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

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.

List of scientific papers

I. Svensson E, Grillner S, Parker D (2002). Synaptically evoked membrane potential oscillations induced by substance P in lamprey motor neurons. J Neurophysiol. 87(1): 113-21.
https://pubmed.ncbi.nlm.nih.gov/11784734

II. Svensson E, Grillner S, Parker D (2003). Substance P differentially modulates Ca2+-conductances in identified spinal neurons in lamprey. [Manuscript]

III. Svensson E, Wikstrom MA, Hill RH, Grillner S (2003). Endogenous and exogenous dopamine presynaptically inhibits glutamatergic reticulospinal transmission via an action of D2-receptors on N-type Ca2+ channels. Eur J Neurosci. 17(3): 447-54.
https://pubmed.ncbi.nlm.nih.gov/12581163

IV. Svensson E, Woolley J, Wikstrom MA, Grillner S (2003). Endogenous dopaminergic modulation of the lamprey spinal locomotor network. Brain Research.

V. Hill RH, Svensson E, Deweal J, Grillner S (2003). 5-HT inhibits N-type but not L-type Ca2+ channels via 5-HT1A receptors in lamprey spinal neurons. [Manuscript]

VI. Svensson E, Grillner S, Hill RH (2003). Modulator-containing midline neurons are rhythmically active during fivtive locomotion in the lamprey spinal cord. [Manuscript]

VII. Svensson E, Grillner S, Parker D (2001). Gating and braking of short- and long-term modulatory effects by interactions between colocalized neuromodulators. J Neurosci. 21(16): 5984-92.
https://pubmed.ncbi.nlm.nih.gov/11487621