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Titolo:
Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice
Autore:
Geter-Douglass, B; Witkin, JM;
Indirizzi:
Natl Inst Drug Abuse, Addict Res Ctr, Drug Dev Grp, Baltimore, MD 21224 USA Natl Inst Drug Abuse Baltimore MD USA 21224 Grp, Baltimore, MD 21224 USA
Titolo Testata:
PSYCHOPHARMACOLOGY
fascicolo: 3, volume: 146, anno: 1999,
pagine: 280 - 289
Fonte:
ISI
Lingua:
ENG
Soggetto:
STRUCTURAL ANALOGS DIZOCILPINE; RECEPTOR-CHANNEL COMPLEX; ANTI-ADDICTIVE DRUG; DISCRIMINATIVE STIMULUS; PHENCYCLIDINE-LIKE; PARKINSONS-DISEASE; IN-VIVO; RAT-BRAIN; IBOGAINE; MEMANTINE;
Keywords:
NMDA antagonist; discriminative stimulus effect; locomotor activity; convulsion; mice;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
64
Recensione:
Indirizzi per estratti:
Indirizzo: Witkin, JM Natl Inst Drug Abuse, Addict Res Ctr, Drug Dev Grp, 5500 NathanShock Dr, Baltimore, MD 21224 USA Natl Inst Drug Abuse 5500 Nathan Shock Dr Baltimore MD USA 21224
Citazione:
B. Geter-Douglass e J.M. Witkin, "Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice", PSYCHOPHAR, 146(3), 1999, pp. 280-289

Abstract

Rationale: It has been hypothesized that low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) antagonists may have therapeutic efficacy (e.g., in epilepsy, stroke, drug dependence) without the adverse side effects associated with high-affinity ligands (e.g., dizocilpine, phencyclidine). Objectives: To determine whether low-affinity NMDA antagonists have a larger predicted therapeutic window than high-affinity ligands. Methods: In Swiss-Webster mice, we compared the effects of uncompetitive antagonists having a rangeof affinities for the NMDA receptor ion channel [dizocilpine, memantine, ibogaine, amantadine and 5-aminocarbonyl-10,11-dihydro-5h-dibenzo[a,d] cyclohepten-5,10-imine (ADCI)] in three behavioral assays typically used to assess NMDA receptor antagonism. Behavioral side effects were compared with theefficacy of the compounds to protect against NMDA-induced seizures. Results: Only dizocilpine and memantine substituted fully in mice trained to discriminate dizocilpine from saline. Dizocilpine (K-i similar to 0.003 mu M) protected against NMDA-induced convulsions at doses that produced ataxia andstimulation of locomotor activity. Conversely, memantine (K-i similar to 0.54 mu M) prevented convulsions at doses that were 8- to 18-fold lower thanthose producing ataxia or effects on locomotion, respectively. Indeed, in contrast to dizocilpine, memantine did not stimulate locomotor activity butonly produced dose-dependent reductions. The low-affinity antagonists ibogaine (K-i similar to 1 mu M) and ADCI (K-i similar to 11 mu M) protected against convulsions at doses that produced significant dizocilpine-like discriminative stimulus effects, ataxia and decreases in locomotor activity. Amantadine (K-i similar to 11 mu M) was ineffective against NMDA-induced convulsions up to doses that produced significant behavioral side effects. Conclusions: These findings indicate that only certain low-affinity, uncompetitive NMDA antagonists (e.g., memantine) may have therapeutic efficacy at doses that do not produce an adverse side-effect profile. For other therapeuticendpoints, different estimates of efficacy and safety require derivation.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 03:37:21