Ketamine and phencyclidine cause a voltage-dependent block of responses to l-aspartic acid

Honey, Christopher R.; Miljkovic, Z.; MacDonald, John F.

doi:10.1016/0304-3940(85)90414-8

Cited by 252 publications

(108 citation statements)

References 8 publications

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“…Previous studies have demonstrated that ketamine acts via the open and closed states of the channel in the muscle type nAChRs (Scheller et al, 1996). On the NMDA receptor, ketamine acts both as an open channel blocker (Honey et al, 1985;MacDonald et al, 1991) and as an allosteric inhibitor (Orser et al, 1997). We can deduce from both previous studies and from the evidence of voltage-and use-dependence in our own studies, that ketamine is acting predominantly as an open channel blocker in the a4b2.…”

Section: Discussionsupporting

confidence: 67%

“…In the early 1980's Lodge described ketamine as a selective inhibitor of NMDA receptor activity and neuronal nicotinic receptors (nAChRs) on Renshaw cells of the cat spinal cord (Anis et al, 1983). Ketamine is also an antagonist of NMDA receptors in rat cortex (Harrison & Simmonds, 1985) and blocks these receptors at sub-clinical concentrations, by acting both as a use-dependent open channel blocker (Honey et al, 1985) and through allosteric inhibition (Orser et al, 1997). Ketamine inhibits the response to acetylcholine or nicotine in both muscle and neuronal type nAChRs (Sumikawa et al, 1983;Wachtel & Wegrzynowicz, 1992;Scheller et al, 1996;Durieux, 1995;Furuya et al, 1999;Flood & Krasowski, 2000;Friederich et al, 2000;Sasaki et al, 2000;Yamakura et al, 2000).…”

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confidence: 99%

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Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

Coates

Flood

2001

British J Pharmacology

106

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1 Ketamine is a dissociative anaesthetic that is formulated as Ketalar, which contains the preservative benzethonium chloride (BCl). We have studied the e ects of pure racemic ketamine, the preservative BCl and the Ketalar mixture on human neuronal nicotinic acetylcholine receptors (nAChRs) composed of the a7 subunit or a4 and b2 subunits expressed in Xenopus laevis oocytes. 2 Ketamine inhibited responses to 1 mM acetylcholine (ACh) in both the human a7 and a4b2 nAChRs, with IC 50 values of 20 and 50 mM respectively. Inhibition of the a7 nAChRs occurred within a clinically relevant concentration range, while inhibition of the a4b2 nAChR was observed only at higher concentrations. The Ketalar formulation inhibited nAChR function more e ectively than was expected given its ketamine concentration. The surprising increased inhibitory potency of Ketalar compared with pure ketamine appeared to be due to the activity of BCl, which inhibited both a7 (IC 50 value of 122 nM) and a4b2 (IC 50 value of 49 nM) nAChRs at concentrations present in the clinical formulation of Ketalar. 3 Ketamine is a noncompetitive inhibitor at both the a7 and a4b2 nAChR. In contrast, BCl causes a parallel shift in the ACh dose-response curve at the a7 nAChR suggesting competitive inhibition. Ketamine causes both voltage-dependent and use-dependent inhibition, only in the a4b2 nAChR. 4 Since a7 nAChRs are likely to be inhibited during clinical use of Ketalar, the actions of ketamine and BCl on this receptor subtype may play a role in the profound analgesia, amnesia, immobility and/or autonomic modulation produced by this anaesthetic. British Journal of Pharmacology (2001) 134, 871 ± 879 Keywords: Neuronal nicotinic acetylcholine receptors; benzethonium chloride; ketamine; anaesthetic mechanism Abbreviations: BCl, benzethonium chloride; nAChRs, neuronal nicotinic acetylcholine receptors IntroductionKetamine is a dissociative anaesthetic, that is an e ective analgesic, amnestic and hypnotic, but causes hallucinations that limit its usefulness as a clinical anaesthetic agent. Due to its potency as an analgesic and its sympathomimetic properties, ketamine ®nds extensive use in the treatment of burn patients in intensive care settings. In the early 1980's Lodge described ketamine as a selective inhibitor of NMDA receptor activity and neuronal nicotinic receptors (nAChRs) on Renshaw cells of the cat spinal cord (Anis et al., 1983). Ketamine is also an antagonist of NMDA receptors in rat cortex (Harrison & Simmonds, 1985) and blocks these receptors at sub-clinical concentrations, by acting both as a use-dependent open channel blocker (Honey et al., 1985) and through allosteric inhibition (Orser et al., 1997). Ketamine inhibits the response to acetylcholine or nicotine in both muscle and neuronal type nAChRs (Sumikawa et al., 1983;Wachtel & Wegrzynowicz, 1992;Scheller et al., 1996;Durieux, 1995;Furuya et al., 1999;Flood & Krasowski, 2000;Friederich et al., 2000;Sasaki et al., 2000;Yamakura et al., 2000). In the case of nAChRs containing the a4 subunit, ...

