Glutamate, learning and dementia-selection of evidence

Abstract

Initial suggestions on the involvement of glutamate in memory came from electrophysiological studies on LTP that is blocked by NMDA-antagonists. Then Morris and colleagues (1986) provided the first evidence that icv infusion of the competitive NMDA antagonist 2-amino-5-phosphonovaleric acid (APV) to rats, inhibits both LTP in vivo and spatial learning in a Morris water maze. This was followed by a great amount of evidence confirming the initial finding in various learning tasks. The present paper is devoted to critical review of the literature focusing on the following problems: which glutamate receptors are involved?, in which tests NMDA antagonists inhibit learning?; which types of memory are affected?; which brain structures are involved?; do NMDA receptor antagonists invariably impair learning?; is the effect of NMDA receptors antagonists on learning specific?; does the stimulation of NMDA receptors result in cognitive enhancement?.

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

“…Indeed, there is ample evidence that relatively low doses of many uncompetitive NMDA receptor antagonists block LTP in vivo and cause memory deficits in rats at similar doses (see Danysz & Archer, 1994;Danysz et al, 1995a, b for review). As such, the fact that chronic treatment with therapeutically-relevant doses of memantine has no negative effects on LTP in the rat dentate gyrus in vivo or in area CAl of hippocampal slices ex vivo (Barnes et al, 1995;Misztal et al, 1995) can be taken as providing further support for the results of the present study.…”

“…Oversimplified interpretation of these observations might lead to the conclusion that they are incompatible with the accepted role of NMDA receptors in mediating synaptic plasticity and cognitive processes (Collingridge et al, 1983;Morris et al, 1986; see Bliss & Collingridge, 1993;Danysz & Archer, 1994;Danysz et al, 1995b for reviews). However, therapeutically-relevant doses of memantine block NMDA receptor-mediated pathology in animal models of both acute excitotoxicity and chronic neurodegenerative diseases but exert none of the overt side effects classically associated with NMDA receptor antagonists (Danysz et al, 1994b;Misztal et al, 1994;Wenk et al, 1994;1995).…”

Effects of Pharmacologically Induced Changes in NMDA-Receptor Activity on Long-Term Memory in Humans

“…Although a large number of animal studies support the notion that NMDA antagonists negatively affect learning and memory processes (for reviews, see Danysz and Archer 1994;Aigner 1995), investigations on memory functions in humans after NMDA-receptor blockade are exceedingly scant. The very few existing studies provide ambiguous results.…”

“…The wide distribution of glutamate within the central nervous system suggests that it mediates normal neural transmission (Collingridge and Singer 1990;Scatton 1993) by activating three major classes of subreceptors: NMDA (N-methyl-D-aspartate), AMPA (␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and kainate (cf. Danysz and Archer 1994). Abnormal excitatory glutamatergic neurotransmission has been suggested as a pathological mechanism in various disorders such as schizophrenia (Tamminga 1998;Duncan et al 1999), hypoxic-ischemic brain damage (Choi and Rothman 1990;Scatton 1993), and Alzheimer's dementia (Greenamyre et al 1988;Foster 1990;Lees 1993).…”

Chronic treatment with the uncompetitive NMDA receptor antagonist memantine influences the polyamine and glycine binding sites of the NMDA receptor complex in aged rats

“…This is unexpected considering that NMDA receptor antagonists, although acting as neuroprotectants, are known to produce impairment of learning and memory (e.g. Danysz and Archer, 1994).…”