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Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats


Year of Publication:
Contact PI Name:
Carol A. Barnes
Contact PI Affiliation:
Arizona Research Laboratories Division of Neural Systems, Memory and Aging and Departments of Psychology and Neurology, University of Arizona, Tucson, Arizona, USA
Wojciech Danysz, Chris Parsons
Primary Reference (PubMED ID):
Funding Source:
National Institute of Mental Health (NIMH)
Study Goal and Principal Findings:

The overall purpose of this study was to investigate the effects of chronic treatment, with therapeutically relevant doses, of memantine on two forms of synaptic plasticity in the rat hippocampal formation in vivo: first, on the induction of long-term potentiation (LTP) in a region of hippocampus rich in NMDA receptors (i.e. the fascia dentata), and second, on the behavior-induced form of plasticity that we have called short-term exploratory modulation (STEM).  Data showed that semichronic treatment of rats with memantine at 30 mg/kg/day p.0. resulted in peak serum levels of 5 uM 5 h after administration, and is likely to have resulted in peak CSF levels of -2.5 uM.  The average serum concentration over 24 h of 2.5 pM was 4-5 times higher than that measured in the serum of demented patients under semi-steady-state memantine therapy. In addition, chronic treatment of adult male F-344 rats (9-1 2 months old) with therapeutically relevant doses of memantine (30 mg/kg/day in chow for >8 weeks) increased the maintenance of long-term potentiation of field excitatory postsynaptic potentials from perforant path-granule cell hippocampal synapses. In contrast, there was no effect of memantine on exploratory behavior or the amount of STEM observed. These studies provided the first electrophysiological evidence that memantine can increase the durability of synaptic plasticity and provided preclinical confirmation of the cognitive improvement seen with memantine in the treatment of demented patients.


Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
NMDA Receptor

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Fischer 344
Model Type:
Strain/Genetic Background:
Not Applicable

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Long Term Potentiation (LTP)
Short Term Exploratory Modulation (STEM)
Drug Concentration-Serum
Drug Concentration-Brain