Effect of milacemide on extracellular and tissue concentrations of dopamine and 5‐hydroxytryptamine in rat frontal cortex

Abstract

1 Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidasetype B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5-hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2 Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400mgkg-1, i.p.), peaking at h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-' milacemide).3 Dialysate 5-HT was significantly increased only at 1.5 h after giving milacemide 400mg kg-'. Dialysate 5-hydroxyindoleacetic acid (5-HIAA) concentration was not affected. 4 Milacemide (400mg kg-1) at 1.5 h post-administration significantly increased frontal cortex tissue concentrations of dopamine and 5-HT; the percentage increase in dopamine being about four times that of 5-HT. Metabolite concentrations, including 5-HIAA, decreased. Changes in tissue and dialysate dopamine, DOPAC and HVA were approximately proportionate to each other. 5 The results are explicable in terms of an inhibition by milacemide of MAO-A.

Glycine Site Agonists of the NMDA Receptor: A Review

“…Milacemide also increases central serotonin and dopamine levels by inhibiting the action of MAO-A; and it is an inhibitor as well as a substrate for MAO-B (60). The actions of milacemide on MAO-A and -B suggest roles for serotonin and dopamine in the mechanism of its action (153,196). The drug also increases brain GABA and blocks bicuculline-induced convulsions, suggesting a role for GABA in its mechanism of action.…”

“…Milacemide effects on other neurotransmitter systems raises questions regarding the role of the glycine site as its primary site of action. Milacemide decreases CSF levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in a dosedependent manner (152,153). Milacemide also increases central serotonin and dopamine levels by inhibiting the action of MAO-A; and it is an inhibitor as well as a substrate for MAO-B (60).…”

The role of dopamine in epilepsy

“…The novel anticonvulsant zonisamide has been reported to increase the extracellular concentrations of dopamine and HVA in the hippocampus and striatum of freely moving rats (Kaneko et al, 1993;Okada et al, 1992). This dopamine-releasing property is shared by sodium valproate (Biggs et al, 19921, which elevated lumbar CSF levels of HVA in human volunteers (Zimmer et al, 1980), and by the putative anticonvulsant milacemide (Semba et al, 1992) and antagonists of the NMDA-type glutamate receptor (e.g., MK 801 [Whitton et al, 19921) but not by lamotrigine (Leach et al, 1991) or benzodiazepines (Doteuchi and Costa, 1973). We would add here that, although the dopaminergic innervation of the hippocampus is sparse (Scatton et al, 1980;Verney et al, 1985), the release of dopamine elicited in this region by some anticonvulsants can be considerably larger than in the striatum .…”

Characterisation of extracellular amino acids in striatum of freely moving rats by in vivo microdialysis

“…and placed in a stereotaxic flame (Narishige Instrument Laboratory, Tokyo, Japan). Concentric type dialysis probes were made as described previously (Hutson etal., 1985;Semba et al, 1992). The probe was 0.25ram in diameter and the effective perfusion length of the membrane (Hospal AN 9AF, France) was 4 ram.…”