 672e681. Funk, D., Harding, S., Juzytsch, W., & Lê, A. D. (2005). Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology (Berl), 183, 341e349. Hall, F. S., Huang, S., Fong, G. W., Pert, A., & Linnoila, M. (1998). Effects of isolationrearing on voluntary consumption of ethanol, sucrose and saccharin solutions in Fawn Hooded and Wistar rats. Psychopharmacology (Berl), 139, 210e216. Hallmark, R. A., & Hunt, P. S. (2004). Social learning about ethanol in preweanling rats: role of endogenous opioids. Developmental Psychobiology, 44, 132e139. Hansen, S., Fahlke, C., Söderpalm, A., & Hård, E. (1995). Significance of adrenal corticosteroid secretion for the food restriction-induced enhancement of alcohol drinking in the rat. Psychopharmacology (Berl), 121, 213e221. Hatton, G., & Vieth, A. (1974). Stress-related and diurnal alcohol drinking in rats. Bulletin of the Psychonomic Society, 4, 195e196. He, J., Overstreet, D. H., & Crews, F. T. (2009). Abstinence from moderate alcohol selfadministration alters progenitor cell proliferation and differentiation in multiple brain regions of male and female P rats. Alcoholism: Clinical and Experimental Research, 33, 129e138. Hostetler, C. M., Anacker, A. M., Loftis, J. M., & Ryabinin, A. E. (2012). Social housing and alcohol drinking in male-female pairs of prairie voles (Microtus ochrogaster). Psychopharmacology (Berl), 224, 121e132. Hunt, P. S., & Hallmark, R. A. (2001). Increases in ethanol ingestion by young rats following interaction with intoxicated siblings: a review. Integrative Physiological and Behavioral Science, 36, 239e248. Hunt, P. S., Holloway, J. L., & Scordalakes, E. M. (2001). Social interaction with an intoxicated sibling can result in increased intake of ethanol by periadolescent rats. Developmental Psychobiology, 38, 101e109. Hunt, P. S., Lant, G. M., & Carroll, C. A. (2000). Enhanced intake of ethanol in preweanling rats following interactions with intoxicated siblings. Developmental Psychobiology, 37, 90e99. Institute of Laboratory Animal Resources Commission on Life Sciences. (1996). Guide for the care of use of laboratory animals. National Research Council (National Academy Press). Juárez, J., & Barrios de Tomasi, E. (1999). Sex differences in alcohol drinking patterns during forced and voluntary consumption in rats. Alcohol, 19, 15e22. Kavaliers, M., Choleris, E., & Colwell, D. D. (2001). Brief exposure to female odors “emboldens” male mice by reducing predator-induced behavioral and hormonal responses. Hormones and Behavior, 40, 497e509. Kruijver, F., de Jonge, F. H., van den Broek, W. T., van der Woude, T., Endert, E., & Swaab, D. F. (1993). Lesions of the suprachiasmatic nucleus do not disturb sexual orientation of the adult male rat. Brain Research, 624, 342e346. Lancaster, F. E., & Spiegel, K. S. (1992). Sex differences in pattern of drinking. Alcohol, 9, 415e420. Larsen, H., Engels, R. C., Granic, I., & Overbeek, G. (2009). An experimental study on imitation of alcohol consumption in same-sex dyads. Alcohol and Alcoholism, 44, 250e255. Larsen, H., Engels, R. C., Souren, P. M., Granic, I., & Overbeek, G. (2010). Peer influence in a micro-perspective: imitation of alcoholic and non-alcoholic beverages. Addictive Behaviors, 35, 49e52. Larsen, H., Engels, R. C., Wiers, R. W., Granic, I., & Spijkerman, R. (2012). Implicit and explicit alcohol cognitions and observed alcohol consumption: three studies in (semi)naturalistic drinking settings. Addiction, 107, 1420e1428. Larsen, H., Overbeek, G., Granic, I., & Engels, R. C. (2010). Imitation of alcohol consumption in same-sex and other-sex dyads. Alcohol and Alcoholism, 45, 557e562. Larsen, H., Overbeek, G., Granic, I., & Engels, R. C. (2012). The strong effect of other people’s drinking: two experimental observational studies in a real bar. The American Journal on Addictions, 21, 168e175. Mackintosh, N. J. (1974). The psychology of animal learning. Oxford, England: Academic Press London. Macrides, F., Bartke, A., & Dalterio, S. (1975). Strange females increase plasma testosterone levels in male mice. Science, 189, 1104e1106. Maisto, S. A., Carey, K. B., & Bradizza, C. M. (1999). Social learning theory. In K. E. Leonard, & H. T. Blane (Eds.), Psychological theories of drinking and alcoholism (pp. 106e157). New York: Guilford Press. Maldonado, A. M., Finkbeiner, L. M., & Kirstein, C. L. (2008). Social interaction and partner familiarity differentially alter voluntary ethanol intake in adolescent male and female rats. Alcohol, 42, 641e648. McCool, B. A., & Chappell, A. M. (2009). Early social isolation in male Long-Evans rats alters both appetitive and consummatory behaviors expressed during operant ethanol self-administration. Alcoholism: Clinical and Experimental Research, 33, 273e282.

