NMDA‐mediated release of glutamate and GABA in the subthalamic nucleus is mediated by dopamine: an in vivo microdialysis study in rats

Abstract

The present study investigated the effects of N-methyl-Daspartic acidAEH 2 O (NMDA) on the dopamine, glutamate and GABA release in the subthalamic nucleus (STN) by using in vivo microdialysis in rats. NMDA (100 lmol/L) perfused through the microdialysis probe evoked an increase in extracellular dopamine in the STN of the intact rat of about 170%. This coincided with significant increases in both extracellular glutamate (350%) and GABA (250%). The effect of NMDA perfusion on neurotransmitter release at the level of the STN was completely abolished by co-perfusion of the selective NMDA-receptor antagonist MK-801 (10 lmol/L), whereas subthalamic perfusion of MK-801 alone had no effect on extracellular neurotransmitter concentrations. Furthermore, NMDA induced increases in glutamate were abolished by both SCH23390 (8 lmol/L), a selective D 1 antagonist, and remoxipride (4 lmol/L), a selective D 2 antagonist. The NMDA induced increase in GABA was abolished by remoxipride but not by SCH23390. Perfusion of the STN with SCH23390 or remoxipride alone had no effect on extracellular neurotransmitter concentrations. The observed effects in intact animals depend on the nigral dopaminergic innervation, as dopamine denervation, by means of 6-hydroxydopamine lesioning of the substantia nigra, clearly abolished the effects of NMDA on neurotransmitter release at the level of the STN. Our work points to a complex interaction between dopamine, glutamate and GABA with a crucial role for dopamine at the level of the STN.

High‐affinity Na+/K+‐dependent glutamate transporter EAAT4 is expressed throughout the rat fore‐ and midbrain

“…In GABAergic cells, glutamate taken up by EAAT4 can serve as a precursor for neosynthesis of GABA (Furuta et al,1997; Seal and Amara,1999) and thus enhance the inhibitory synaptic strength. In addition, the presence of EAAT4 on striatal neurons might be part of the glutamatergic regulation of the dopaminergic activity in the striatum as well as the STN, described by Wüllner et al (1994) and Ampe et al (2007), respectively. Small fractions of ionotropic and metabotropic striatal EAA binding sites are located on dopaminergic terminals where they may have a distinct impact on dopaminergic activity.…”

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

“…In PD, disturbance of glutamate homeostasis and excitotoxicity are associated with excessive NMDAR activation ( Wang J. et al, 2020 ; Trudler et al, 2021 ) and insufficient glutamate reuptake in the striatum ( Calon et al, 2003 ; Iovino et al, 2020 ). In early PD, this glutamatergic hyperactivity may compensate for the loss of neurons in SN ( Ampe et al, 2007 ; Shimo and Wichmann, 2009 ), but as the disease progresses, it causes impairment of the striatal signaling loop. In addition, VGluT1 and VGluT2 levels are altered in specific regions of the Parkinson’s brain.…”

Etiology and Pathophysiology of Parkinson's Disease

“…Several anatomical studies provided evidence for a direct and substantial nigrosubthalamic dopaminergic projection in rats (Campbell et al, 1985;Canteras et al, 1990;Hassani et al, 1996). Moreover, we and others have shown that dopamine is released within the STN in vivo (Cragg et al, 2004;Ampe et al, 2007). However, despite numerous investigations, many discrepancies still exist with regard to the effect of dopamine and its receptor agonists on the activity of STN neurons.…”