Participation of GABAA, GABA(B) receptors and neurosteroids in toluene-induced hypothermia: evidence of concentration-dependent differences in the mechanism of action

Abstract

Toluene is a misused substance that modifies γ-aminobutyric acid (GABA) release and shares behavioral and molecular effects with GABA(A) and GABA(B) receptor agonists. GABAergic compounds are involved in thermoregulation processes and volatile substance users have reported that one of the reasons to inhale is to avoid feeling cold. At present, no studies have analyzed the effects of inhalants on body temperature and the mechanism of action involved. Thus, the main purpose of this study was to evaluate the effects of a (60 min) acute toluene inhalation (2000, 4000 and 6000 ppm) in core temperature. In addition, we tried to prevent the changes of temperature induced by toluene with the specific GABA(A) receptor blockers picrotoxin (0.01-0.1mg/kg), bicuculline (0.1-0.3mg/kg), and flumazenil (3-30 mg/kg); the GABA(B) receptor antagonist phaclofen (10-30 mg/kg) and the neurosteroid synthesis inhibitor finasteride (10-30 mg/kg). Results show that toluene reduced core temperature in mice in a concentration-dependent manner. The hypothermia produced by 4000 ppm toluene was prevented by picrotoxin, bicuculline, phaclofen and finasteride but not by flumazenil. In contrast none of these antagonists tested blocked the effects of 6000 ppm toluene. In conclusion, toluene decreases core temperature, GABA receptors and neurosteroids participate in toluene's action at 4000 ppm; but other mechanisms of action are involved in the hypothermic effects of 6000 ppm toluene.