Voltage‐dependent block of NMDA responses by 5‐HT agonists in ventral spinal cord neurones

Abstract

1 Modulation by 5-hydroxytryptamine receptor agonists of the NMDA responses of ventral spinal cord neurones was studied by use of the whole-cell patch-clamp technique. 2 In a Mg-free solution containing tetrodotoxin and glycine, 5-hydroxytryptamine (5-HT, 10-100 ,UM) reduced the NMDA response, the block increasing with hyperpolarization. Kainate responses were little affected. 3 Some classical agonists of 5-HT receptors induced similar blocking effects. At 10 IM, both a selective agonist of 5-HT2 receptors, (±)-2,5-dimethoxy-4 iodo amphetamine (DOI), and a selective agonist of some 5-HTI receptors, (±)-8-hydroxy-2(n-dipropyl amino) tetralin (8-OH-DPAT), induced pronounced blocking effects, of 48% and 33% respectively at -100 mV, whereas another 5-HT1 agonist, 5-carboxamidotryptamine (5-CT) was ineffective. At 100 gIM, 5-methoxytryptamine (5-MeOT) induced a complete block of the NMDA responses recorded at -100 mV. The order of potency was: 5-MeOT DOI> 8-OH-DPAT > 5-HT > 5-CT. 4 Neither spiperone nor ketanserin (1 riM) prevented the blocking effect of 5-HT or DOI. 5 Prolonged preincubations with 5-HT did not block the response if NMDA was applied without 5-HT. When 5-HT agonists were applied both by preincubation and with NMDA, the degree of block increased during the NMDA application.6 Lowering the NMDA concentration (from 100 to 20 giM) slightly decreased the blocking effect of 5-MeOT. 7 External Mg2+ ions (1 mM) also reduced the blocking effects of 5-HT and 5-MeOT. 8 The blocking effects described appear to be independent of classical 5-HT receptors. Their voltagedependence suggests a mechanism of open channel block consistent with all the results obtained.

The ascending median raphe projections are mainly glutamatergic in the mouse forebrain

“…However, 5HT 3 -like receptors were also shown to directly inhibit NMDA receptor-dependent responses in pyramidal cells of the mPFC in a longer timescale (Liang et al 1998). In addition, 5HT was shown to directly block NMDA responses in rat ventral spinal cord cultures (Chesnoy-Marchais and Barthe 1996). Thus, upon strong MRR activation, serotonin could exert a direct temporary negative feedback of excitation, if these synapses became over-activated, protecting the cell from excitotoxicity.…”

Voltage‐dependent inhibition of recombinant NMDA receptor‐mediated currents by 5‐hydroxytryptamine

“…The binding site for 5‐HT is located deep within the membrane electric field and competitive interactions of 5‐HT and 5‐MeOT with Mg 2+ suggest that the indolealkylamine and Mg 2+ ‐binding sites are in close proximity. Our data support the view that inhibition of NMDA receptors by 5‐HT may contribute to CNS synaptic physiology, particularly in the spinal cord and hippocampus, which are well known to receive serotogenic innervation, with potent effects on somatosensory transmission, motorneuron activity and LTP (Murase et al ., 1990; Staubli & Otaky, 1994; Chesnoy‐Marchais & Barthe, 1996; Siegel et al ., 1998). 5‐HT and related compounds may modify the action of these pathways in a Mg 2+ ‐dependent manner and thus may provide a basis for drug treatment of pain, seizures and glutamate‐mediated excitoxic neurodegeneration.…”

“…This neuroanatomical organization, as well as the finding that 5‐HT and glutamate are co‐released by single raphe neurons (Johnson, 1994), raised the possibility of a direct interaction of 5‐HT and NMDA receptors. Indeed, the modulation of NMDA‐mediated responses by 5‐HT has been described previously (Blank et al ., 1996; Chesnoy‐Marchais & Barthe, 1996; MacLean & Schmidt, 2001). These effects appear to be either presynaptic, mediated by members of the 5‐HT receptor family (Wu et al ., 1991; Elliott & Wallis, 1992), or postsynaptic, possibly via a direct effect on the NMDA receptor.…”

“…These effects appear to be either presynaptic, mediated by members of the 5‐HT receptor family (Wu et al ., 1991; Elliott & Wallis, 1992), or postsynaptic, possibly via a direct effect on the NMDA receptor. In the spinal cord, the interplay between 5‐HT and NMDA receptors has been suggested to underlie the control and generation of motor rhythm activity (Chesnoy‐Marchais & Barthe, 1996; MacLean & Schmidt, 2001). Furthermore, 5‐HT and related indolealkylamines were found to inhibit LTP via NMDA receptor‐mediated responses in hippocampal slices (Staubli & Otaky, 1994) and modulate somatosensory synaptic transmission (Murase et al ., 1990).…”

Serotonergic Modulation of Spinal Sensory Circuits

“…Several pieces of evidence suggest that modulation of responses to NMDA by serotonin could depend on direct or indirect (receptor mediated) actions of 5-HT on the magnesium block of the NMDA receptor [42,43].…”