dizocilpine-maleate and 3-hydroxybenzylhydrazine

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.

Topics: 5-Hydroxytryptophan; Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Dizocilpine Maleate; Electrophysiology; Hydrazines; Male; Neurons; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Serotonin; Synaptic Transmission

Following intraperitoneal administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801), levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in mouse striatum and limbic forebrain. When dizocilpine was given to animals treated with NSD 1015, an inhibitor of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase and monoamine oxidase, there was an increase in levels of DOPA and 3-methoxytyramine (3-MT). These findings suggest that dizocilpine stimulates DA synthesis and release in mouse brain. Following dizocilpine treatment a clear-cut increase in spontaneous locomotor activity was observed, probably partly due to enhanced dopaminergic tone. The competitive NMDA antagonist D-CPPene produced locomotor stimulation as well, but in contrast to following dizocilpine treatment levels of 3-MT decreased. Thus the stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems. However, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminergic system plays a permissive role in this context.

Topics: Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Brain Chemistry; Dizocilpine Maleate; Dopamine; Hydrazines; Male; Mice; Motor Activity; N-Methylaspartate; Organophosphorus Compounds; Piperazines