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The lateral posterior nucleus (LP) receives inputs from both neocortex and superior colliculus (SC), and is involved with integration and processing of higher-level visual information. Relay neurons in LP contain tachykinin receptors and are innervated by substance P (SP)-containing SC neurons and by layer V neurons of the visual cortex. In this study, we investigated the actions of SP on LP relay neurons using whole-cell recording techniques. SP produced a graded depolarizing response in LP neurons along the rostro-caudal extent of the lateral subdivision of LP nuclei (LPl), with a significantly larger response in rostral LPl neurons compared with caudal LPl neurons. In rostral LPl, SP (5–2000 nm) depolarized nearly all relay neurons tested (> 98%) in a concentration-dependent manner. Voltage-clamp experiments revealed that SP produced an inward current associated with a decreased conductance. The inward current was mediated primarily by neurokinin receptor (NK)1 tachykinin receptors, although significantly smaller inward currents were produced by specific NK2 and NK3 receptor agonists. The selective NK1 receptor antagonist RP67580 attenuated the SP-mediated response by 71.5% and was significantly larger than the attenuation of the SP response obtained by NK2 and NK3 receptor antagonists, GR159897 and SB222200, respectively. The SP-mediated response showed voltage characteristics consistent with a K+ conductance, and was attenuated by Cs+, a K+ channel blocker. Our data suggest that SP may modulate visual information that is being processed and integrated in the LPl with inputs from collicular sources. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that substance P (SP) neurokinin-1 (NK1) receptors are involved in stress and emotional responses, representing a potential target for the treatment of anxiety and depression in humans. Given the important role of the amygdaloid complex in the regulation of emotional behavior, we examined the mRNA levels of preprotachykinin A[PPT-A, a precursor of both SP and neurokinin A (NKA)] and3H-SP binding sites in the amygdala of patients affected by bipolar disorder, major depression or schizophrenia as compared with matched control individuals. By means ofin situhybridization, a significant reduction of PPT-A mRNA expression levels was detected in the three diagnostic groups, mainly in the basal, lateral and accessory basal amygdaloid nuclei, but not in the temporal cortical area proximal to the amygdala. Receptor autoradiography performed on adjacent sections showed no change in3H-SP binding sites as compared with controls. No significant correlation was found between levels of PPT-A mRNA expression or binding sites and subject age, gender, hemisphere side, cause of death or history of substance misuse (marijuana, alcohol, cocaine/amphetamine). An inverse relationship between PPT-A mRNA expression levels and lifetime antipsychotic treatment (Fluphenazine) in the schizophrenic and bipolar disorder groups was found. Post-mortem delay was also negatively correlated with NK1 binding sites. The results confirm an involvement of the tachykinins in psychiatric disorders, suggesting there is a generalized impairment of the SP system in the amygdala in mood disorders and schizophrenia rather than this being a disease-related phenomenon. [ABSTRACT FROM AUTHOR]

Abstract Using sharp microelectrode recording from CA1 pyramidal neurons of the adult mouse hippocampal slice preparation, we studied the modulatory action of the selective neurokinin 1 (NK1) receptor agonist substance P methyl ester (SPME), a peptidase-resistant analogue of the peptide substance P (SP), on cholinergic responses. While SPME (0.1–1 μm) had only slight effects on membrane potential and input resistance of CA1 neurons, it largely and reversibly enhanced the membrane depolarization and oscillatory activity induced by the cholinergic agonist carbachol (CCh; 0.1–100 μm). This effect of SPME was prevented by the selective NK1 receptor antagonist SR 140333 (4 μm). In about half of the tested neurons the action of SPME was preserved in tetrodotoxin (TTX) solution, suggesting that it partly occurred at the level of pyramidal cells. Cholinergic slow excitatory postsynaptic potentials (sEPSPs) were reversibly enhanced by SPME which increased their amplitude and prolonged any associated bursting activity. This action was also blocked by SR 140333. The present results suggest that SPME largely enhances cholinergic activity in the mouse hippocampus, an effect which can help to explain, in this brain area, the recently reported facilitation of seizures by SP. [ABSTRACT FROM AUTHOR]

