The effects of NMDA and GABAA pharmacological manipulations on ethanol sensitivity in immature and mature animals

Background: Sensitivity to the hypnotic effects of ethanol dramatically increases with age (Silveri and Spears, 1998). Little is known regarding the neural mechanisms that might underlie this relative resistance of young animals to ethanol. The present study used a psychopharmacological approach to examine the influence of NMDA (N-methyl-D-aspartate) and GABA (gamma-Aminobutyric acid) receptor systems in modulating age differences in ethanol responsiveness between young [postnatal day (P26)] and mature (P70) female and male Sprague-Dawley rats. Method: Dose response curves were established for the effects of intraperitoneal (ip) administration of the NMDA antagonist (+)MK-801 (0.75, 1.0, or 1.25 mg/kg), the GABA(A) agonist muscimol (0.75, 1.25, or 1.75 mg/kg), or saline on loss and regain of the righting reflex and trunk blood alcohol levels following 3.5 g/kg of ethanol. Results: (+)MK-801 increased time to regain the righting reflex at both ages, maintaining the age-related increase in ethanol sensitivity typically observed, although a gender effect also emerged at P70, with females being more sensitive than males to (+)MK-801-induced increases in duration of loss of the righting reflex, In contrast to the across-age similarity in responsiveness to (+)MK-801, P26 animals were considerably more sensitive to muscimol's enhancing effect on ethanol sedation than mature animals. Conclusion: Although modulation of either the NMDA or GABA system enhances the sedative effects of ethanol at both ages, stimulation of the GABA(A) receptor is a more effective means of prolonging ethanol sedation in immature than mature animals.