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The Journal of Neuroscience, September 1, 1998, 18(17):6977-6989

The Striatal Neurotensin Receptor Modulates Striatal and Pallidal Glutamate and GABA Release: Functional Evidence for a Pallidal Glutamate-GABA Interaction via the Pallidal-Subthalamic Nucleus Loop

Luca Ferraro¹, Tiziana Antonelli¹, William T. O'Connor², Kjell Fuxe³, Philippe Soubrié⁴, and Sergio Tanganelli¹

¹ Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, 44100 Ferrara, Italy, ² Department of Human Anatomy and Physiology, University College of Dublin, Dublin, Ireland, ³ Department of Neuroscience, Karolinska Institute, Stockholm, Sweden, and ⁴ Sanofi Recherche, 34184 Cedex 04, Montpellier, France

In the present study, we used dual-probe microdialysis to investigate the effects of intrastriatal perfusion with neurotensin (NT) on striatal and pallidal glutamate and GABA release. The role of the pallidal GABA_A receptor in the intrastriatal NT-induced increase in pallidal glutamate release was also investigated.

Intrastriatal NT (100 and 300 nM) increased striatal glutamate and GABA (100 nM, 155 ± 9 and 141 ± 6%, respectively; 300 nM, 179 ± 8 and 166 ± 11%, respectively) release, as well as pallidal glutamate and GABA (100 nM, 144 ± 8 and 130 ± 5%; 300 nM, 169 ± 9 and 157 ± 8%, respectively) release. These effects were dose-dependently antagonized by the NT receptor antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1.^3.7)-decan-2-carboxylic acid (SR48692).

Intrasubthalamic injection of the GABA_A receptor antagonist ()-bicuculline (10 pmol/100 nl, 30 sec) rapidly increased pallidal glutamate release, whereas the intrastriatal NT-induced increase in pallidal glutamate release was counteracted by intrapallidal perfusion with ()-bicuculline, suggesting that an increase in striopallidal GABA-mediated inhibition of the GABAergic pallidal-subthalamic pathway results in an increased glutamatergic drive in the subthalamic-pallidal pathway.

These results demonstrate a tonic pallidal GABA-mediated inhibition of excitatory subthalamic-pallidal neurons and strengthen the evidence for a functional role of NT in the regulation of glutamate and GABA transmission in the basal ganglia. The ability of intrastriatal SR48692 to counteract the NT-induced increase in both striatal and pallidal glutamate and GABA release suggests that blockade of the striatal NT receptor may represent a possible new therapeutic strategy in the treatment of those hypokinetic disorders implicated in disorders of the indirect pathway mediating motor inhibition.

Key words: basal ganglia; striatum; globus pallidus; neurotensin; SR48692; microdialysis; awake rat

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18176977-13$05.00/0

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