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

2003 ◽  
Vol 89 (2) ◽  
pp. 728-737 ◽  
Author(s):  
Samuel B. Kombian ◽  
Kethireddy V. V. Ananthalakshmi ◽  
Subramanian S. Parvathy ◽  
Wandikayi C. Matowe
Keyword(s):  
Nucleus Accumbens ◽  
Substance P ◽  
Synaptic Transmission ◽  
Input Resistance ◽  
Nmda Receptor Antagonist ◽  
Excitatory Synaptic Transmission ◽  
Nk1 Receptor ◽  
Dose Dependent Decrease ◽  
Neurokinin 1 ◽  
Synaptic Effects

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, [Sar9, Met (O2)11]-SP and blocked by a NK1 receptor-selective antagonist, L 732 138. Both the SP- and [Sar9, Met (O2)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 (τ), 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.

scholarly journals Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

2009 ◽  
Vol 102 (2) ◽  
pp. 1139-1151 ◽  
Author(s):  
Liang Zhang ◽  
Donna L. Hammond
Keyword(s):  
Substance P ◽  
Synaptic Transmission ◽  
Cellular Level ◽  
Excitatory Synaptic Transmission ◽  
Rostral Ventromedial Medulla ◽  
Ventromedial Medulla ◽  
Inward Currents ◽  
Inflammatory Nociception ◽  
Neurokinin 1

It has been proposed, but not directly tested, that persistent inflammatory nociception enhances excitatory glutamatergic inputs to neurons in the rostral ventromedial medulla (RVM), altering the activity and function of these neurons. This study used whole cell patch-clamp methods to record evoked excitatory postsynaptic currents (eEPSCs) in spinally projecting RVM neurons from rats injected with saline or complete Freund's adjuvant (CFA) 3–4 days earlier and to examine the role of substance P (SP) in modulating excitatory synaptic transmission. Input-output relationships demonstrated that CFA treatment facilitated fast excitatory glutamatergic inputs to type 1 and type 2 nonserotonergic spinally projecting RVM neurons, but not to type 3 neurons. The facilitation in type 1 and 2 neurons was dependent on neurokinin-1 (NK1) and N-methyl-d-aspartate (NMDA) receptors and prevented by the PKC inhibitor GF109203X. In a subset of neurons from naïve rats, SP mimicked the effects of CFA and increased the potency and efficacy of glutamatergic synaptic transmission. The facilitation was prevented by 10 μM GF109203X, but not by 10 μM KN93, a CaMKII inhibitor. SP (0.3–3 μM) by itself produced concentration-dependent inward currents in most nonserotonergic, but not serotonergic neurons. The present study is the first demonstration, at the cellular level, that persistent inflammatory nociception leads to a sustained facilitation of fast excitatory glutamatergic inputs to RVM neurons by an NK1 and NMDA receptor-dependent mechanism that involves PKC. Further, it demonstrates that the facilitation is restricted to specific populations of RVM neurons that by inference may be pain facilitatory neurons.

Tachykinin-mediated modulation of sensory neurons, interneurons, and synaptic transmission in the lamprey spinal cord

1996 ◽  
Vol 76 (6) ◽  
pp. 4031-4039 ◽  
Author(s):  
D. Parker ◽  
S. Grillner
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Synaptic Transmission ◽  
Dorsal Root ◽  
Input Resistance ◽  
Dorsal Column ◽  
Giant Interneurons ◽  
Potassium Conductances ◽  
Dorsal Cells ◽  
Measurable Change

1. Tachykinin-like immunoreactivity is found in the dorsal roots, dorsal horn, and dorsal column of the lamprey. The effect of tachykinins on sensory processing was examined by recording intracellularly from primary sensory dorsal cells and second-order spinobulbar giant interneurons. Modulation of synaptic transmission was examined by making paired recordings from dorsal cells and giant interneurons, or by eliciting compound depolarizations in the giant interneurons by stimulating the dorsal root or dorsal column. 2. Bath application of tachykinins depolarized the dorsal cells. This effect was mimicked by stimulation of the dorsal root, suggesting that dorsal root afferents may be a source of endogenous tachykinin input to the spinal cord. The depolarization was reduced by removal of sodium or calcium from the Ringer, or when potassium conductances were blocked, and was not associated with a measurable change in input resistance. Dorsal root stimulation also caused a depolarization in the dorsal cells, and this effect and that of bath-applied substance P, was blocked by the tachykinin antagonist spantide. 3. The tachykinin substance P could reduce inward and outward rectification in the dorsal cells, the effect on outward rectification only being seen when potassium conductances were blocked by tetraethylammonium (TEA). 4. Substance P increased the excitability of the dorsal cells and giant interneurons, shown by the increased spiking in response to depolarizing current pulses. The increased excitability was blocked by the tachykinin antagonist spantide. 5. Substance P modulated the dorsal cell action potential, by increasing the spike duration and reducing the amplitude of the afterhyperpolarization. The spike amplitude was not consistently affected. 6. Stimulation of the dorsal column resulted in either depolarizing or hyperpolarizing potentials in the giant interneurons. The amplitude of the depolarization was increased by substance P, whereas the amplitude of the hyperpolarization was reduced. These effects occurred independently of a measurable change in postsynaptic input resistance, suggesting that the modulation occurred presynaptically. Paired recordings from dorsal cells and giant interneurons failed to reveal an effect of substance P on dorsal cell-evoked excitatory postsynaptic potentials (EPSPs), suggesting that the potentiation of the dorsal column-evoked depolarization was due to an effect on other axons in the dorsal column. Dorsal root-evoked potentials could also be increased in the presence of substance P, although this effect was less consistent than the effect on dorsal column stimulation. 7. These results suggest that tachykinins modulate sensory input to the lamprey spinal cord by increasing the excitability of primary afferents and second-order giant interneurons, and also by modulating synaptic transmission. Tachykinins may result in potentiation of local spinal reflexes and also modulation of descending reticulospinal inputs to the spinal locomotor network as a result of potentiation of spinobulbar inputs.

