Gating and braking of short- and long-term modulatory effects by interactions between colocalized neuromodulators

Spinal locomotor networks in the lamprey are modulated by tachykinin neurop eptides. A single 10 min application of the tachykinin substance P evokes a short-term (similar to1 hr) presynaptic facilitation of glutamate release and the postsynaptic potentiation of NMDA responses. The latter effect indu ces a long-term (>24 hr) protein synthesis-dependent increase in the freque ncy of network activity. Tachykinins are contained in a ventromedial spinal plexus into which the medial dendrites of network neurons project. Neurons in this plexus also contain colocalized dopamine and 5-HT. Here, dynamic p lasticity evoked by modulator interactions has been examined by investigati ng the effects of 5-HT and dopamine on specific cellular, synaptic, and net work effects of substance P. Preapplied 5-HT blocked the substance P-mediated increase in the network bu rst frequency and the potentiation of NMDA-evoked cellular responses that u nderlies its induction. 5-HT also blocked the presynaptic facilitation of g lutamatergic synaptic transmission by substance P. The presynaptic, but not postsynaptic, effect of 5-HT was reduced by the protein phosphatase 2B inh ibitor cypermethrin. Dopamine did not directly modulate the effects of substance P. However, it reduced the presynaptic interactive effect of 5-HT and thus gated the presy naptic potentiation of glutamatergic inputs by substance P. However, the su bstance P-mediated potentiation of NMDA responses was not gated by dopamine , and thus the long-term network modulation was not induced. Neuromodulator effects and their interactions can thus be modulated. By sel ecting components from the modulatory repertoire of substance P, these inte ractions evoke dynamic changes in short- and long-term synaptic and network plasticity.