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

Abstract

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 (125)I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evaluated using (3)H-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, (125)I-CGP64213 and selective probes for GABA(B(1a+b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, (125)I-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 (3)H-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, (125)I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, (125)I-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.

Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Substantia Nigra

“…Given the fact that GABAergic neurons neither uptake nor respond to MPP ϩ , the only plausible mechanisms that could support a contribution to the observed gene dysregulation are circuit related or bystander. To the former point, previous work with an MPTP mouse model found a significant decrease in GABA B mRNA by ISH within the SN pars compacta (Calon et al, 2001). Because our array studies did not detect alteration in this transcript within either the MME or MML suggests the signal contribution and likely overall GABAergic neuronal contributions are quite small relative to the changes within the TH-positive population.…”

Quantitative1H Magnetic Resonance Spectroscopic Imaging Determines Therapeutic Immunization Efficacy in an Animal Model of Parkinson's Disease

“…An unexpected observation made was the degree of [NAA] reduction seen in the SNpc indicated that secondary damage can occur to surrounding glutaminergic and GABAergic neurons (Calon et al, 1999(Calon et al, , 2001 All together, whether severely affected dopaminergic neurons can be protected from the ravages of PD-associated neurodegeneration using therapeutic strategies outlined in this study is not yet known. However, the data outlined in this report and by others support the idea that such a goal is achievable.…”

Origins of GABAA and GABAB Receptor-Mediated Responses of Globus Pallidus Induced after Stimulation of the Putamen in the Monkey

“…In patients and in the animal models of Parkinson's disease, GPe neurons have more burst firing than in normal conditions (Filion and Tremblay, 1991;Sterio et al, 1994;Nini et al, 1995;Beric et al, 1996;Boraud et al, 2001;Wichmann and Soares, 2006) that might effectively activate GABA B receptors at their innervation sites. The expression of GABA B receptors in the pallidum and STN was altered in parkinsonian subjects (Calon et al, 2001(Calon et al, , 2003; Johnston and Duty, (A-b). B, Another GPe neuron induced a similar slow inhibition to both single and burst stimulation (B-a).…”