Effect of substance P on colonic mechanoreceptors, motility, and sympathetic neurons

1982 ◽  
Vol 243 (4) ◽  
pp. G259-G267 ◽  
Author(s):  
J. Krier ◽  
J. H. Szurszewski
Keyword(s):  
Substance P ◽  
Synaptic Transmission ◽  
Sympathetic Neurons ◽  
Colonic Motility ◽  
Input Resistance ◽  
Intraluminal Pressure ◽  
Excitatory Postsynaptic Potentials ◽  
Postsynaptic Potentials ◽  
Recording Techniques

Intracellular recording techniques were used in vitro to analyze the effects of substance P (SP) on synaptic transmission and electrical properties of sympathetic neurons in the inferior mesenteric ganglion (IMG) of the guinea pig. Intraluminal pressure-recording techniques were used to study the effects of SP on colonic motility. Superfusion of the ganglia with SP (10(-7) to 10(-6) M) depolarized the cell soma (2--12 mV) and increased cell input resistance (8--11 M omega). These effects converted synchronous excitatory postsynaptic potentials, in response to electrical stimulation of preganglionic nerves, and asynchronous excitatory postsynaptic potentials, in response to activation of colonic mechanoreceptors, to action potentials. Administration of SP to only the colon increased basal intraluminal pressure and the frequency and amplitude of phasic changes in intraluminal pressure. These changes increased mechanoreceptor synaptic input to neurons in the IMG. We conclude that SP facilitates synaptic transmission along noradrenergic pathways and increases colonic motility.

scholarly journals GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Oliver H Miller ◽  
Lingling Yang ◽  
Chih-Chieh Wang ◽  
Elizabeth A Hargroder ◽  
Yihui Zhang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Cortical Neurons ◽  
Low Dose ◽  
Nmda Receptor Antagonist ◽  
Excitatory Synaptic Transmission ◽  
Glutamatergic Neurotransmission ◽  
Treatment Resistant ◽  
Cellular Mechanisms ◽  
Ambient Glutamate

A single, low dose of the NMDA receptor antagonist ketamine produces rapid antidepressant actions in treatment-resistant depressed patients. Understanding the cellular mechanisms underlying this will lead to new therapies for treating major depression. NMDARs are heteromultimeric complexes formed through association of two GluN1 and two GluN2 subunits. We show that in vivo deletion of GluN2B, only from principal cortical neurons, mimics and occludes ketamine's actions on depression-like behavior and excitatory synaptic transmission. Furthermore, ketamine-induced increases in mTOR activation and synaptic protein synthesis were mimicked and occluded in 2BΔCtx mice. We show here that cortical GluN2B-containing NMDARs are uniquely activated by ambient glutamate to regulate levels of excitatory synaptic transmission. Together these data predict a novel cellular mechanism that explains ketamine's rapid antidepressant actions. In this model, basal glutamatergic neurotransmission sensed by cortical GluN2B-containing NMDARs regulates excitatory synaptic strength in PFC determining basal levels of depression-like behavior.

