Substance P Depresses Excitatory Synaptic Transmission in the Nucleus Accumbens Through Dopaminergic and Purinergic Mechanisms

Abstract

Substance P (SP) is an undecapeptide that is co-localized with conventional transmitters in the nucleus accumbens (NAc). Its neurochemical and behavioral effects resemble those of cocaine and amphetamine. How SP accomplishes these effects is not known, partly because its cellular and synaptic effects are not well characterized. Using whole cell and nystatin-perforated patch recording in rat forebrain slices, we show here that SP, an excitatory neuropeptide, depresses evoked excitatory postsynaptic currents (EPSCs) and potentials (EPSPs) in NAc through intermediate neuromodulators. SP caused a partially reversible, dose-dependent decrease in evoked EPSCs. This effect was mimicked by a neurokinin-1 (NK1) receptor-selective agonist, [Sar(9), Met (O(2))(11)]-SP and blocked by a NK1 receptor-selective antagonist, L 732 138. Both the SP- and [Sar(9), Met (O(2))(11)]-SP-induced synaptic depressions were accompanied by increases in paired pulse ratio (PPR), effects that were also blocked by L 732 138. In contrast to its effect on PPR, SP did not produce significant changes in the holding current, input resistance, EPSC decay rate (tau), and steady-state I-V curves of the recorded cells. The SP-induced synaptic depressions were prevented by dopamine receptor blockade using SCH23390 and haloperidol, but not by sulpiride. In addition, the SP-induced synaptic depression was blocked by an adenosine A1 receptor blocker 8-cyclopentyltheophylline (8-CPT) but not the N-methyl-D-aspartate (NMDA) receptor antagonist D-APV. These data show that SP, by activating presynaptic NK1 receptors, depresses excitatory synaptic transmission indirectly by enhancing extracellular dopamine and adenosine levels. Since the cellular and synaptic effects of SP resemble those of cocaine and amphetamine, it may serve as an endogenous psychogenic peptide.

17β‐estradiol attenuates excitatory neurotransmission and enhances the excitability of rat parabrachial neurons in vitro

“…In this regard, 17β‐estradiol is not the only neuromodulator that causes excitatory synaptic inhibition while increasing excitability. Other neuromodulators such as cholecystokinin have been shown to depress excitatory synaptic transmission that is preceded by depolarization of neurons leading to increased action potential firing (Kombian et al,2003). As mentioned previously, 17β‐estradiol may influence postsynaptic membrane responsiveness to various electrical and chemical stimuli by modulating several structures or mechanisms including ion channels, receptors and receptor‐mediated intracellular signalling.…”

Lithium Chloride Regulation of the Substance P Encoding Preprotachykinin A, Tac1 Gene in Rat Hippocampal Primary Cells

“…Finally, the affect of LiCl in increasing PPTA may seem counterproductive to the role of lithium in treating affective disorders, in which an increase in an excitatory neuropeptide may not seem beneficial; however, SP is also known to modulate the monoaminergic neurotransmitter systems that act to decrease cell excitability and that are major therapeutic targets for bipolar disorder, depression and addition (Santarelli et al 2001;Kombian et al 2003;Guiard et al 2007;Haddjeri and Blier 2008). Thus, the end result of lithium-mediated increases in SP could be excitatory or inhibitory depending on the neural networks on which SP is acting.…”

Neurokinin-1 receptor activation in globus pallidus

“…Consistent with this idea, morphological studies indicated that lesion of the nigrostriatal pathway increased the expression of substance P immunoreactivity in numerous pallidal cell bodies (Martorana et al, 2003), which may reflect a compensatory mechanism. However, since other basal ganglia nuclei (including striatum, entopeduncular nucleus) also express substance P receptors (Arai and Emson, 1986; Jakab and Goldman-Rakic, 1996; Mounir and Parent, 2002; Chen et al, 2003), and show electrophysiological response to substance P (Aosaki and Kawaguchi, 1996; Galarraga et al, 1999; Kombian et al, 2003a,b), the therapeutic effects of substance P administration would depend on the interaction of its actions on these nuclei. Thus, more experiments and evidence are needed before we could fully understand the functions of substance P in the whole basal ganglia circuit in normal conditions and movement disorders.…”