Striatal NTS1 , dopamine D2 and NMDA receptor regulation of pallidal GABA and glutamate release--a dual-probe microdialysis study in the intranigral 6-hydroxydopamine unilaterally lesioned rat.
The current microdialysis study elucidates a functional interaction between the striatal neurotensin NTS(1) receptor and the striatal dopamine D(2) and N-methyl-d-aspartic acid (NMDA) receptors in the regulation of striatopallidal gamma-aminobutyric acid (GABA) and glutamate levels after an ipsilateral intranigral 6-hydroxydopamine-induced lesion of the ascending dopamine pathways to the striatum. Lateral globus pallidus GABA levels were higher in the lesioned group while no change was observed in striatal GABA and glutamate levels. The 6-hydroxydopamine-induced lesion did not alter the ability of intrastriatal NT (10 nm) to counteract the decrease in pallidal GABA and glutamate levels induced by the dopamine D(2) -like receptor agonist quinpirole (10 μm). A more pronounced increase in the intrastriatal NMDA- (10 μm) induced increase in pallidal GABA levels was observed in the lesioned group while it attenuated the increase in striatal glutamate levels and amplified the increase in pallidal glutamate levels compared with that observed in the controls. NT enhanced the NMDA-induced increase in pallidal GABA and glutamate and striatal glutamate levels; these effects were counteracted by the NTS(1) antagonist SR48692 (100 nm) in both groups. These findings demonstrate an inhibitory striatal dopamine D(2) and an excitatory striatal NMDA receptor regulation of striatopallidal GABA transmission in both groups. These actions are modulated by NT via antagonistic NTS(1) /D(2) and facilitatory NTS(1) /NMDA receptor-receptor interactions, leading to enhanced glutamate drive of the striatopallidal GABA neurons associated with motor inhibition, effects which all are counteracted by SR48692. Thus, NTS(1) antagonists in combination with conventional treatments may provide a novel therapeutic strategy in Parkinson's disease.
Department of Clinical and Experimental Medicine, Pharmacology Section and LTTA Centre, University of Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. frl@unife.it
Luca
L
Ferraro
William T
WT
O'Connor
Sarah
S
Beggiato
Maria C
MC
Tomasini
Kjell
K
Fuxe
Sergio
S
Tanganelli
Tiziana
T
Antonelli
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009434:Neural Pathways / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D018028:Receptors, Neurotensin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
D018663:Adrenergic Agents; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine