Involvement of brain GABAAR-coupled Cl-/HCO3--ATPase in phenol-induced the head-twitching and tremor responses in rats.

Phenol-induced neurotoxicity manifests as twitching/tremor and convulsions, but its molecular mechanisms underlying the behavioral responses remain unclear. We assessed the role of the brain Cl-/HCO3--ATPase in behavioral responses in rats following an in vivo intraperitoneal injection of phenol (20-160 mg/kg). Low concentrations of phenol (20-80 mg/kg) increased the ATPase activity as well as the head twitching responses in rat, whereas higher phenol concentrations (>60 mg/kg) increased the tremor but reduced the ATPase activity. At phenol concentrations >120 mg/kg, no ATPase activity was detected. Phenobarbital (10 mg/kg) and picrotoxin (1 mg/kg) as well as o-vanadate (2 mg/kg), significantly prevented (˜55-70%) the phenol-induced change in the behavioral responses and completely restored the enzyme activity. In vitro experiments confirmed that phenol stimulated the Cl-/HCO3--ATPase activity at low concentrations, but had no stimulating effect on other transport ATPases. Low doses of phenol increased the formation of phosphoprotein and the rate of ATP-consuming Cl- transport by the reconstituted enzyme. The present findings provide evidence that phenol-induced neurotoxicity involves the Cl-/HCO3--ATPase in the behavioral responses in mammals and indicate the potential benefit of this enzyme as a target for the treatment of head twitching and other types of tremor diseases.