Blockade of neurokinin<INF>3</INF> receptors antagonizes drug-induced population response and depolarization block of midbrain dopamine neurons in guinea pigs

In vivo extracellular recording techniques were used to investigate the effects of neurokinin<INF>3</INF> (NK<INF>3</INF>) receptor blockade on the pharmacological activation of midbrain dopamine (DA) neurons in the guinea pig substantia nigra (A9) and ventral tegmental area (A10). The number of spontaneously active DA cells (population response) was largely increased in A10 and A9 by acute administration of haloperidol (1 and 0.5 mg/kg i.p., respectively) and this effect was dose-dependently prevented in both areas by the selective NK<INF>3</INF> receptor antagonist SR142801 (0.3, 1, 3, and 1, 3, 10 mg/kg i.p., respectively). This compound, which was totally inactive by itself, also antagonized the increase of population response induced in A10 cells by the neurotensin receptor antagonist SR142948 (1 mg/kg i.p.) and in A9 cells by the NK<INF>2</INF> receptor antagonist SR144190 (1 mg/kg i.p.). None of the effects of SR142801 were reproduced by SR142806, its (R)-enantiomer with 240-fold lower affinity for NK<INF>3</INF> receptors. In addition, neither SR144190 (0.3 mg/kg i.p.) nor the NK<INF>1</INF> receptor antagonist GR205171 (1 mg/kg i.p.) affected the haloperidol-induced response. The antagonistic effects of SR142801 (3 mg/kg i.p.) were also observed on the depolarization block-related decrease of A10 cell population response evoked by repeated administration (22 days) of haloperidol. Finally, SR142801 (3 mg/kg i.p.) prevented depolarization block induced in A10 cells by acute co-administration of SR142948 and haloperidol, both on population response and on single cell firing. These results on pharmacologically induced activation and depolarization block of dopamine neurons suggest that NK<INF>3</INF> receptors play a key role in the midbrain DA function, presumably through activation by neurokinin B. Synapse 33:71–79, 1999. © 1999 Wiley-Liss, Inc.