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. 2009 Oct 26:3:58.
doi: 10.3389/neuro.23.002.2009. eCollection 2009.

Neurokinin-1 receptor activation in globus pallidus

Lei Chen  1 , Qiao-Ling Cui, Wing-Ho Yung
Affiliations

Neurokinin-1 receptor activation in globus pallidus

Lei Chen et al. Front Neurosci. .

Abstract

The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O2)11] substance P (SM-SP) at 1 muM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson's disease.

Keywords: globus pallidus; neurokinin-1 receptor; substance P.

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Figures

Figure 1
Figure 1
Effects of SM-SP on globus pallidus neurons. (A) Application of 1 μM SM-SP increased spontaneous firing rate of globus pallidus neuron. (B) In the presence of 0.5 μM TTX, 1 μM SM-SP depolarized globus pallidus neuron. (C) Inward current induced by 1 μM SM-SP in the presence of TTX under voltage-clamp recordings. (D) The presence of neurokinin-1 receptor antagonist, SR140333B, blocked SM-SP-induced depolarization.
Figure 2
Figure 2
Dose-dependent effects of SM-SP. The magnitude of membrane depolarization of globus pallidus neurons was dependent of the concentration of SM-SP. n indicates the number of cells studied. Only one dose of SM-SP was tested on one cell.
Figure 3
Figure 3
Inhibition of potassium conductance in SM-SP-induced depolarization. (A) Depolarization induced by 1 μM SM-SP was associated with an increase in input resistance. Voltage deflections were responses to periodic current injections of 100 pA for 100 ms at 0.5 Hz. (B) SM-SP-induced inward current was blocked by potassium channel blockers. (C) A typical current-voltage relationship revealed the decrease in membrane conductance induced by SM-SP with a reversal potential at −96 mV.
Figure 4
Figure 4
Enhancement of sIPSCs by SM-SP. (A) The uppermost trace showed that application of 1 μM SM-SP significantly increased the frequency but not the amplitude of sIPSCs recorded from a globus pallidus neuron. (B) The cumulative probability distributions of the inter-event intervals and amplitudes of the sIPSCs from the experiment shown in (A). Significant differences were found in the distributions of inter-event intervals. ***P < 0.001.
Figure 5
Figure 5
Transient presynaptic facilitation of GABA release by 1 μM SM-SP. Typical traces showing that 1 μM SM-SP induced a transient increase in the frequency of mIPSCs. a and b indicated the time from which the traces plotted on a fast time-base were taken.
Figure 6
Figure 6
Expression of substance P receptors in globus pallidus of rat aged 14 days. (A) Substance P receptors were moderately expressed by rat globus pallidus neurons. (B) High-magnification photomicrograph shows that substance P receptor immunoreactive neurons were either multipolar or fusiform in shape, and that immunoreactivity was observed predominately along the membrane of both the soma (arrows) and dendrites (arrowheads) of rat globus pallidus neurons. Scale bars: 100 μm (A); 25 μm (B).
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