Effects of memantine on synaptic transmission in the hippocampus in vitro

CA1 pyramidal cell response (population spike) in the hippocampal slice preparation was monitored after electrical stimulation of the Schaffer collaterals at CA2 in the presence of different concentrations of memantine (1-amino-3,5-dimethyladamantane, Akatinol Memantine, CAS 41100-52-1) currently being prescribed for the treatment of e.g. dementia. Memantine increased the amplitude of the population spike by 100% compared to the predrug level with an EC50 of approximately 8 mumol/l. Long-term potentiation induced by a brief theta stimulus was likewise increased by a factor of 2. The concentration dependent action of D-serine, an agonist acting at the strychnine insensitive glycine-site of the NMDA (N-methyl-d-aspartic acid) receptor was enhanced in the presence of 1 mumol/l of memantine. These effects of memantine were antagonized completely by very low concentrations of the selective non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzoe (F) quinoxyline) as well as by less selective antagonists such as DNQX (6,7-dinitroquinoxaline-2,3-dione) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione). In contrast, dizocilpine tested under identical conditions and in concordance with the literature decreased long-term potentiation. Thus, memantine clearly has different effects on glutamatergic synaptic transmission compared to dizocilpine. The ability of memantine to enhance synaptic transmission in the hippocampus is in concordance with the reported positive influence on cognition deficits in humans.