Effects of Toluene Exposure during Brain Growth Spurt on GABAA Receptor-Mediated Functions in Juvenile Rats

Abstract

Toluene is a commonly abused inhalant. Its neurobiological effects are, at least in part, mediated by gamma-aminobutyric acid (GABA(A)) receptors. Since GABA(A) receptor function is critical during brain development, the long-term effects of toluene exposure during brain growth spurt were investigated. Spargue-Dawley male rats were administered with toluene (500 mg/kg, i.p.) on postnatal day (PN) 4-9. Behavioral and electrophysiological measures and the levels of messenger RNA (mRNA) expression of GABA(A) receptor subunits were examined on PN 28-32. The seizure sensitivity induced by bicuculline (a GABA(A) receptor antagonist), methyl beta-carboline-3-carboxylate (inverse agonists of the GABA(A)/benzodiazepine receptor) but not 3-mercaptopropionic acid (a glutamate decarboxylase inhibitor) was enhanced by toluene exposure. Toluene exposure had no effect on the performance in the elevated plus-maze and rotarod test but reduced the responses to diazepam in these two tests. In vitro intracellular electrophysiological recordings employing brain slices from rats treated with toluene demonstrated a significant decrease in GABA(A) receptor-mediated inhibitory postsynaptic currents in CA1 neurons but an increased response to GABA perfusion. The relative abundance of the mRNAs encoding various subunits of GABA(A) receptor (alpha1, alpha2, alpha4, alpha5, alpha6, beta2, beta3, gamma2S, gamma2L) was examined in four brain regions (hippocampus, striatum, cortex, and cerebellum) by semiquantitative reverse transcription-PCR. These results demonstrated that subunit- and brain area-selective alterations in GABA(A) receptors after toluene exposure during brain growth spurt. The alterations in GABA(A) receptors might be associated with the neurobehavioral disturbance in offspring of toluene-abusing women.