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 p ars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybr idization. The extent of the lesion was measured with striatal catecholamin e content, striatal binding of I-125-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evalu ated using H-3-CGP54626 and its expression was measured with oligonucleotid es probes targeting the mRNAs of GABA(B(1a + b)), GABA(B(1a)), GABA(B(1b)), GABA(B(2)) subunits. In monkeys, I-125-CGP64213 and selective probes for G ABA(B(1a + b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, I -125-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 M PTP, respectively. In monkeys, dopamine content and DAT expression were dec reased by more than 90% and 80%, respectively. In the striatum and the subt halamic nucleus, GABA(B) receptors were unchanged following MPTP in both sp ecies. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of H-3-CGP54626 binding (-10%) and of the expression of GABA(B(1a + b)) mR NA (-13%). The decrease of the expression of GABA(B(1a + b)) mRNA was corre lated with dopamine content, I-125-RTI-121 binding and DAT expression. In M PTP-treated monkeys, I-125-CGP64213 binding (-40%), GABA(B(1a + b)) mRNA (- 69%) and GABA(B(2)), mRNA (-66%) were also significantly decreased in the S Npc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA(B) receptors restricted to the SNpc. These observations m ay be relevant to the pathophysiology of motor disorders involving dysfunct ion of the basal ganglia such as Parkinson disease. Synapse 40:225-234, 200 1. (C) 2001 Wiley-Liss, Inc.