The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor

Tricklebank, Mark D.; Singh, Lakhbir; Oles, Ryszard J.; Preston, Cliff; Iversen, Susan D.

doi:10.1016/0014-2999(89)90754-1

Cited by 423 publications

(170 citation statements)

References 23 publications

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“…In accordance with previous reports (Koek et al, 1988;Tricklebank et al, 1989), a single administration of dizocilpine (0.5 mg/kg) to female rats produced head weaving and biting in a stationary posture, and increased locomotion within 15 min of injection; rats then exhibited occasional movements in the flat-body posture until the end of the experiment (4 h after injection). Pretreatment with CCPA (0.1, 0.3, 1, or 3 mg/kg) or CPA (1, 3, or 10 mg/kg) did not alter the abnormal behavioral changes induced in rats by dizocilpine, although we did not evaluate it quantitatively.…”

Section: Resultssupporting

confidence: 92%

Adenosine A1 Receptor Agonists Block the Neuropathological Changes in Rat Retrosplenial Cortex after Administration of the NMDA Receptor Antagonist Dizocilpine

Okamura

Hashimoto

Shimizu

et al. 2003

Neuropsychopharmacol

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Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) is known to induce neurotoxicity in rat retrosplenial cortex after systemic administration. The present study was undertaken to examine the effects of adenosine A 1 receptor agonists on the neurotoxicity in rat retrosplenial cortex after administration of dizocilpine. Pretreatment with adenosine A 1 receptor agonists, 2-chloro-N 6 -cyclopentyladenosine (CCPA) (0.1, 0.3, 1, or 3 mg/kg, intraperitoneally (i.p.)), or N 6 -cyclopentyladenosine (CPA) (1, 3, or 10 mg/kg, i.p.), attenuated neurotoxicity by dizocilpine (0.5 mg/kg, i.p), in a dose-dependent manner. Coadministration with adenosine A 1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 3 mg/kg, i.p.) significantly blocked the protective effects of CCPA for dizocilpine-induced neurotoxicity. Furthermore, pretreatment with CCPA (3 mg/kg) attenuated significantly the dizocilpineinduced expression of HSP-70 protein, which is known as a sensitive marker of reversible neuronal damage, and coadministration with DPCPX (3 mg/kg) blocked the inhibitory effects of CCPA for marked expression of HSP-70 protein by administration of dizocilpine. Moreover, pretreatment with CCPA (3 mg/kg, i.p.) significantly suppressed the increase of extracellular acetylcholine (ACh) levels in the retrosplenial cortex by administration of dizocilpine (0.5 mg/kg). In contrast, local perfusion of CCPA (1 mM) into the retrosplenial cortex via the dialysis probe did not alter the ACh levels by administration of dizocilpine (0.5 mg/kg), suggesting that the locus of action of CCPA is not in the retrosplenial cortex. These findings suggest that adenosine A 1 receptors agonists could protect against neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.

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Section: Resultssupporting

confidence: 92%

Adenosine A1 Receptor Agonists Block the Neuropathological Changes in Rat Retrosplenial Cortex after Administration of the NMDA Receptor Antagonist Dizocilpine

Okamura

Hashimoto

Shimizu

et al. 2003

Neuropsychopharmacol

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“…and saline (i.p.) by a two-lever, operant drug discrimination paradigm with a fixed ratio FR1O schedule of food reinforcement as previously described (Tricklebank et al, 1989 …”

Section: Morphine Drug Discriminationmentioning

confidence: 99%

Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine

Singh

Oles

Field

et al. 1996

British J Pharmacology

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1 The ability of a selective CCKA receptor antagonist PD 140548 and a selective CCKB receptor antagonist CI-988 (formerly PD 134308) to modulate the various in vivo properties of morphine was investigated in the rat. 2 PD 140548 dose-dependently (0.001 -1.0 mg kg-1, i.p.) antagonised the development of conditioned place preference to morphine (2.0 mg kg'-, s.c.). In contrast, CI-988 (0.01 -1.0 mg kg-', i.p.) did not affect this morphine-induced behaviour. Neither of the CCK receptor antagonists blocked or generalised to the morphine (3.0 mg kg-', i.p.) discriminative stimulus. 3 CI-988 (0.001-10.0 mg kg-', s.c.) at doses of 0.05 and 0.1 mg kg-' (s.c.), potentiated the antinociceptive action of a threshold dose of morphine (5.0 mg kg-', i.p.) in a radiant heat model of acute nociception, the rat tail flick test. Furthermore, at 0.01 mg kg-' it potentiated the antinociceptive action of morphine (3.0 mg kg-') during the acute phase of the rat paw formalin test. And at doses of 0.01 and 0.1 mg kg-' it also potentiated the antinociceptive action of morphine (1.0 mg kg-') during the tonic phase of the formalin test. However, in both models, higher doses of CI-988 were ineffective. In contrast, PD 140548 (0.001 -10 mg kg-', s.c.) was only active at a dose of 1.0 mg kg-1 (s.c.) and only in the tonic phase of the formalin test. Neither CI-988 nor PD 140548 possessed any intrinsic antinociceptive action in either of the tests. Chronic treatment with CI-988 (0.01 mg kg-', s.c.) prevented the development of tolerance to morphine antinociception (4 mg kg-', s.c.) following a 6 day period of twice daily injections of morphine escalating from 1 to 16 mg kg-' (i.p.). 4 Morphine dose-dependently (1-10 mg kg-', s.c.) reduced the distance travelled by a charcoal meal in the rat intestine. Neither PD 140548 (0.01 -1.0 mg kg-', i.p.) nor CI-988 (0.01 -1.0 mg kg-', i.p.) potentiated or suppressed this inhibitory action of morphine. 5 In conclusion, the results of the present study indicate that CCKA and CCKB receptors modulate different properties of morphine. Thus, whilst a selective CCKA receptor antagonist blocked the rewarding properties of morphine, a selective CCKB receptor antagonist potentiated the antinociceptive action. However, neither compound displayed a potential for modulating the influence of morphine on gastro-intestinal motility. It is suggested that these findings may have important implications for development of CCK receptor antagonists as analgesic adjuncts to the therapeutic use of morphine.

