D-Cycloserine, a positive modulator of NMDA receptors, inhibits serotonergic function

The administration of the N-methyl-D-aspartate (NMDA)-associated glycine recognition site agonist D-cycloserine (DCS) to rats inhibited the head shakes and the forepaw treading induced by the serotonin (5HT) precursor, L-5-hydroxy-tryptophan [(-)5HTP], as well as the forepaw treading and motility elicited by the selective 5HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The head shakes typically induced by the 5HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), were unaffected by DCS pretreatment. The results are consistent with reduced serotonergic transmission produced by NMDA activation, as suggested by other authors. Due to the important role played in the pathogenesis of schizophrenia by glutamate deficiency/serotonin activation, the results support the view that positive modulators of NMDA receptors, activating glutamate receptors and reducing serotonergic tone, might be useful in the alleviation of psychotic symptoms. However, because of its partial agonist properties at the glycine recognition site, D-cycloserine shows some effects that might make it unsuitable for clinical use.