Blockade of neurokinin(3) 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 eff ects of neurokinin(3) (NK3) receptor blockade on the pharmacological activa tion 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 a dministration of haloperidol (1 and 0.5 mg/kg i.p., respectively) and this effect was dose-dependently prevented in both areas by the selective NK3 re ceptor antagonist SR142801 (0.3, 1, 3, and 1, 3, 10 mg/kg i.p., respectivel y). This compound, which was totally inactive by itself, also antagonized t he 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 NK2 rece ptor antagonist SR144190 (1 mg/kg i.p.). None of the effects of SR142801 we re reproduced by SR142806, its (R)-enantiomer with 240-fold lower affinity for NK3 receptors. In addition, neither SR144190 (0.3 mg/kg i.p.) nor the N K1 receptor antagonist GR205171 (1 mg/kg i.p.) affected the haloperidol-ind uced response. The antagonistic effects of SR14280 1 (3 mg/kg i.p.) were al so observed on the depolarization block-related decrease of A10 cell popula tion response evoked by repeated administration (22 days) of haloperidol. F inally, SR142801 (3 mg/kg i.p.) prevented depolarization block induced in A 10 cells by acute co-administration of SR142948 and haloperidol, both on po pulation response and on single cell firing. These results on pharmacologic ally induced activation and depolarization block of dopamine neurons sugges t that NK3 receptors play a key role in the midbrain DA function, presumabl y through activation by neurokinin B. Synapse 33:71-79, 1999. (C) 1999 Wile y-Liss, Inc.