Actions of Substance P on Rat Neostriatal NeuronsIn Vitro

Abstract

Actions of substance P (SP) on the neostriatal neurons in in vitro rat slice preparations were studied via whole-cell patch-clamp recording. Almost all large aspiny neurons (cholinergic cells) and half of the low-threshold spike (LTS) cells (somatostatin/ NOS-positive cells) showed depolarization or an inward shift of the holding currents in response to bath-applied SP in a dosedependent manner. In contrast, no responses were observed in fast-spiking (FS) cells (parvalbumin-positive cells) and medium spiny cells. Spike discharges followed by slow EPSPs/EPSCs were evoked by intrastriatal electrical stimulation in the large aspiny neurons. Pretreatment with [D-Arg 1 ,D-Pro 2 ,DTrp 7,9 ,Leu 11 ]-SP, an antagonist of the SP receptor, reversibly suppressed the induction of the slow EPSPs/EPSCs and unmasked slow IPSCs. The SP-induced inward current, although almost unchanged even after the blockade of I h channels and voltage-dependent Na ϩ , Ca 2ϩ , and K ϩ channels, changed its amplitude according to the Na ϩ concentration used in both the large aspiny neurons and LTS cells. Thus, the cation current could account for virtually all of the inward current at resting levels in both neurons. These results suggest that the firing of afferent neurons such as striatonigral medium spiny neurons, one of the possible sources of SP, would increase the firing probability of the two types of interneurons of the neostriatum by SP-receptor-mediated opening of tetrodotoxin-insensitive cation channels.Key words: striatum; basal ganglia; cholinergic; somatostatin; interneurons; substance P; tachykinin; neuropeptide; cations; slice preparations; patch clampThe undecapeptide substance P (SP), one of the neuropeptides known as tachykinins, is thought to play an important role as a neurotransmitter/neuromodulator in the CNS (Otsuka and Yoshioka, 1993). Evidence suggests that SP-containing fiber terminals in the striatum originate from thalamocaudate neurons in the center median-parafascicular complex (Sugimoto et al., 1984). There are two distinct populations of SP-containing medium-sized neurons in the striatum: the striatonigral medium-sized spiny projection neurons (Hong et al., 1977; Brownstein et al., 1983;Gerfen and Young, 1988) and the medium-sized aspiny interneurons with indented nuclei (Bolam et al., 1983). The striatum has also been shown to contain three G-protein-coupled neurokinin receptor subtypes: NK1, NK2, and NK3, among which SP preferentially binds to the first. The NK1 receptor is not expressed, however, in the medium spiny neurons but, rather, in the somatostatinergic and large cholinergic interneurons of the striatum of the rat (Gerfen, 1991;Kaneko et al., 1993), as well as nonhuman primates and human (Aubry et al., 1994;Parent et al., 1995). Both cell types have been reported to have synapses on their somatodendritic trees at the SP-containing terminals (Bolam and Izzo, 1988). However, the cholinergic neurons are especially important because, although they represent only a small population in the striatum, their wi...

Substance P-Mediated Modulation of Pacemaker Properties in the Mammalian Respiratory Network

“…Despite the fact that we cannot rule out that SP might induce a slow depolarization by interacting with other neurotransmitter systems or ionic pumps different from Na ϩ /K ϩ ATPase, all our experiments are consistent with the modulation of a low-voltageactivated, TTX-insensitive sodium current (Delmas et al, 1997): (1) this current is activated by various neurotransmitters including SP (Koyano et al, 1993;Aosaki and Kawaguchi, 1996); (2) the current is activated at resting potential (Delmas et al, 1996;Gola et al, 1998a,b); (3) because the slow depolarization persisted in the presence of SP, it does not undergo inactivation; (4) this current is TTX insensitive, yet sodium dependent (Wang and Aghajanian, 1987;Raggenbass and Dreifuss, 1992;Delmas et al, 1996); (5) this current is not blocked by TEA (10 -20 mM) (Alberi et al, 1993;Delmas et al, 1996); (6) characterizations of this current have also described the absence of an obvious change in input resistance (for review, see Delmas et al, 1997); and (7) lowering the physiological levels of calcium (2-25 mM) to 0.1 mM reversibly enhances the low-threshold sodium currents (Raggenbass and Dreifuss, 1992;Alberi et al, 1993;Delmas et al, 1996), which explains the observed dramatic depolarization of respiratory neurons caused by SP in low calcium (Fig. 6 A).…”

“…SP activates voltage-dependent Ca 2ϩ channels, voltage-dependent K ϩ conductances, Cl Ϫ currents, Ih currents, voltage-dependent Na ϩ channels, and nonselective cationic channels (Adams et al, 1983;Stanfield et al, 1985;Bley and Tsien, 1990;Shen and North, 1992;Bertrand and Galligan, 1994;Aosaki and Kawaguchi, 1996). In most neurons, SP depolarizes membrane potential by decreasing resting K ϩ conductances (Akasu et al, 1996;Lepre et al, 1996;Ptak et al, 2000;Yasuda et al, 2001).…”

Stimulation of Nitric Oxide–cGMP Pathway Excites Striatal Cholinergic Interneurons via Protein Kinase G Activation

“…We measured, therefore, the effects of 100 M hydroxylamine after 10 min preincubation of the slices in a solution containing 1 M -conotoxin GVIA, 20 M nifedipine, and 20 nM -agatoxin TK (to block, respectively, N-type, L-type, and P-type high voltage-activated calcium channels) and 300 M MCPG plus 10 M [D--Arg 1 ,D--Pro 2 ,D--Trp 7,9 ,Leu 11 ]-SP (to block mGluRs and substance P receptors, respectively). Noticeably, -conotoxin GVIA has already been found to block synaptic inputs to striatal cholinergic interneurons (Pisani et al, 2000), and MCPG and [D--Arg 1 ,D--Pro 2 ,D--Trp 7,9 ,Leu 11 ]-SP prevented in previous studies the depolarizing effects mediated by mGluR and substance P receptor activation on these cells (Aosaki and Kawaguchi, 1996;Takeshita et al, 1996). This pharmacological treatment, however, failed to affect the amplitude of the NOinduced membrane depolarization of striatal interneurons ( p Ͼ 0.05; n ϭ 5; Fig.…”

The Role of the Neuropeptide Substance P in the Pathogenesis of Parkinson’s Disease

“…Like in other areas of the brain, SP is released in the BG due to an elevation in Ca 2+ (Otsuka www.intechopen.com and Yoshioka, 1993). Once released, it may bind to NK 1 receptors located on striatal interneurons to increase the firing rate and depolarise membrane potentials causing the release of other BG neurotransmitters such as GABA, glutamate and acetylcholine (Aosaki and Kawaguchi, 1996, Bailey, et al, 2004, Kemel, et al, 2002. It is now known that NK 1 receptors are also located on 90% of DA neurons in the SNc (L-W. Chen, et al, 2004).…”