Effect of the acute and chronic administration of the selective neurokinin2 receptor antagonist SR 48968 on midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

Abstract

In this study, we examined the effect of the acute and chronic administration of the selective neurokinin2 (NK2) receptor antagonist SR 48968 on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male rats. This was accomplished using the technique of in vivo, extracellular single cell recording. The intravenous (i.v.) administration of SR 48968 (10-1280 micrograms/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to control. However, the acute administration of 1 mg/kg, i.p., of SR 48968, but not its inactive enantiomer SR 48965, produced a significant increase in the number of spontaneously active DA cells in the SNC (48%) and VTA (28%) compared to vehicle controls. The i.p. administration of SR 48968 did not alter the basal firing pattern of either SNC or VTA DA neurons compared to vehicle controls. The pretreatment of animals with 1 mg/kg, i.p., of SR 48968 significantly potentiated the suppressant action of (+)-apomorphine on spontaneously active SNC and VTA DA cells. In contrast to its acute effects, the administration of 1 mg/kg, i.p. of SR 48968 once daily for 21 days produced a significant decrease in the number of spontaneously active DA cells in the SNC and VTA. The decrease in the number of spontaneously active VTA DA cells was not reversed by (+)-apomorphine administration in fact, a further decrease in the number of VTA DA cells was observed. This suggests that the SR 48968-induced decrease in the number of spontaneously active DA neurons may not be the result of depolarization block. Overall, these results suggest that the acute and chronic administration of SR 48968 alters the number of spontaneously active midbrain DA neurons in anesthetized rats.

Blockade of neurokinin3 receptors antagonizes drug-induced population response and depolarization block of midbrain dopamine neurons in guinea pigs

“…The present electrophysiological study has reproduced in guinea pigs the drug-induced changes in population response of midbrain DA neurons currently reported in rats (Grace and Bunney, 1986;Bunney et al, 1991;Grace, 1992;Gully et al, 1997;Minabe and Ashby, 1997;Santucci et al, 1997). Thus, acute administration of DA receptor antagonists, as well as NT and NK 2 receptor antagonists, increase population response, whereas chronic administration of haloperidol leads to an opposite effect.…”

“…It has recently been shown that acute administration of selective neurotensin (NT) receptor antagonists, such as SR48692 and its more potent structural analog SR142948, which block the effects of NT and interact with dopamine systems in various animal models (Azzi et al, 1994;Gully et al, 1993Gully et al, , 1997, almost exclusively increase the population response of rat A10 neurons (Gully et al, 1997;Santucci et al, 1997). On the other hand, the selective NK 2 receptor antagonist SR48968, which blocks NKA-related central effects in rodent models Santucci et al, 1993), increases the response of both A10 and A9 cells (Minabe and Ashby, 1997). Blockade of NK 3 receptors was therefore also studied for its ability to alter the effects of SR142948 in the A10 area, as well as those, exemplified in A9, of SR144190, a structural analog of SR48968 with higher activity in brain NK 2 receptor-related models (Emonds-Alt et al, 1997).…”

Acute and repeated administration of the selective 5‐HT2A receptor antagonist M100907 significantly alters the activity of midbrain dopamine neurons: An in vivo electrophysiological study

“…Consequently, (ϩ)-apomorphine could interact with D 2 /D 3 autoreceptors, which could subsequently inactivate spontaneously active DA cells that were not inactivated by chronic M100907 administration. This hypothesis is partially supported by studies showing that the decrease in the number of midbrain DA neurons produced by chronic administration of compounds, which are not DA receptor antagonists, such as the 5-HT 3 antagonists LY 277359, BRL 46470A, MDL73, 147EF, and granisetron (Ashby et al, 1994;Minabe et al, 1991aMinabe et al, , b, 1992Rasmussen et al, 1991a;Sorensen et al, 1990), the NK 2 receptor antagonist SR48968 (Minabe et al, 1997), CP96,345, a selective NK 1 receptor antagonist (Minabe et al, 1996), and the CCK B antagonist LY 262691 (Rasmussen et al, 1991b) is not reversed by the systemic administration of (ϩ)-apomorphine. However, in order to determine if M100907 produces depolarization block, one must conduct in vivo, intracellular electrophysiological studies to ascertain membrane potential.…”