Abstract Bath application of the tachykinin neuropeptide substance P (1 μm) for 10 min causes long-lasting (> 24 h) modulation of the frequency and regularity of NMDA-evoked locomotor bursts in the lamprey. The change in burst frequency has an induction phase (< 2 h), which depends on the potentiation of NMDA responses and an increase in intracellular calcium levels, and a maintenance phase (> 2 h), that is blocked by translational protein synthesis inhibitors. Here, the maintenance phase has been examined further. Unlike translation inhibitors, the transcription inhibitors actinomycin D and 5,6-dichlorobenzimidazole riboside (DRB) failed to reverse the change in burst frequency 2–3 h after substance P application, suggesting that the protein synthesized at this time does not require de novo RNA synthesis. Transcription inhibitors, however, reversed the change in burst frequency 15–24 h after substance P application, as did brefeldin A, which disrupts the Golgi complex and thus interferes with the post-translational transport of proteins. The change in burst regularity was unaffected by transcription or translation inhibitors, but was partially reversed by protein kinase A inhibitors applied 2.5–8 h after substance P. The glycoprotein synthesis inhibitor 2-deoxygalactose did not affect the changes in burst frequency or burst regularity. These results suggest that there are two phases to the maintenance of the change in burst frequency: an intermediate protein-, but not RNA-, synthesis-dependent phase, and a final RNA-synthesis-dependent phase. The change in burst regularity is protein-synthesis-independent, but may depend on activation of protein kinase A for at least 8 h after substance P application. [ABSTRACT FROM AUTHOR]

AbstractThe modulatory action of substance P on synaptic transmission of CA1 neurons was studied using intra‐ or extracellular recording from the mouse hippocampal slice preparation. Bath‐applied substance P (2–4 μm) or the selective NK1 receptor agonist substance P methylester (SPME, 10 nm–5 μm) depressed field potentials (recorded from stratum pyramidale) evoked by focal stimulation of Schaffer collaterals. This effect was apparently mediated via NK1 receptors since it was completely blocked by the selective NK1 antagonist SR 140333. The field potential depression by SPME was significantly reduced in the presence of bicuculline. Intracellular recording from CA1 pyramidal neurons showed that evoked excitatory postsynaptic potentials (EPSPs) and evoked inhibitory postsynaptic potentials (IPSPs) were similarly depressed by SPME, which at the same time increased the frequency of spontaneous GABAergic events and reduced that of spontaneous glutamatergic events. The effects of SPME on spontaneous and evoked IPSPs were prevented by the ionotropic glutamate receptor blocker kynurenic acid. In tetrodotoxin (TTX) solution, no change in either the frequency of spontaneous GABAergic and glutamatergic events or in the amplitude of responses of pyramidal neurons to 4 μm α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) or 10 μm N‐methyl‐d‐aspartate (NMDA) was observed. On the same cells, SPME produced minimal changes in passive membrane properties unable to account for the main effects on synaptic transmission. The present data indicate that SPME exerted its action on CA1 pyramidal neurons via a complex network mechanism, which is hypothesized to involve facilitation of a subset of GABAergic neurons with widely distributed connections to excitatory and inhibitory cells in the CA1 area. [ABSTRACT FROM AUTHOR]

Abstract Substance P exerts its various biochemical effects mainly via interactions through neurokinin-1 receptors (NK1). Recently, the NK1 receptor has attracted considerable interest for its possible role in a variety of psychiatric disorders including depression and anxiety. However, little is known regarding the anatomical distribution of NK1 in the human central nervous system (CNS). Riboprobe in situ hybridization, quantitative PCR and in vitro autoradiography were performed. Highest NK1 mRNA levels were localized in the locus coeruleus and ventral striatum, while moderate hybridization signals were observed in the cerebral cortex (most abundant in the visual cortex), hippocampus and different amygdaloid nuclei. Very low levels of the NK1 mRNA were detected in the cerebellum and thalamus. In view of the existence of a long and short isoform of the NK1 receptor, it was of interest to assess whether there was a differential distribution of the two splice variants in the human CNS and peripheral tissues. A quantitative TaqMan PCR analysis showed that the long NK1 isoform was the most prevalent throughout the human brain, while in peripheral tissues the truncated form was the most represented. 3 H-Substance P autoradiography revealed a good correlation between receptor binding sites and NK1 mRNA expression throughout the brain, with the highest levels of binding in the locus coeruleus. These results provide the anatomical evidence that the NK1 receptors have a strong association with neuronal systems relevant to mood regulation and stress in the human brain, but do not suggest a region-specific role of the two isoforms in the CNS. [ABSTRACT FROM AUTHOR]