TACHYKININ NEUROKININ-1 AND NEUROKININ-3 RECEPTOR-MEDIATED RESPONSES IN GUINEA-PIG SUBSTANTIA-NIGRA - AN IN-VITRO ELECTROPHYSIOLOGICAL STUDY

The effects of tachykinin receptor agonists and antagonists were inves tigated using intra- and extracellular recordings on spontaneously fir ing nigral neurons in guinea-pig brain slices. In 70 of 76 electrophys iologically identified dopaminergic neurons, a concentration-dependent increase in firing rate was induced by the selective neurokinin-3 tac hykinin agonist senktide and by the natural tachykinin agonists neurok inin B and substance P, with EC50 values of 14.7, 31.2 and 12200 nM re spectively. These responses were inhibited in a concentration- and tim e-dependent manner by the selective non-peptide neurokinin-3 receptor antagonist SR 142801 (1-100 nM; n = 23), but neither by its S-enantiom er SR 142806 (100 nM; n = 4) nor by selective antagonists of neurokini n-1 (SR 140333) or neurokinin-2 (SR 48968) receptors (both at 100 nM; n = 3). The selective neurokinin-1 agonist [Sar(9),Mer(O-2)(11)]substa nce P (30-100 nM; n = 23) and the selective neurokinin-2 agonist [Nle( 10)]neurokinin A(4-10) (30-100 nM; n = 13) were without any effect on dopaminergic cells. In 13 of 21 electrophysiologically identified, pre sumably GABAergic neurons located in the pars compacta of the substant ia nigra, excitatory responses were evoked concentration dependently b y substance P and [Sar(9),Met(O-2)(11)]substance P, with EC50 values o f 18.6 and 41.9 nM respectively. These responses were inhibited by SR 140333 (100 nM; n = 3), but neither by its R-enantiomer SR 140603 nor by SR 142801 (both at 100 nM; n = 3). Senktide and [Nle(10)]neurokinin A(4-10) (both at 30-100 nM; n = 10) were without effect on these pres umed GABAergic neurons. A small population (12%) of pars compacta neur ons was insensitive to any of the three selective tachykinin agonists. In the nigral pars reticulata, 12 neurons were recorded which had an electrophysiological profile similar to that of presumed GABAergic neu rons in the pars compacta. Of these 12 cells, seven did not respond to any of the selective tachykinin agonists tested, while five were exci ted by senktide in a concentration-dependent manner (EC50 = 98.5 nM). Although this value was significantly higher than that found for dopam inergic neurons in the pars compacta, senktide-evoked responses were i nhibited by SR 142801 (100 nM; n = 3). We conclude that, in the guinea -pig substantia nigra, tachykinins evoke excitatory responses in both dopaminergic and non-dopminergic neurons; however, the senstivity to t achykinin agonists (neurokinin-1 versus neurokinin-3) depends on both neuronal type and localization. (C) 1997 IBRO.