Effect of MPTP-induced denervation on basal ganglia GABA_B receptors: Correlation with dopamine concentrations and dopamine transporter

We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA_B receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of ¹²⁵I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA_B receptors in mice brain were evaluated using ³H-CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABA_B(1a+b), GABA_B(1a), GABA_B(1b), GABA_B(2) subunits. In monkeys, ¹²⁵I-CGP64213 and selective probes for GABA_B(1a+b) and GABA_B(2) mRNAs were used. In mice, dopamine content, ¹²⁵I-RTI-121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABA_B receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of ³H-CGP54626 binding (-10%) and of the expression of GABA_B(1a+b) mRNA (-13%). The decrease of the expression of GABA_B(1a+b) mRNA was correlated with dopamine content, ¹²⁵I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, ¹²⁵I-CGP64213 binding (-40%), GABA_B(1a+b) mRNA (-69%) and GABA_B(2) mRNA (-66%) were also significantly decreased in the SNpc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA_B receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease.