Dramatic increase in nigral t-[ 35S]butylbicyclophosphorothionate binding sites elicited by the degeneration of the striato-nigral GABAergic pathway: reversal by diazepam

Abstract

In rats, the degeneration of the striato-nigral GABAergic pathway caused by the intrastriatal injection of kainic acid induced a marked decrease (65%) of GABA content and glutamic acid decar☐ylase (GAD) activity and a dramatic increase (225%) in the binding of t-[ 35S]butylbicyclophosphorothionate ([ 35S]TBPS) to a membrane preparation from the substantia nigra homolateral to the injected striatum. The increase in [ 35S]TBPS binding in the denervated substantia nigra was exclusively due to an increased density of binding sites ( B max) with no change in the dissociation constant ( k d). The enhancement in [ 35S]TBPS binding was almost completely reversed by the intraperitoneal administration of diazepam (3 mg/kg) to kainic acid-lesioned rats. Moreover, diazepam produced a significant decrease (30%) in the density of [ 35S]TBPS binding sites also in the sham-operated side. In contrast the ‘in vitro’ addition of the GABA A receptor antagonist bicuculline (1 μM) to the membrane preparation from the denervated substantia nigra further increased [ 35S]TBPS binding. These findings suggest the view that the increase of nigral [ 35S]TBPS binding is directly related to the inhibition in the function of nigral GABAergic synapses following the loss of the striato-nigral GABAergic pathway. Our results indicate that [ 35S]TBPS binding to brain structure is a potential tool to reveal alteration in the function of GABA A receptor complex elicited by physiological, pharmacological and pathological conditions.