Dopamine release in the prefrontal cortex in response to memantine following sub-chronic NMDA receptor blockade with memantine: a microdialysis studyin rats

Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist whic h blocks the NMDA receptor with moderate-affinity in a use- and voltage dep endent manner. In clinical practice it is used chronically in the treatment of dementia and does not induce psychotomimetic effects as, high affinity, uncompetitive antagonists. Thus, it was of interest to determine dopamine (DA) and metabolite (DOPAC - dihydroxyphenylacetic acid and HVA - homovanil lic acid) concentrations in the prefrontal cortex (PFC) in response to 14 d ays administration of memantine (20 mg/kg/day). It was previously determine d that in rats this treatment induces sensitization to the locomotor effect and tolerance to the learning impairing properties of high doses of memant ine. Acute administration of memantine (20 mg/kg, ip) did not affect dopami ne levels in the PFC. It did however increase DA metabolite (DOPAC and HVA) concentrations. Administration of memantine (20 mg/kg/day) for 14 days bef ore the acute challenge only slightly changed memantine's effect on PFC neu rochemistry even though pharmacokinetic tolerance was observed. When memant ine was administered to the sham group, which had been repeatedly treated w ith Hypnorm (including neuroleptic), an increase in PFC dopamine and metabo lite content was seen. In accordance with the fact that memantine does not possess psychotomimetic activity at therapeutically relevant doses, these e xperiments showed that it does not affect the prefrontal cortex dopamine le vels.