Blockade of transmission at NMDA receptors facilitates the electrical and synthetic activity of ascending serotoninergic neurones.
This study examined the influence of N-methyl-D-aspartate (NMDA) receptors upon the activity of serotoninergic neurones projecting from the rat dorsal raphe nucleus (DRN) to the striatum of rats. The channel blocker (+)-MK 801 (0.04-0.63 mg/kg, s.c.) augmented striatal accumulation of the serotonin (5-HT) precursor, 5-hydroxytryptophan (5-HTP), in rats treated with the inhibitor of decarboxylase, NSD 1015: the maximal effect of (+)-MK 801 was 164% relative to vehicle values (= 100%). In analogy, (+)-MK 801 (0.01-0.5 mg/kg, i.v.) increased the firing rate of DRN neurones with a maximal effect of 204%. This action was stereospecific in that (-)-MK 801, which shows lower affinity at NMDA receptors, enhanced firing only at higher doses. The selective, competitive antagonist at the NMDA recognition site, CPP (0.5-8.0 mg/kg, i.v.), also facilitated the firing rate of DRN neurones, though with a maximal effect (137%) less than that of (+)-MK 801. Further, CPP (40.0 mg/kg, s.c.) did not significantly modify striatal 5-HT synthesis. While NMDA did not significantly modify DRN firing alone, it abolished the facilitatory action of CPP, consistent with a competitive interaction at the NMDA recognition site. In conclusion, blockade of NMDA receptors specifically facilitates the activity of ascending serotoninergic neurones.
Lejeune
F
F
Department of Psychopharmacology, Centre de Recherches de Croissy, Paris, France.
Gobert
A
A
Rivet
J M
JM
Millan
M J
MJ
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004594:Electrophysiology; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D006834:Hydrazines; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012701:Serotonin; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C004297:3-hydroxybenzylhydrazine; D006916:5-Hydroxytryptophan