The effect of the acute and chronic administration of CP 96,345, a selective neurokinin1 receptor antagonist, on midbrain dopamine neurons in the rat: A single unit, extracellular recording study

Abstract

In this study, we examined the effect of acute and chronic administration of the selective neurokinin1 receptor antagonist CP 96,345 on the basal activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA). This was accomplished using the technique of in vivo, extracellular single unit recording in anesthetized rats. The intravenous (i.v.) administration of CP 96,345 (0.01-1.28 mg/kg) did not significantly alter the firing rate of spontaneously active DA neurons in the SNC and VTA areas. The acute administration of 5 or 10 mg/kg, i.p., of CP 96,345 produced a significant decrease in the number of spontaneously active SNC and VTA dopamine cells compared to vehicle-treated rats. In contrast to its effect on the number of spontaneously active DA neurons, the administration of 5 mg/kg, i.p., of CP 96,345 did not significantly alter the basal firing pattern of either SNC or VTA DA neurons. The acute administration of CP 96,345 (10 mg/kg, i.p.) significantly potentiated the suppressant action of (+)-apomorphine on the basal firing rate of spontaneously active SNC and VTA DA cells. The chronic administration of CP 96,345 (5 or 10 mg/kg, i.p.) for 21 days also produced a significant decrease in the number of spontaneously active SNC and VTA DA cells compared to vehicle controls. This effect was not reversed by the systemic administration of (+)-apomorphine (50 micrograms/kg, i.v.), suggesting that the reduction in the number of spontaneously active DA cells produced by CP 96,345 is probably not the result of depolarization inactivation. Overall, our results indicate that the tonic activation of NK1 receptors by substance P may be necessary to maintain the spontaneous activity of a proportion of midbrain DA neurons.

Substance P excites globus pallidus neurons in vivo

“…Firstly, as mentioned above, substance P and its receptor are densely and widely distributed in the basal ganglia. Secondly, substance P can not only excite dopaminergic neurons in substantia nigra but also increase dopamine levels in the striatum under parkinsonian conditions (Arenas et al ., 1991; Humpel et al ., 1991; Overton et al ., 1992; Glowinski et al ., 1993; Minabe et al ., 1996; Nalivaiko et al ., 1997). In addition, the substance P system in globus pallidus exhibits pronounced variations under parkinsonian conditions, with substance P immunoreactivity increasing markedly while the expression of substance P receptor decreases significantly (Fernandez et al ., 1994; Martorana et al ., 2003).…”

“…In line with our hypothesis, the increased striatopallidal substance P immunoreactivity in Parkinson's disease may reflect a compensatory mechanism. However, morphological (Jakab et al ., 1996; Futami et al ., 1998; Chen et al ., 2001) and electrophysiological (Aosaki & Kawaguchi, 1996; Minabe et al ., 1996; Nalivaiko et al ., 1997; Galarraga et al ., 1999) studies have revealed the expression of substance P receptors in other basal ganglia nuclei, including striatum and substantia nigra. Therefore, the therapeutic effects of substance P in Parkinson's disease, if any, would depend on its mutual actions on these nuclei.…”

“…In the guinea‐pig substantia nigra, substance P evoked excitatory responses in both dopaminergic and nondopaminergic neurons (Nalivaiko et al ., 1997). The tonic activation of neurokinin‐1 receptors may be necessary to maintain the spontaneous activity of a proportion of midbrain dopaminergic neurons (Minabe et al ., 1996). In addition, substance P has also been involved in the release of neurotransmitters.…”

C/EBPβ couples dopamine signalling to substance P precursor gene expression in striatal neurones

“…However, a selective NK‐1 agonist increases the activity of VTA and SN cells (Overton et al . 1992), whereas a selective NK‐1 antagonist decreases it (Minabe et al . 1996).…”

“…In the striatum, DA can induce the expression of preprotachykinin‐A (PPT‐A) mRNA coding for SP, as has been shown in slice cultures (Campbell and Walker 2001). In addition, SP originating from the striatum can stimulate midbrain neurones to produce DA, as shown by the fact that the administration of a SP receptor antagonist can decrease the activity of VTA and SN neurones (Minabe et al . 1996).…”