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“…Major questions have centred on the therapeutic window of NMDA receptor antagonists (loss of muscle tone occurs at sufficient dosage; see Turski et al, 1988), their possible psychotomimetic effects (based on experience in man with noncompetitive blockers such as PCP and ketamine; see Domino & Luby, 1981;Lodge et al, 1988), and their potentially detrimental effects on learning (Morris et al, 1986;Collingridge & Bliss, 1987). In this respect, recent evidence indicates that competitive NMDA receptor antagonists may have significant advantages over non-competitive blockers (Meldrum, 1985;Ferkany et al, 1988;Leander et al, 1988;France et al, 1989;Tricklebank et al, 1989). Studies on the novel competitive NMDA receptor antagonists described here indicate, especially in the case of CGP 39551, a therapeutic window at least as great as clinically-used anticonvulsant agents (Fagg et al, 1989a;Schmutz et al, unpublished observations), no direct impairments of learning performance in the anticonvulsant dose-range (Mondadori, Buerki & Petschke, unpublished), and no generalization to the discriminative stimulus effects of ketamine or MK801 in rhesus monkeys (France & Woods, personal communication).…”

Section: Anticonvulsant Properties Of Cgp 37849 and Cgp 39551mentioning

confidence: 99%

“…In addition to the transmitter recognition site, the NMDA receptor complex comprises an allosteric regulatory site and a channel binding domain (Foster & Fagg, 1987b), and possibly also sites defined by the actions of Zn2", polyamines, tricyclic antidepressants, ifenprodil and CGP 31358 (see Lodge, 1989;Baud et al, 1989). At present, however, the two most well characterized sites are (1) the transmitter recognition site, at which substances such as D-2-amino-5-phosphonopentanoate (D-AP5), (±)-3-(2-carboxypiperazin-4-yl) propyl-l-phosphonate (CPP) (± )-cis-4-phosphonomelthylpiperidine-2-carboxylic acid (CGS 19755) competitively antagonize the actions of excitatory amino acids (Evans et al, 1982;Davies et al, 1986;Lehmann et al, 1987;, and (2) a channel site at which non-competitive antagonists such as phencyclidine (PCP) and (+ }5-methyl-10,1 1-dihydro-5H-dibenzo [ad] cyclohepten-5,10-imine maleate (MK 801, Wong et al, 1986;Lodge et al, 1988) bind to function as open-channel blockers.The potential therapeutic advantage of competitive antagonists is that, following systemic administration, their beneficial effects may be discriminated from their side-effects (Meldrum, 1985;Lehmann et al, 1987;Ferkany et al, 1988;France et al, 1989;Tricklebank et al, 1989) 1989;Schmutz et al, 1989). …”

mentioning

confidence: 99%

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CGP 37849 and CGP 39551: novel and potent competitive N‐methyl‐d‐aspartate receptor antagonists with oral activity

Fagg

Olpe²,

Pozza³

et al. 1990

British J Pharmacology

189

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1 The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the Nmethyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2 Radioligand binding experiments demonstrated that CGP 37849 potently (K1 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-( ±)-342-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nm, and was 4, 5 and 7 fold more potent than the antagonists ((±)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3 CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4 In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CAI pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10pM suppressed burst firing evoked in CAl neurones by stimulation of Schaffer collateral-commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoreticallyapplied NMDA, without affecting the responses to quisqualate or kainate. al., 1988). Many studies have demonstrated that activation of the NMDA receptor is involved in the generation of epileptiform activity and in hypoxic-ischaemic neuronal damage, and conversely that NMDA receptor antagonists are anticonvulsant and cerebroprotective in animal models of epilepsy and stroke (see reviews by Meldrum, 1985;Rothman & Olney, 1986;Choi, 1988;Patel et al., 1988;Iversen et al., 1989;Albers et al., 1989 (Meldrum, 1985;Rothman & Olney, 1986;Albers et al., 1989;.Antagonism of NMDA receptor mechanisms potentially may be achieved by a number of different approaches. In addition to the transmitter recognition site, the NMDA receptor complex comprises an allosteric regulatory site and a channel binding domain (Foster & Fagg, 1987b), and possibly also sites defined by the actions of Zn2", polyamines, tricyclic antidepressants, ifenprodil and CGP 31358 (see Lodge, 1989;Baud et al., 1989). At present, however, the two most well characterized sites are (1) the transmitter recognition site, at which substances such as ...

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The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor

Cited by 423 publications

References 23 publications

Adenosine A1 Receptor Agonists Block the Neuropathological Changes in Rat Retrosplenial Cortex after Administration of the NMDA Receptor Antagonist Dizocilpine

Adenosine A1 Receptor Agonists Block the Neuropathological Changes in Rat Retrosplenial Cortex after Administration of the NMDA Receptor Antagonist Dizocilpine

Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine

CGP 37849 and CGP 39551: novel and potent competitive N‐methyl‐d‐aspartate receptor antagonists with oral activity

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