82

A. Tomie et al. / Alcohol 48 (2014) 73e82

Michalikova, S., van Rensburg, R., Chazot, P., & Ennaceur, A. (2010). Anxiety responses in Balb/c, c57 and CD-1 mice exposed to a novel open space test. Behavioural Brain Research, 207, 402e417. Molina, B. S., Donovan, J. E., & Belendiuk, K. A. (2010). Familial loading for alcoholism and offspring behavior: mediating and moderating influences. Alcoholism: Clinical and Experimental Research, 34, 1972e1984. Nevison, C. M., Barnard, C. J., & Hurst, J. L. (2003). The consequence of inbreeding for modulating social relationships between competitors. Applied Animal Behaviour Science, 81, 387e398. Núñez, M. J., Rivas, M., Riveiro, P., Suárez, J., Balboa, J., Núñez, L. A., et al. (2002). Effects of nefazodone on voluntary ethanol consumption induced by isolation stress in young and aged rats. Pharmacology, Biochemistry, and Behavior, 73, 689e696. Opsahl, C. A., & Hatton, G. I. (1972). Volitional ethanol increases during acquisition and extinction of avoidance responding. Physiology & Behavior, 8, 87e93. Piano, M. R., Carrigan, T. M., & Schwertz, D. W. (2005). Sex differences in ethanol liquid diet consumption in Sprague-Dawley rats. Alcohol, 35, 113e118. Porter, J. H., & Bryant, W. E., Jr. (1978). Adjunctive behavior in the Mongolian gerbil. Physiology & Behavior, 21, 151e155. Prasad, C., & Prasad, A. (1995). A relationship between increased voluntary alcohol preference and basal hypercorticosteronemia associated with an attenuated rise in corticosterone output during stress. Alcohol, 12, 59e63. Randall, C. L., & Lester, D. (1975). Social modification of alcohol consumption in inbred mice. Science, 189, 149e151. Rashotte, M. (1981). Second-order autoshaping: contributions to the research and theory of Pavlovian reinforcement by conditioned stimuli. In C. M. Locurto, H. S. Terrace, & J. Gibbon (Eds.), Autoshaping and conditioning theory (pp. 139e180). New York: Academic Press. Retana-Márquez, S., Bonilla-Jaime, H., Vázquez-Palacios, G., Domínguez-Salazar, E., Martínez-García, R., & Velázquez-Moctezuma, J. (2003). Body weight gain and diurnal differences of corticosterone changes in response to acute and chronic stress in rats. Psychoneuroendocrinology, 28, 207e227. Robinson, T. E., & Flagel, S. B. (2009). Dissociating the predictive and incentive motivational properties of reward-related cues through the study of individual differences. Biological Psychiatry, 65, 869e873. Sawrey, D. K., & Dewsbury, D. A. (1981). Effects of space on the copulatory behavior of deer mice (Peromyscus maniculatus). Bulletin of the Psychonomic Society, 17, 249e251. Smith, H. V., Gannon, K. N., & Tierney, K. J. (1984). Effect of procurement wheel running on the rate of drinking in rats. Physiology & Behavior, 33, 927e930. Tambour, S., Brown, L. L., & Crabbe, J. C. (2008). Gender and age at drinking onset affect voluntary alcohol consumption but neither the alcohol deprivation effect nor the response to stress in mice. Alcoholism: Clinical and Experimental Research, 32, 2100e2106. Taylor, G. T., Weiss, J., & Rupich, R. (1987). Male rat behavior, endocrinology and reproductive physiology in a mixed-sex, socially stressful colony. Physiology & Behavior, 39, 429e433.

