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Therapeutically relevant plasma concentrations of memantine produce significant L-N-methyl-D-aspartate receptor occupation and do not impair learning in rats
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Morè, Lorenzo, Gravius, Andreas, Nagel, Jens, Valastro, Barbara, Greco, Sergio and Danysz, Wojciech (2008) Therapeutically relevant plasma concentrations of memantine produce significant L-N-methyl-D-aspartate receptor occupation and do not impair learning in rats. Behavioural Pharmacology , 19 (7). pp. 724-734. doi:10.1097/FBP.0b013e3283123cad ISSN 1473-5849.
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Official URL: http://dx.doi.org/10.1097/FBP.0b013e3283123cad
Abstract
Subchronic treatment with memantine using osmotic pumps in male rats was used to verify whether plasma levels significantly blocking L-N-methyl-D-aspartate (NMDA) receptors (and shown previously to be neuroprotective) may impair learning. Treatment with 6.27, 12.5 and 18.8 mg/rat/day provided plasma levels of 1.03±0.08, 5.07±0.68 and 11.68±0.90 μmol/l. Only the lowest plasma level is therapeutically relevant and has previously been shown to be neuroprotective. Significant deficits in a passive avoidance task were only observed at the highest dose. Working memory, tested as spontaneous alternation in the cross maze, was impaired by the middle and highest doses, and these doses also induced hyperlocomotion. Microdialysis experiments with in-vivo recovery (27.4%) showed that infusion of memantine at 6.27 mg/rat/day (ca. 23 mg/kg/day) produced a concentration of 990±105 nmol/l in extracellular fluid. In-vivo NMDA receptor occupancy experiments demonstrated significant, dose-dependent receptor occupancy of 32.7 and 65.7% by memantine at the doses producing 1 and 5 μmol/l plasma levels, respectively. Moreover, acute administration (2.5 mg/kg intraperitoneally) of memantine to mature female rats produced approximately two-fold higher plasma levels than in young male rats. In conclusion, a dose of memantine which produces a plasma level (1 μmol/l) within the therapeutic range, reported previously to be neuroprotective, leads to intracellular brain levels similar to the affinity of memantine for NMDA receptors (receptor binding, patch clamp). This has been also extended by the experiments showing that at this plasma concentration, memantine occupies ca. 30% NMDA receptors in the brain and produces no cognitive impairment.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | B Philosophy. Psychology. Religion > BF Psychology | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
| Library of Congress Subject Headings (LCSH): | Cognition -- Research -- Physiological aspects, Cognition -- Testing | ||||
| Journal or Publication Title: | Behavioural Pharmacology | ||||
| Publisher: | Lippincott Williams & Wilkins | ||||
| ISSN: | 1473-5849 | ||||
| Official Date: | 2008 | ||||
| Dates: |
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| Volume: | 19 | ||||
| Number: | 7 | ||||
| Page Range: | pp. 724-734 | ||||
| DOI: | 10.1097/FBP.0b013e3283123cad | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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