Sensitivity and Tolerance to the Hypnotic and Ataxic Effects of Ethanol in Adolescent and Adult C57BL/6J and DBA/2J Mice

Abstract

Background There is considerable research examining differences in adolescent and adult sensitivity and tolerance to ethanol related behavioral phenotypes. However, the available published data has almost exclusively assessed these behaviors in outbred rats. The present study was conducted using the alcohol preferring inbred mouse strain C57BL/6J (B6) and the alcohol non-preferring inbred mouse strain DBA/2J (D2) to determine if differences in the sedative and ataxic effects of ethanol exist between adolescents and adults, and to determine whether there are any genetic influences involved therein. Methods Adolescent and adult mice of each sex and genotype were given intraperitoneal (i.p.) injections of ethanol (1.5, 1.75 or 4.0 g/kg) or saline and assessed for the loss of righting reflex (LORR) or hind footslips on the balance beam apparatus. These animals were then tested for the development of tolerance to these behaviors on subsequent days. Results Despite evident pharmacokinetic differences, D2 adults were found to be relatively more sensitive than their adolescent D2 counterparts in addition to B6 animals of both age groups. Furthermore, although adult animals appeared to develop significantly greater degrees of tolerance to ethanol-induced hypnosis compared to adolescents, these effects are likely in part related to differences in ethanol absorption/metabolism across time. Taking into account pharmacokinetic differences and the overall poor performance of male adults, adolescent animals were found to be equally if not more sensitive to the motor incoordinating (ataxic) effects of ethanol. Overall, tolerance to these effects varied by age and genotype but appeared to be related to changes in ethanol pharmacokinetics rather than strict behavioral sensitivity. Conclusion The current work suggests that adolescent B6 and D2 inbred mice exhibit ontogenetic differences in sensitivity to ethanol’s hypnotic and ataxic effects. Importantly, in some cases age differences emerge as a function of differential ethanol pharmacokinetics. These results extend the current literature examining this critical developmental period in mice and illustrate the benefits of comparing ethanol related developmental differences in different genetic mouse populations.

Sensitization to the Stimulant Motor Effects of Ethanol Is Not Dependent On Tolerance to Ataxic or Sedative Properties of Ethanol in Female Mice

“…Our data strongly suggest dissociation between tolerance to the depressant properties of EtOH and sensitization to the locomotor activating effect of EtOH. This study indicates that the enhancement of locomotor activity following repeated administrations Chronic tolerance to the ataxic [31,37,47] and sedative [29,48,49] effects of EtOH has been extensively demonstrated in rodents. In line with these reports, we confirmed that a chronic regimen of EtOH administration induced tolerance to both ataxic and sedative effects of EtOH in adult DBA/2J mice.…”

“…Yet, our results showed that the decrease in LORR duration after repeated EtOH injections was not paralleled by higher BECs at regain. Chronic tolerance to LORR is expected to lead to an earlier regain of righting reflex together with higher BECs at regain [29]. Therefore, we cannot exclude that a metabolic tolerance may participate in tolerance to the sedative effect of EtOH as commonly described in the literature [29,48,49,54].…”

“…Interestingly, both tolerance to the depressant effects of EtOH and sensitization to its locomotor activating properties occur concomitantly. One part of the scientific community legitimately raised the question of whether EIBS could derive from tolerance to the depressant effects of EtOH [10,29]. According to this hypothesis, if tolerance to the depressant properties of EtOH was responsible for the increase in locomotion following administrations of EtOH, one would expect that individuals who exhibit the most tolerance would also develop the highest sensitization levels.…”

“…The latency to LORR (time elapsed between EtOH injection and LORR), the LORR duration (time elapsed between LORR and regain) and the blood ethanol concentrations (BECs) at regain were determined. The dose of 4 g/kg was chosen based on literature [29,46]. Linear regression analyses were performed to investigate correlations between both sensitization scores and latency to LORR, LORR duration and BECs at regain.…”

“…The development of locomotor sensitization is not fully understood and its reliability as a model of addiction-like behavior remains controversial. It is believed that the increase in locomotion following repeated exposure to EtOH may be a by-product of tolerance to the depressant effect of EtOH that would progressively unmask the locomotor stimulant effect of EtOH [10,29].…”