Systemically administered N-methyl-D-aspartate interferes with acquisition of a passive avoidance response in rats

Jones, Keith; Schaeffer, Christina L.; DeNoble, Victor J.

doi:10.1016/0091-3057(89)90370-5

Cited by 23 publications

(4 citation statements)

References 24 publications

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“…It has been proposed that tonic activation of NMDA receptors (that is, gating of the channel unassociated with synaptic activity), could contribute to impairment of cognition and memory in AD. In fact, low levels of NMDA can impair the induction of LTP as well as inhibit learning in passive avoidance models (66,164). Such tonic glutamatergic activation presumably reduces the magnitude of the change in NMDA receptor activation that can be produced by a relevant signal.…”

Section: Memantine Synaptic Plasticity and Memorymentioning

confidence: 99%

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The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

2003

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Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase in-hibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates â-amyloid (Aâ) toxicity and possibly inhibits Aâ production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists , particularly those that act by a similar channel blocking mechanism such as dis-sociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of chan-275 nel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate-an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity-while sparing synaptic responses required for normal be-havioral functioning, cognition and memory.

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Section: Memantine Synaptic Plasticity and Memorymentioning

confidence: 99%

“…In fact, low levels of NMDA can impair the induction of LTP as well as inhibit learning in passive avoidance models (66,164). Such tonic glutamatergic activation presumably reduces the magnitude of the change in NMDA receptor activation that can be produced by a relevant signal.…”

Section: Memantine Synaptic Plasticity and Memorymentioning

confidence: 99%

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

2003

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“…Preliminary experiments had been carried out to establish an effective dose range for the effects of AP5 in the water maze and demonstrated that animals treated with 10 or 20 fig of AP5 had a very weak muscle tonus and could hardly swim. Therefore, lower doses of AP5 as compared to other studies (Koek et al, 1987;Danysz et al, 1988;Leung et al, 1988;Kim et al, 1991)-3, 4, and 5 fig--were used in the present study. NMDA (N-methyl-D-aspartate: Siama) was dissolved in a Tris buffer with a nH of 7.2.…”

Section: Surgery and Drugsmentioning

confidence: 99%

“…The NMDA receptor is essential for long-term potentiation (Collingridge and Bliss, 1987) a model for changes in the synaptic circuitry underlying memory (McNaughton et al, 1986;Walker and Gold, 199 1). Selective impairment in place learning can be induced by the NMDA antagonist AP5 (D,L-2-amino-Sphosphonopentanoic acid) as compared to other drugs modulating NMDA receptor activity that has been extensively dem-onstrated (McNaughton et al, 1986;Morris et al, 1986;Leung and Desborough, 1988;Jones et al, 1989;Morris, 1989) and elegantly reviewed by McNamara and Skelton (1993).…”

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confidence: 99%

The ACTH(4-9) analog Org2766 modulates the behavioral changes induced by NMDA and the NMDA receptor antagonist AP5

et al. 1994

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In studies on aged and brain-lesioned rats the chronic administration of the ACTH(4–9) analog Org2766 has been demonstrated to improve the behavioral performance. Those results suggest that maintenance of hippocampal functioning in senescence and facilitation of functional recovery after brain damage are not due to facilitated reinnervation of denervated structures as suggested in previous studies concerning regeneration of the PNS. Alternative explanations may refer to either the neuroprotective properties of the peptide as demonstrated when chronic treatment immediately follows the damage, or a peptide-induced general change in attention that indirectly may contribute to functional recovery. The behavioral effects after acute treatment with ACTH-like peptides have been previously associated with sustained attention by enhanced neuronal excitability of limbic structures. Now, a hypothesis accounting for both neuroprotection and enhanced attention is forwarded by supposing that the peptide exerts its influence by modulation of NMDA receptor activation. Therefore, the acute effects and interactions between the peptide and the NMDA receptor antagonist AP5 (D,L-2-amino-5-phosphonopentanoic acid), and the peptide and NMDA were studied in a water maze and an open field. Impaired water maze performance induced by an acute intracerebroventricular administration of AP5 was counteracted by the ACTH(4–9) analog Org2766, whereas the peptide alone did not affect spatial orientation. NMDA induced extreme locomotor activity at the periphery of the open field. Interestingly, the ACTH(4–9) analog strongly suppressed NMDA-induced enhanced locomotor activity and normalized the pattern of exploratory behavior.

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The function of the NMDA-receptor during normal brain aging

Müller

Stoll

Scheuer

et al. 1994

Cell and Animal Models in Aging and Dementia Research

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Systemically administered N-methyl-D-aspartate interferes with acquisition of a passive avoidance response in rats

Cited by 23 publications

References 24 publications

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

The ACTH(4-9) analog Org2766 modulates the behavioral changes induced by NMDA and the NMDA receptor antagonist AP5

The function of the NMDA-receptor during normal brain aging

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