Differential expression of ethanol-induced hypothermia in adolescent and adult rats induced by pretest familiarization to the handling/injection procedure

During adolescence, organisms undergo dramatic changes in behavior and brain structure that may increase their vulnerability to drug use and abuse (for a review, see Spear, 2000). According to the Monitoring the Future Study, binge ethanol use (the consumption of 5 or more drinks in a row) increases steadily during adolescence, with a similar trend evident in ethanol abuse (Johnston et al., 2003). Additional research from the U.S. Department of Health and Human Services has indicated that as many as 48.7% of Americans between the ages of 18 and 25 reported binge drinking in 2001 (U.S. Department of Health and Human Services, 2002). Such ethanol exposure during adolescence may be associated with damage in certain forebrain regions (Crews et al., 2000) and long-lasting effects that persist into adulthood, including cognitive deficits (Tapert and Schweinsburg, 2005). Precisely why adolescents are more likely than adults to experiment with and abuse ethanol is not fully understood. One potential contributing factor is that adolescents may be less sensitive to ethanol effects that normally serve as cues to limit intake, perhaps permitting increased consumption relative to more mature animals (see Doremus et al., 2003; Ristuccia and Spear, 2005 for a discussion). Given that this issue is very difficult to investigate ethically in human adolescents, various animal models have been used. Ontogenetic increases in ethanol sensitivity through adolescence have been reported in laboratory animals using a variety of response measures, including ethanol-induced motor impairment (e.g., White et al., 2002a, 2002b), sedation (Silveri and Spear, 1998), dysphoria (Shram et al., 2005), anxiolysis (Varlinskaya and Spear, 2002), and analgesia (Hernandez and Spear, in preparation). In contrast to the developmental insensitivities seen with these ethanol effects, adolescents have been found to exhibit greater sensitivity to ethanol-induced impairments in memory function (Markwiesse et al., 1998; White et al., 2000) and brain plasticity (Swartzwelder et al., 1995), as well as to ethanol-induced social facilitation (Varlinskaya and Spear, 2002). When examining the ontogeny of ethanol’s effects on the autonomic nervous system indexed through assessment of ethanol-induced hypothermia, however, the available data are more mixed. Some studies have found adolescent rats to exhibit less hypothermia than mature animals following injected or intubated ethanol (Ristuccia and Spear, 2004; Silveri and Spear, 2000). Brasser and Spear (2002) also found adolescents to show less ethanol-induced hypothermia than adult rats following intragastric (i.g.) administration of 2.0 g/kg of ethanol, although adolescents conversely exhibited a greater hypothermic response than adults at a high, sedating dose (4.0 g/kg). More marked ethanol-induced hypothermia also emerged in adolescent relative to adult rats in response to a 4-hour long ethanol vapor inhalation session (Ristuccia and Spear, 2005). That study also found adolescents to develop chronic tolerance to ethanol-induced hypothermia at a slower rate than adults, findings that contrast with those previously reported when ethanol was administered via chronic intubations (Swartzwelder et al., 1998). One possible explanation for these contrasting ontogenetic findings across studies—and even within the same laboratory (e.g., Ristuccia and Spear, 2004 vs 2005)—may be the amount of perturbation associated with the experimental procedures. In Ristuccia and Spear (2005), the animals underwent minimal handling immediately before and during daily ethanol exposure, core body temperature was assessed using indwelling telemetry probes, and ethanol was administered via a minimally invasive route, vapor inhalation. However, in Silveri and Spear (2000), ethanol was injected intraperitoneally (i.p.) and temperatures were taken with a rectal probe, whereas Brasser and Spear (2002) and Ristuccia and Spear (2004) intubated the animals i.g. even though temperatures were recorded using telemetry probes. These procedures presumably were more invasive and hence more disruptive than when ethanol was administered via vapor inhalation. Although pharmacokinetic differences could also contribute to the differing findings obtained across routes of administration, the relative invasiveness of the test procedures seems a potentially likely contributor to the differences in the hypothermic response observed across studies. Therefore, the experiments presented here examined whether manipulating the amount of perturbation at the time of test differentially influenced expression of ethanol-induced hypothermia in adolescent versus adult rats. Experimental perturbation was manipulated using indwelling gastric cannulae versus i.g. intubation (Experiment 1) and via either familiarizing animals with the handling and injection procedure before testing or not manipulating them between surgery and testing (Experiment 2). Based on the findings of previous studies, it was anticipated that greater disruption at the time of test would diminish ethanol sensitivity of adolescents but not adults, with the result that adolescents would show less hypothermia than adults after ethanol was administered when the amount of test disruption was high but greater sensitivity than adults when ethanol was administered under presumably less disrupting test circumstances. Results supported the adolescent/adult differences predicted, although surprisingly it was the adult animals rather than the adolescents whose hypothermic reaction to ethanol was differentially influenced by variations in test circumstances.