Tomie, A., Burger, K. M., Di Poce, J., & Pohorecky, L. A. (2004). Social opportunity and ethanol drinking in rats. Progress in Neuro-psychopharmacology & Biological Psychiatry, 28, 1089e1097. Tomie, A., Gittleman, J., Dranoff, E., & Pohorecky, L. A. (2005). Social interaction opportunity and intermittent presentations of ethanol sipper tube induce ethanol drinking in rats. Alcohol, 35, 43e55. Tomie, A., Hosszu, R., Rosenberg, R. H., Gittleman, J., Patterson-Buckendahl, P., & Pohorecky, L. A. (2006). An inter-gender effect on ethanol drinking in rats: proximal females increase ethanol drinking in males. Pharmacology, Biochemistry, and Behavior, 83, 307e313. Tomie, A., Lewis, K., Curiotto, J., & Pohorecky, L. A. (2007). Intermittent exposure to a social stimulus enhances ethanol drinking in rats. Pharmacology, Biochemistry, and Behavior, 87, 341e348. Tomie, A., Uveges, J. M., Burger, K. M., Patterson-Buckendahl, P., & Pohorecky, L. A. (2004). Effects of ethanol sipper and social opportunity on ethanol drinking in rats. Alcohol and Alcoholism, 39, 197e202. van Erp, A. M., & Miczek, K. A. (2000). Aggressive behavior, increased accumbal dopamine, and decreased cortical serotonin in rats. The Journal of Neuroscience, 20, 9320e9325. van Erp, A. M., & Miczek, K. A. (2001). Persistent suppression of ethanol selfadministration by brief social stress in rats and increased startle response as index of withdrawal. Physiology & Behavior, 73, 301e311. Van Loo, P., Van der Meer, E., Kruitwagen, C., Koolhaas, J., Van Zutphen, L., & Baumans, V. (2003). Strain-specific aggressive behavior of male mice submitted to different husbandry procedures. Aggressive Behavior, 29, 69e80. Vega Matuszczyk, J., & Larsson, K. (1993). Sexual orientation and sexual motivation of the adult male rat. Physiology & Behavior, 53, 747e750. Vetter-O’Hagen, C., Varlinskaya, E., & Spear, L. (2009). Sex differences in ethanol intake and sensitivity to aversive effects during adolescence and adulthood. Alcohol and Alcoholism, 44, 547e554. Watabe, T., & Endo, A. (1994). Sexual orientation of male mouse offspring prenatally exposed to ethanol. Neurotoxicology and Teratology, 16, 25e29. Wilson, G. T. (1981). The effects of alcohol on human sexual behavior. Advances in Substance Abuse, 2, 1e40. Wiren, K. M., Hashimoto, J. G., Alele, P. E., Devaud, L. L., Price, K. L., Middaugh, L. D., et al. (2006). Impact of sex: determination of alcohol neuroadaptation and reinforcement. Alcoholism: Clinical and Experimental Research, 30, 233e242. Wolffgramm, J. (1990). Free choice ethanol intake of laboratory rats under different social conditions. Psychopharmacology (Berl), 101, 233e239. Wolffgramm, J., & Heyne, A. (1991). Social behavior, dominance, and social deprivation of rats determine drug choice. Pharmacology, Biochemistry, and Behavior, 38, 389e399. Yanai, J., & Ginsburg, B. E. (1976). Increased sensitivity to chronic ethanol in isolated mice. Psychopharmacologia, 46, 185e189. Zuckerman, M. (1984). Sensation seeking: a comparative approach to a human trait. Behavioral and Brain Sciences, 7, 413e434.