Ontogeny of acute tolerance to ethanol-induced social inhibition in Sprague-Dawley rats.

Unique adolescent-specific neural alterations may influence responsiveness to ethanol among adolescents in a way that differs from adult responding (Spear, 2000a, 2000b; Witt, 1994). And, indeed, there is convincing experimental evidence that responsiveness to ethanol changes across ontogeny, although these ontogenetic patterns of ethanol responsivity vary with the effect of ethanol being examined. For instance, adolescent rats appear to be more sensitive than adults to ethanol-induced impairments in hippocampal long-term potentiation (Pyapali et al., 1999; Swartzwelder et al., 1995a, 1995b) and spatial memory (Markwiese et al., 1998), as well as to the facilitation in social behavior that is seen following challenge with low doses of ethanol (Varlinskaya and Spear, 2002). On the other hand, when compared with their adult counterparts, adolescent rats are less sensitive to a variety of acute effects of ethanol, including ethanol-induced motor impairment (Hollstedt et al., 1980; Silveri and Spear, 1998, 2001; White et al., 2002), sedation (Little et al., 1996; Moy et al., 1998), and anxiolysis (Varlinskaya and Spear, 2002). Sensitivity to hypothermic effects of ethanol has been also reported to increase across ontogeny (Silveri and Spear, 2000), although findings with this measure are more mixed (Brasser and Spear, 2002; Ristuccia and Spear, 2005; Swartzwelder et al., 1998) and may be related to the amount of perturbation of the test circumstances (Ristuccia and Spear, under revision). Among the ethanol consequences to which adolescent animals appear to be less sensitive than adults is ethanol-induced social inhibition. When tested for social interactions in a familiar (low-anxiety producing) environment 30 minutes after challenge with moderate doses of ethanol, adolescent rats at postnatal day (P) 35 showed less social inhibition than their adult (P70) counterparts (Varlinskaya and Spear, 2002). It seems unlikely that this adolescent-associated attenuation in sensitivity to the suppressing effects of ethanol on social interactions is a function of ontogenetic differences in ethanol pharmacokinetics, given that no age-related differences in blood ethanol concentrations (BECs) were found 30 minutes after the ethanol challenge doses. Interestingly, ontogenetic increases in responsiveness to the inhibitory effects of ethanol on social behavior are apparent even across the adolescent period, with early (P28) adolescents being less sensitive to ethanol-induced social inhibition than mid (P35) and late (P42) adolescents (Varlinskaya and Spear, 2004). A relative insensitivity of adolescent rats to ethanol-induced social inhibition could be related in part to age differences in compensatory responses, including acute tolerance, that serve to counteract these inhibitory effects of ethanol. Acute tolerance, defined as a reduced sensitivity to ethanol that emerges within a single exposure, is traditionally characterized by less impairment at the same BEC on the descending than the ascending portion of the BEC time curve (Mellanby, 1919) or by higher BECs or brain ethanol concentrations (BrECs) at the offset than at the onset of a particular behavioral or physiological impairment (Le et al., 1992). Acute tolerance has been observed for a number of ethanol effects, including motor impairment, sedation, and hypothermia in adult rodents (see Le and Mayer, 1996, for references and review). Studies examining the ontogeny of acute tolerance have been restricted to the assessments of ethanol-induced sedation emerging at relatively high doses of ethanol and have reported ontogenetic declines in acute tolerance to the hypnotic effects of ethanol, with more pronounced acute tolerance expressed in adolescent than adult rodents (Draski et al., 2001; Grieve and Littleton, 1979; Silveri and Spear, 1998, 2002). Ontogenetic alterations in the development of acute tolerance to other ethanol effects have not been explored. These initial assessments reporting an ontogenetic decline in acute tolerance focused on ethanol’s sedative effects at relatively high doses (from 2.5 to 5 g/kg). It is not yet known whether similar ontogenetic differences in acute tolerance would be seen at lower doses, more typical of those associated with human ethanol consumption levels (see Eckardt et al., 1998, for references and review). In contrast to the relatively high doses required for the assessment of ethanol-induced sedation, the social interaction test is sensitive to acute effects of low-to-moderate doses of ethanol. With this test, social impairment can be detected at doses of 1 g/kg in adolescents and even less in adults (Varlinskaya and Spear, 2002), doses in the range of those used in studies of acute tolerance in human volunteers (e.g., Bennett et al., 1993; Hiltunen, 1997a, 1997b). Therefore, the social interaction test shows promise as a tool for assessing the development of acute tolerance to social inhibition induced by moderate doses of ethanol in adolescent and adult animals. Acute tolerance can be assessed in a number of ways, many of which have focused on the relationship between BECs and ethanol-induced impairment of a certain function during the descending portion of the blood alcohol curve. For instance, to the extent that acute tolerance is a linear process with time, this tolerance can be indexed by the increasing dissociation between BEC and ethanol-induced impairment following a given dose of ethanol, with ethanol-induced impairment declining more rapidly than BECs (Khanna et al., 2002; Radlow, 1994). There is experimental evidence, however, that acute tolerance to some ethanol effects emerges extremely rapidly and may be seen within minutes following ethanol administration in both electrophysiological (Palmer et al., 1992; Pearson et al., 1997; Sorensen et al., 1980) and behavioral studies (Deitrich et al., 2000; Gill and Deitrich, 1998). This rapid emergence of acute tolerance can be detected in animals given a single ethanol dose by examining the association between the incidence of the target behavior and BEC beginning shortly following injection. For instance, with the later approach, acute tolerance has been assessed by testing animals at 1-minute intervals for the first 5 minutes following ethanol administration and then at 5-minute intervals thereafter for a total of 30 minutes (Deitrich et al., 2000; Gill and Deitrich, 1998), thus examining animals during the ascending, peak, and early descending portions of the blood curve. Using this paradigm, some strains of mice were observed to develop tolerance to the ataxic effects of ethanol measured on the rotorod within 10 minutes following a single ethanol injection (Gill and Deitrich, 1998). Given that previous studies reporting ontogenetic declines in the development of acute tolerance used relatively high doses of ethanol and assessed emergence of tolerance to ethanol-induced sedation over a period of several hours (Draski et al., 2001; Grieve and Littleton, 1979; Silveri and Spear, 1998, 2002), the main objective of the present study was to examine ontogenetic development of acute tolerance to a relatively low dose of ethanol (1 g/kg) when examined within 30 minutes after ethanol administration, using ethanol-induced social impairment as the target response measure. Because of recent findings (e.g., Philpot et al., 2003; Varlinskaya and Spear, 2004) that point to age differences in ethanol responsiveness even within the adolescent period, rats tested at a variety of ages (P28, P35, P42) in adolescence were compared with young adult (P70) animals.