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.1998 Jun 15;18(12):4800-13.
doi: 10.1523/JNEUROSCI.18-12-04800.1998.

Substance P modulates NMDA responses and causes long-term protein synthesis-dependent modulation of the lamprey locomotor network

Affiliations

Substance P modulates NMDA responses and causes long-term protein synthesis-dependent modulation of the lamprey locomotor network

D Parker et al. J Neurosci..

Abstract

Tachykinin immunoreactivity is found in a ventromedial spinal plexus in the lamprey. Neurons in this plexus project bilaterally and are thus in a position to modulate locomotor networks on both sides of the spinal cord. We have examined the effects of the tachykinin substance P on NMDA-evoked locomotor activity. Brief (10 min) application of tachykinin neuropeptides results in a prolonged concentration-dependent (>24 hr) modulation of locomotor activity, shown by the increased burst frequency and more regular burst activity. These effects are blocked by the tachykinin antagonist spantide II. There are at least two phases to the burst frequency modulation. An initial phase (approximately 2 hr) is associated with the protein kinase C-dependent potentiation of cellular responses to NMDA. The long-lasting phase (>2 hr) appears to be protein synthesis-dependent, with protein synthesis inhibitors causing the increased burst frequency to recover after washing for 2-3 hr. The modulation of the burst regularity is caused by a separate effect of tachykinins, because unlike the burst frequency modulation it does not require the modulation of NMDA receptors for its induction and is blocked by H8, an inhibitor of cAMP- and cGMP-dependent protein kinases. The effects of substance P were mimicked by the dopamine D2 receptor antagonist eticlopride. The effects of eticlopride were blocked by the tachykinin antagonist spantide II, suggesting that eticlopride may endogenously release tachykinins. Because locomotor activity in vitro corresponds to that during swimming in intact animals, we suggest that endogenously released tachykinins will result in prolonged modulation of locomotor behavior.

