Ethanol-induced locomotor sensitization in DBA/2J mice is associated with alterations in GABA A subunit gene expression and behavioral sensitivity to GABA A acting drugs

Abstract

Repeated exposure to ethanol may produce increased sensitivity to its acute locomotor stimulant actions, a process referred to as locomotor sensitization. Neuroadaptation within certain brain circuits, including those possessing GABA A receptors, may underlie locomotor sensitization to ethanol. Indeed, GABA A receptors are documented mediators of ethanol's cellular and behavioral actions. Moreover, because subunit composition of this receptor is predictive of its pharmacology, it is possible that alterations in subunit composition contribute to the expression of locomotor sensitization to ethanol. The goal of the present study was to determine if alterations in GABA A subunit composition are associated with the expression of locomotor sensitization in DBA/2J mice, a strain known to be particularly susceptible to the development of this behavioral phenomenon. Following a modified 14 day sensitization procedure (Phillips et al., 1994) relative changes in GABA A subunit gene expression were assessed in discrete mesolimbic brain regions. To determine if the observed changes in gene expression produced functional changes in the locomotor responses to drugs known to either preferentially or generally activate GABA A receptors normally possessing the significantly altered subunits, separate cohorts of animals were challenged with one of several low doses of zolpidem (α1-selective), etomidate (β2/3-selective), or flurazepam (γ2-directed) and assessed for locomotor alterations. Sensitized animals displayed increased expression of the α1, β2, and γ2 (v1) subunits in the Nucleus Accumbens (NAc) but not Ventral Tegmental Area (VTA). Additionally, sensitized animals displayed altered sensitivity to the locomotor actions of etomidate and flurazepam. These results support the hypothesis that neuroadaptive changes in GABA A subunit composition participate in the expression of locomotor sensitization.