Sensitivity and tolerance to the hypnotic and ataxic effects of ethanol in adolescent and adult C57BL/6J and DBA/2J mice.

Alcohol (ethanol) use often begins during the teenage years, a sensitive period during which a number of neurobiological, hormonal, and behavioral changes occur. A recent survey suggests that approximately 30% of high school seniors have had five or more drinks in a row (i.e., have engaged in binge drinking) during the previous two weeks (Johnston et al., 2002). Moreover, clinical reports indicate that adolescents frequently exhibit the symptoms of alcohol dependence. For example, some adolescents have difficulty controlling their alcohol intake and display signs of tolerance (Hawkins et al., 1997; Spear, 2000; Stewart and Brown, 1995). Such alcohol use during adolescence may have profound effects on brain development/maturation, and may even influence the propensity to use the drug in later life. Additional research is clearly needed to better understand how alcohol’s actions during this critical developmental period differ from its actions during adulthood. The development of useful animal models is crucial if we are to understand the complex interaction between alcohol sensitivity and the profound changes that occur during adolescence. Although human adolescents undergo developmental changes unparalleled in lower organisms, other mammalian species (including rodents) also experience a developmental period similar to adolescence (Spear, 2000). These changes have been reviewed for both rats (Spear, 2004) and mice (Laviola et al., 2003). With regard to ethanol, a number of studies have demonstrated that adolescent rats exhibit an altered behavioral sensitivity to the compound compared to their adult counterparts (see Spear and Varlinskaya, 2004 for review). Adolescent rats have been documented to display reduced sensitivity to the sedative/hypnotic (Silveri and Spear, 1998; Silveri and Spear, 1999), motor impairing or ataxic (Silveri and Spear, 2001), hypothermic (Silveri and Spear, 2000), and anxiolytic (Varlinskaya and Spear, 2002) effects of ethanol. Adolescent rats have demonstrated increased sensitivity to still other ethanol-related behavioral traits. Adolescent rats are more sensitive to the amnestic (Markwiese et al., 1998) and social faciliatory (Varlinskaya and Spear, 2002) actions of ethanol. Moreover, recent evidence suggests that adolescent rats may develop greater acute (within session) ethanol tolerance compared to their adult counterparts (Silveri and Spear, 1998; Varlinskaya and Spear, 2006). Taken together, the above evidence indicates that rodents might provide a powerful model system for investigating the neurobiological underpinnings of ethanol’s actions during the critical developmental period of adolescence. Although much is known about the behavioral actions of ethanol in adolescent rats, little work has been done in adolescent mice despite the fact that mice have been one of the most widely used animal models in ethanol research for decades. Inbred mouse strains have been particularly well studied. An inbred strain is a population of mice in which members have been brother-sister mated for 20 generations or more, effectively rendering all mice within the strain genetically identical. Differences among the members of an inbred strain are likely due to environmental influences, whereas differences between inbred strains are likely due to genetic differences (assuming environmental parameters have been rigorously controlled). The C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains differ widely in their relative behavioral sensitivities to ethanol. For example, in the earliest of these studies, McClearn and Rodgers (1959) demonstrated that whereas B6 mice will readily consume ethanol in a standard two-bottle choice paradigm, D2 mice avoid the solution. Since then, the relative sensitivity of these two inbred strains has been shown to exhibit widely different sensitivities on a number of other ethanol-related behavioral traits, including ethanol’s locomotor (Phillips et al., 1995), hangover (Metten and Crabbe, 1994), hypnotic (Crabbe et al., 2006), ataxic (Crabbe et al., 2003), and reinforcing actions (Cunningham et al., 1992). Thus, the use of inbred mouse strains provides a means by which to rigorously control for genetic differences in ethanol sensitivity. Moreover, because the ethanol behavioral sensitivities of B6 and D2 adults are so extensively characterized, examination of adolescent sensitivity in these strains will provide a useful picture of how ethanol behavioral sensitivity during adolescence relates to that of adulthood. Several labs have recently published reports describing ethanol behavioral sensitivity in adolescent and adult B6 (Hefner and Holmes, 2007) or D2 (Stevenson et al., 2007) inbred mice, but neither has compared the two, or examined tolerance to these actions. Indeed, a number of ethanol-related behaviors may undergo tolerance. Three different types of tolerance have been described. Whereas acute or within session tolerance is that which develops over a single ethanol exposure, rapid tolerance develops within 24 hours after first exposure and chronic tolerance develops with repeated ethanol exposures over days (Kalant, 1993). Although each of these forms of tolerance has been investigated in adolescent rats (Silveri and Spear; 1998, 1999; Ristuccia and Spear, 2004, 2005; Varlinskaya and Spear, 2006, 2007; Spear and Varlinskaya, 2005), they have not been thoroughly investigated with respect to hypnosis or ataxia in mice. The goal of the present study was to investigate sensitivity as well as rapid and chronic tolerance to the sedative and motor impairing effects of ethanol in adolescent and adult B6 and D2 inbred mice. Based on the available adult mouse sensitivity literature we hypothesized that D2 mice of both age groups would display greater sensitivity to the hypnotic (Crabbe et al., 2006) and motor impairing (Crabbe et al., 2003) actions of ethanol than B6 animals of the same age. Furthermore, based on the available adolescent mouse (Hefner and Holmes, 2007) and rat (previously mentioned) literature we predicted that adolescent animals would exhibit reduced sensitivity to both behavioral actions of ethanol and that the development of tolerance to these actions would also be greater.