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

In the present study, we used dual-probe microdialysis to investigate the effects of intrastriatal perfusion with neurotensin (NT) on striat al and pallidal glutamate and GABA release. The role of the pallidal G ABA(A) receptor in the intrastriatal NT-induced increase in pallidal g lutamate 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 ant agonist ethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo) 3.3.1.1.(3. 7))-decan-2-carboxylic acid (SR48692). Intrasubthalamic injection of t he GABA(A) receptor antagonist (-)-bicuculline (10 pmo1/100 nl, 30 sec ) rapidly increased pallidal glutamate release, whereas the intrastria tal NT-induced increase in pallidal glutamate release was counteracted by intrapallidal perfusion with (-)-bicuculline, suggesting that an i ncrease in striopallidal GABA-mediated inhibition of the GABAergic pal lidal-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. T he ability of intrastriatal SR48692 to counteract the NT-induced incre ase 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 inhibi tion.