Modulatory effects and interactions of substance P, dopamine and 5-HT in a neuronal network

Abstract: The spinal neuronal network that generates the locomotor rhythm in lamprey contains excitatory and inhibitory interneurons, reticulospinal inputs from the brainstem, and motor neurons. In this thesis, I have studied how the spinal locomotor network cart be modulated by a tachykinin, dopamine and 5- HT that are co-localized in midline neurons situated below the central canal. ' The midline neurons are rhythmically active during NMDA-induced fictive locomotion and are thus an integral part of the spinal locomotor network. ' Substance P alone induces synaptically-driven membrane potential oscillations in motor neurons. It also depolarizes the membrane potential by the reduction of a potassium conductance, and potentiates the Ca2+ current in motor neurons, while it reduces the Ca2+ current in inhibitory interneurons. ' Endogenously released dopamine has a biphasic effect on fictive locomotion, as does exogenously applied dopamine. The effect is manifested as an increase in the frequency at low dopamine concentrations followed by a decrease in frequency with higher dopamine concentrations. Endogenous and exogenous dopamine reduces the amplitude of reticulospinal glutamatergic EPSPs, via an action of D2-receptors on Ntype Ca2+ channels. ' 5-HT inhibits the N-type Ca 2+_channels via a 5-HT1A receptor coupled to a pertussis toxin sensitive G-protein. This will in turn reduce the Ca2+-dependent sAHP in spinal neurons. ' The interactions between these three modulators were investigated. 5-HT, but not dopamine, counteracted the long-lasting potentiation (>24 h) of the frequency of fictive locomotion caused by a short lasting application of substance P (10 min) that is dependent on potentiation of postsynaptic NMDA-responses. Substance P also presynaptically potentiates glutamate release, which is blocked by 5-HT, but not by dopamine. Dopamine, on the other hand, reduces the inhibitory effect of 5-HT on the substance P-induced glutamate release. Dopamine thus presynaptically promotes the effect of substance P. 5-HT can be considered a "metamodulator" of substance P, and dopamine as a metamodulator of 5-HT and a "tertiary modulator" of the 5HT/substance P interaction.