Substance P and cocaine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbensin vitro

2009 ◽  
Vol 29 (8) ◽  
pp. 1579-1587 ◽  
Author(s):  
Samuel B. Kombian ◽  
Kethireddy V. V. Ananthalakshmi ◽  
Jeffrey A. Zidichouski ◽  
Tarek M. Saleh
Keyword(s):  
Substance P ◽  
Synaptic Transmission ◽  
Excitatory Synaptic Transmission

NK1 receptors mediate neurogenic inflammatory increase in blood flow in rat airways

1993 ◽  
Vol 74 (5) ◽  
pp. 2462-2468 ◽  
Author(s):  
G. Piedimonte ◽  
J. I. Hoffman ◽  
W. K. Husseini ◽  
R. M. Snider ◽  
M. C. Desai ◽  
...  
Keyword(s):  
Blood Flow ◽  
Substance P ◽  
Neurogenic Inflammation ◽  
Sensory Nerves ◽  
Nk1 Receptor ◽  
Nk1 Receptors ◽  
Calcitonin Gene ◽  
Nk1 Receptor Antagonist ◽  
Selective Agonists ◽  
Neurokinin 1

We studied the effect of neurogenic inflammation on airway blood flow in anesthetized F-344 rats. Three successive determinations of blood flow were made by injecting radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. A selective agonist of the tachykinin receptor neurokinin 1 (NK1) increased airway blood flow, but NK2- and NK3-selective agonists were without effect. The natural agonist of NK1 receptors, substance P (1 micrograms/kg), increased airway blood flow, an effect that was abolished by the selective NK1 receptor antagonist CP-99,994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] but not by the (2R,3R)-enantiomer CP-100,263. Capsaicin (25 micrograms/kg), a drug that releases tachykinins and calcitonin gene-related peptide from sensory nerves, increased airway blood flow, and again this effect was abolished by CP-99,994. We also studied the effect of a selective inhibitor (captopril, 2.5 mg/kg) of the tachykinin-degrading enzyme kininase II [or angiotensin-converting enzyme (ACE)] on substance P-induced airway vasodilation. Captopril potentiated and prolonged the vasodilator effect of substance P. We conclude that neurogenic vasodilation in rat airways is due to the release of substance P, acts via NK1 receptors, and may be modulated by ACE.

scholarly journals Frequency-Dependent Release of Substance P Mediates Heterosynaptic Potentiation of Glutamatergic Synaptic Responses in the Rat Visual Thalamus

2010 ◽  
Vol 104 (3) ◽  
pp. 1758-1767 ◽  
Author(s):  
Sean P. Masterson ◽  
Jianli Li ◽  
Martha E. Bickford
Keyword(s):  
Substance P ◽  
High Frequency ◽  
Input Resistance ◽  
Resistance Change ◽  
Frequency Dependent ◽  
Dorsal Thalamus ◽  
Nk1 Receptors ◽  
Neurokinin 1 ◽  
Synaptic Responses

To investigate the interaction between peptides and glutamatergic synapses in the dorsal thalamus, we compared the frequency-dependent plasticity of excitatory postsynaptic potentials (EPSPs) in the tectorecipient zone of rodent lateral posterior nucleus (LPN), which is densely innervated by axons that contain the neuromodulator substance P (SP). Immunocytochemistry and confocal and electron microscopy revealed that neurokinin 1 (NK1) receptors are distributed on the dendrites of LPN cells, whereas SP is contained in axons originating from the superior colliculus (SC) and is reduced following SC lesions. In vitro whole cell recordings in parasagittal slices revealed that stimulation of the SC or optic radiations (corticothalamic axons [CTXs]) evoked LPN EPSPs that increased in amplitude with increasing stimulation intensity, suggesting convergence. With 0.5- to 10-Hz stimulus trains, CTX EPSP amplitudes displayed frequency-dependent facilitation, whereas SC EPSP amplitudes were unchanged. High-frequency SC stimulation (100 Hz for 0.5 s), or bath application of SP, resulted in gradual increases in both SC and CTX EPSP amplitudes to twofold or greater above baseline within 15–20 min poststimulation/application. This enhancement correlated with increases in input resistance and both the potentiation and resistance change were abolished in the presence of the NK1 antagonist L-703,606. These results indicate that SP is released when SC-LPN neurons fire at high frequency and SP acts postsynaptically via NK1 receptors to potentiate subsequent LPN responses to both cortical and tectal inputs. We suggest that the SP-mediated potentiation of synaptic responses may serve to amplify responses to threatening objects that move across large regions of the visual field.

scholarly journals Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder

2013 ◽  
Vol 16 (1) ◽  
pp. 1-11 ◽  
Author(s):  
David Michelson ◽  
Richard Hargreaves ◽  
Robert Alexander ◽  
Paulette Ceesay ◽  
Jarmo Hietala ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Anxiety Disorder ◽  
Substance P ◽  
Generalized Anxiety Disorder ◽  
Receptor Occupancy ◽  
Generalized Anxiety ◽  
Proof Of Concept ◽  
Nk1 Receptor ◽  
Neurokinin 1 ◽  
Nk1 Receptor Antagonists

Abstract Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1–6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) −1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = −2.7, 95% CI −5.0 to −0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5–6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder.

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