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Figures

Fig. 1.
Fig. 1.
A, Schematic diagram showing the location of potential tachykinin inputs to locomotor networks in the lamprey spinal cord.B, Bath application of substance P (1 μm) for 10 min increased the frequency of NMDA-induced ventral root bursts and increased the activity of an unidentified locomotor network neuron.C, The increase in burst frequency by substance P was concentration-dependent, as was the recovery on washing (10 nm,n = 8; 100 nm,n = 8; 1 μm,n = 63).D, The percentage substance P-mediated increase in the frequency of locomotor bursts was greatest when the initial frequency was low. Thebar indicates the time and duration of substance P application.
Fig. 2.
Fig. 2.
Substance P makes the locomotor activity more regular.A, This was shown quantitatively by a reduction of the coefficient of variation (CV; SD divided by mean cycle duration), the effects of substance P again being concentration-dependent (10 nm,n = 8; 100 nm,n = 8; 1 μm,n = 63).B, Traces showing ventral root activity on both sides of the spinal cord in control, and 1 hr after the application of 1 μm substance P for 10 min.C, The reduction of the CV with 10 nm and 100 nm substance P was greatest when the initial CV was high. With 1 μm substance P, however, the CV was reduced regardless of its initial value.D, The reduction of the CV was not caused by the increased frequency of locomotor bursts, as shown by the lack of a relationship between frequency and CV of NMDA-evoked locomotor bursts in different experiments (n = 48).
Fig. 3.
Fig. 3.
The effects of substance P on the burst frequency did not require the presence of substance P or network activity. This was shown by washing out NMDA after the control frequency (A) and CV (B) had been established. Substance P (1 μm) was applied 30 min after all locomotor activity had stopped. NMDA was then reapplied at different times after the washout of substance P had started.Numbers underneath the bars indicate the time (in minutes) when NMDA was reapplied after substance P washout. 0 means that substance P was applied in the presence of NMDA. Data from three cords are shown at each time.
Fig. 4.
Fig. 4.
A, The tachykinin antagonist spantide (4 μm) reduced the frequency of ventral root bursts and blocked the effects of 1 μm substance P. After wash-off of spantide for at least 1 hr, application of substance P resulted in an increase in the burst frequency.B, Bath application of the peptidase inhibitor phosphoramidon (2 μm) in the absence of exogenously applied substance P also increased the frequency of ventral root bursts, suggesting a potentiating effect of endogenous tachykinin levels. Data from three experiments are shown inA and from four experiments inB.
Fig. 5.
Fig. 5.
Substance P modulates non-NMDA-mediated locomotor activity.A, Bath application of 1 μmsubstance P increased the frequency and reduced the CV of locomotor bursts elicited by 10 μm kainate.Graphsshow the effect of 10 min application of 1 μm substance P on the frequency (B) and CV (C) of kainate-evoked ventral root bursts in control and in the presence of 100 μm AP-5.Bar above the graph indicates the onset and duration of substance P and AP-5 (100 μm) application. Data from four AP-5-incubated and four non-AP-5-incubated cords are shown inB andC.
Fig. 6.
Fig. 6.
Substance P potentiates cellular responses to NMDA. The effects of 1 μm substance P on responses to pressure-applied NMDA (1 mm) in an identified motor neuron (Ai, Aii) and a CC interneuron (Bi, Bii) are shown. NMDA was applied in the presence of 1.5 μmTTX. Thebottom trace on each graph shows the lack of effect of substance P on the input resistance of the neuron during the experiment. The effects of substance P in unidentified gray matter neurons persisted in the presence of bath-applied glycine (5 μm) (C) and in nominally magnesium-free Ringer’s solution (D).Graphs show representative data from a single experiment in each case.
Fig. 7.
Fig. 7.
The effects of substance P on cellular responses to NMDA are mediated by protein kinase C.Ai, Aii, Bath application of phorbol 12,13-dibutyrate (10 μm) potentiated the responses to pressure-applied NMDA in an unidentified gray matter neuron. This effect was reversed by the protein kinase C antagonist chelerythrine (10 μm).Bi, Bii, Chelerythrine (10 μm) also blocked the potentiation of NMDA responses elicited by bath application of 1 μmsubstance P.Bi, Data from four unidentified gray matter neurons showing the effects of substance P in control and in the presence of chelerythrine.
Fig. 8.
Fig. 8.
The role of protein kinases in the network potentiation. Bath application of the protein kinase C antagonist chelerythrine (10 μm) blocked the increase in the frequency of NMDA-evoked locomotor bursts (Ai) and the reduction of the CV (Aii). H8, an inhibitor of cAMP- and cGMP-dependent protein kinases, did not block the increased burst frequency (Bi), but it did block the reduction of the CV (Bii). Chelerythrine and H8 did not affect the frequency (Ci) or CV (Cii) of locomotor bursts when applied 3–4 hr after substance P.Ai, Aii,n = 6;Bi, Bii,n = 5;Ci, Cii, chelerythrine,n = 5; H8,n = 4.
Fig. 9.
Fig. 9.
Bath application of the intracellular calcium chelator EGTA-AM (20 μm for 2 hr) resulted in a smaller, reversible effect of substance P on the burst frequency and blocked the effect on the CV.Ai, Aii, Traces showing the effects of EGTA-AM and BAPTA-AM (20 μm for 2 hr) on locomotor activity. Effects of substance P on NMDA-evoked burst frequency (B) and CV (C) in cords incubated in EGTA-AM. Data from six EGTA-AM-treated and six non-EGTA-treated cords are shown.
Fig. 10.
Fig. 10.
Protein synthesis inhibitors block the long-term substance P-mediated potentiation of the burst frequency.Ai, Graph showing the effects of 1 μmsubstance P on NMDA-evoked burst frequency in control cords and in cords incubated in the protein synthesis inhibitor anisomycin (10 μm) for 1–4 hr before substance P application. Data from seven anisomycin-treated and seven nonanisomycin-treated cords are shown.Aii, Graph showing the effects of substance P on the CV in seven anisomycin-treated and seven nontreated cords.Traces show the effects of substance P on ventral root activity in a control (Bi) and an anisomycin-treated cord (Bii).
Fig. 11.
Fig. 11.
Bath application of the dopamine D2 receptor antagonist eticlopride (20 μm) increased the frequency of ventral root bursts.A, Sample traces of ventral root activity.B, The effects of 20 μmeticlopride did not recover after washing for 10 hr and were blocked by the tachykinin antagonist spantide II (4 μm).C, After wash-off of spantide, application of eticlopride again resulted in a prolonged increase in burst frequency.
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