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Published on: July 13, 2014
The effects of NMDA and GABAA pharmacological manipulations on acute and rapid tolerance to ethanol during ontogeny
1Department of Psychiatry, Harvard Medical School and Cognitive Neuroimaging and Neuropsychology Laboratory, Brain Imaging Center, McLean Hospital, Belmont, Massachusetts 02478, USA. msilveri@hms.harvard.edu
Background:
Sensitivity to several ethanol effects increases during ontogeny, perhaps in part because of a notable decline in acute tolerance. In contrast, rapid tolerance to ethanol-induced sedation emerges slowly during ontogeny. This study tested the hypothesis that ontogenetic differences in glutamate and/or gamma-aminobutyric acid systems influence tolerance expression.
Methods:
Sprague-Dawley rats at postnatal day (P)26 or P70 received (+)MK-801, muscimol, or saline before ethanol (3.5 or 4.5 g/kg) or saline on day 1 and ethanol only on day 2. Loss of and time to regain the righting reflex and blood alcohol levels at recovery were recorded. The presence of acute tolerance was indicated as a positive slope of the linear regression of blood alcohol levels at recovery versus ethanol dose. Rapid tolerance was estimated on day 2 by comparing animals given ethanol only on day 2 with those given ethanol on both days.
Results:
Acute tolerance on day 1 only was observed at P26; this was disrupted by (+)MK-801 but not muscimol. Evidence for acute tolerance also emerged in adults on day 2. Whereas both drugs increased ethanol sedation at both ages, they did not facilitate ontogenetic expression of rapid tolerance: rapid tolerance was not evident at P26 regardless of pretreatment when indexed in terms of recovery time.
Conclusions:
These data provide further evidence for an ontogenetic dissociation in the expression of acute and rapid tolerance to ethanol-induced sedation. Pharmacological attenuation of the expression of acute tolerance was sufficient but not necessary to delay recovery of righting after ethanol. The greater propensity of young animals to develop acute tolerance, seemingly modulated in part by NMDA receptors, may contribute to their relative resistance to ethanol, although other factors, including pharmacokinetic factors, also contribute to their more rapid recovery from ethanol sedation.