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Section: Discussionsupporting

confidence: 67%

mentioning

confidence: 99%

Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

Coates

Flood

2001

British J Pharmacology

106

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“…For example, noncompetitive NMDA receptor antagonist MK-801 can only bind to the receptor when it is activated by depolarization, which causes removal of magnesium (23). However, the ability of MK-801 but not AP5 to block the NMDAactivated ion channel is voltage-dependent and reduced by depolarization (16,22). On the other hand, the competitive NMDA receptor antagonist AP5 shares the same binding site as glutamate and has a higher binding affinity compared with MK-801 (21).…”

Section: Discussionmentioning

confidence: 99%

Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat

Hung¹,

Covașă²,

Ritter³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Hindbrain administration of MK-801, a noncompetitive N-methyl-d-aspartate (NMDA) channel blocker, increases meal size, suggesting NMDA receptors in this location participate in control of food intake. However, dizocilpine (MK-801) reportedly antagonizes some non-NMDA ion channels. Therefore, to further assess hindbrain NMDA receptor participation in food intake control, we measured deprivation-induced intakes of 15% sucrose solution or rat chow after intraperitoneal injection of either saline vehicle or D(-)-2-amino-5-phosphonopentanoic acid (AP5), a competitive NMDA receptor antagonist, to the fourth ventricular, or nucleus of the solitary tract (NTS). Intraperitoneal injection of AP5 (0.05, 0.1, 1.0, 3.0, and 5.0 mg/kg) did not alter 30-min sucrose intake at any dose (10.7 Ϯ 0.4 ml, saline control) (11.0 Ϯ 0.8, 11.2 Ϯ 1.0, 11.2 Ϯ 1.0, 13.1 Ϯ 2.2, and 11.0 Ϯ 1.9 ml, AP5 doses, respectively). Fourth ventricular administration of both 0.2 g (16.7 Ϯ 0.6 ml) and 0.4 g (14.9 Ϯ 0.5 ml) but not 0.1 and 0.6 g of AP5 significantly increased 60-min sucrose intake compared with saline (11.2 Ϯ 0.4 ml). Twenty-four hour chow intake also was increased compared with saline (AP5: 31.5 Ϯ 0.1 g vs. saline: 27.1 Ϯ 0.6 g). Furthermore, rats did not increase intake of 0.2% saccharin after fourth ventricular AP5 administration (AP5: 9.8 Ϯ 0.7ml, vs. saline: 10.5 Ϯ 0.5ml). Finally, NTS AP5 (20 ng/30 nl) significantly increased 30-(AP5: 17.2 Ϯ 0.7 ml vs. saline: 14.6 Ϯ 1.7 ml), and 60-min (AP5: 19.4 Ϯ 0.6 ml vs. saline: 15.5 Ϯ 1.4 ml) sucrose intake, as well as 24-h chow intake (AP5: 31.6 Ϯ 0.3 g vs. saline: 26.1 Ϯ 1.2 g). These results support the hypothesis that hindbrain NMDA receptors participate in control of food intake and suggest that this participation also may contribute to control of body weight over a 24-h period. satiation; nucleus of the solitary tract; N-methyl-d-aspartate channel blockerN-METHYL-D-ASPARTATE (NMDA)-type glutamate receptors are expressed in many neurons in the central nervous system (4, 24, 33, 52), as well as by some peripheral neurons, including primary vagal afferents (1) and the intrinsic neurons of the gastrointestinal tract (7,19,52). Over the past decade, evidence of NMDA receptor participation in meal termination has steadily accumulated. Studies from our laboratory (6), as well as others (17), have demonstrated that intraperitoneal administration of dizocilpine (MK-801), a noncompetitive antagonist of NMDA receptors, increases intake of both solid chow and palatable food, but not water, in rats after overnight food deprivation. Administration of MK-801 into the fourth ventricle or directly into the caudal medial nucleus of the solitary tract (NTS) increases the size of a 15% sucrose meal (49). Furthermore, lesions of the dorsal vagal complex abolish increased meal size evoked by systemic administration of MK-801 (50). Finally, systemic MK-801 administration increases only nutritive sucrose but not nonnutritive saccharin solution (5), indicating that blockade of NMDA receptors by MK-801 delays me...

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“…It is possible that MK-801 acts as an open channel blocker, as has been suggested for PCP and ketamine (Honey et al, 1985;MacDonald & Milkjovic, 1986). Thus, the increase in [3H]-MK-801 binding induced by NMDA agonists may reflect a higher affinity of this ligand for the open state of the NMDA-activated ion channel.…”

Section: Preparation Of Membranesmentioning

confidence: 94%

The novel anticonvulsant MK‐801 binds to the activated state of the N‐methyl‐d‐aspartate receptor in rat brain

Foster

Wong

1987

British J Pharmacology

443

160

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Ketamine and phencyclidine cause a voltage-dependent block of responses to l-aspartic acid

Cited by 252 publications

References 8 publications

Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat

The novel anticonvulsant MK‐801 binds to the activated state of the N‐methyl‐d‐aspartate receptor in rat brain

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