The NMDA positive modulator D-cycloserine potentiates the neuroleptic activity of D1 and D2 dopamine receptor blockers in the rat.

According to the view that N-methyl-D-aspartate (NMDA) agonists could be seen as putative therapeutic agents in schizophrenia, the present study was aimed at investigating whether the NMDA positive modulator D-cycloserine (DCS) could show neuroleptic activity. When given alone, DCS (1.5, 3, 6, 12 mg/kg) failed to affect the stereotyped behavior induced by 0.5 mg/kg SC apomorphine, a test routinely used to detect neuroleptic activity. Nevertheless, the administration of different doses of DCS (1.5, 3, 6 mg/kg) in combination with the D1 dopamine receptor blocker SCH 23390 or the D2 antagonist YM 09151-2, both given in doses which by themselves were ineffective in blocking apomorphine elicited behavior, induced a dose- dependent neuroleptic effect. Furthermore the positive NMDA modulator allowed (-)-sulpiride, which given alone never antagonized the apomorphine-induced stereotypy, to exhibit a full neuroleptic activity. The lower dose of DCS effective in potentiating antipsychotic effect of dopaminergic blockers also counteracted the behavioral response (hypermotility) induced by the NMDA negative modulator MK-801 (0.25 mg/kg), thus indicating the specificity of DCS effect. The results strengthen the view that drugs which increase NMDA receptor function could be a useful supplement in the therapy of psychotic disorders.