Antagonism of <i>N</i>-methyl-<scp>D</scp>-aspartate (NMDA) evoked increases in cerebellar cGMP and striatal ACh release by phencyclidine (PCP) receptor agonists; evidence for possible allosteric coupling of NMDA and PCP receptors

Wood, Paul L.; Steel, Douglas; McPherson, Stephen E.; Cheney, D. L.; Lehmann, John

doi:10.1139/y87-299

Cited by 44 publications

(19 citation statements)

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“…Several studies have demonstrated a tight functional coupling between NMDA receptors and PCP recognition sites by receptor autoradiographic, behavioral, electrophysiological, and neurochemical lines of evidence (Lehmann and Scatton, 1982;Anis et al, 1983;Greenamyre et al, 1984;Snell and Johnson, 1986;Compton et al, 1987;Lodge et al, 1987;Loo et al, 1987;Wood et al, 1987Wood et al, , 1989aBennett et al, 1988). Such functional coupling between the NMDA receptors and PCP recognition sites results in antagonism of responses mediated by the NMDA receptor complex by PCP ligands in a noncompetitive manner.…”

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confidence: 99%

“…The paradoxical biochemical effects of tiletamine (vide supra) led us to examine the effects of tiletamine on cerebellar cyclic GMP (cGMP) levels (in the mouse and rat) and behavior (in the rat), two well-characterized NMDA-coupled PCP recognition site-mediated responses (Wood et al, , 1987(Wood et al, , 1989aContreras et al, 1986;Compton et al, 1987), and effects on rat pyriform cortex DA metabolism release, a response mediated by the NMDA-uncoupled PCP recognition sites (Wood and Rao, 1989a;Rao et al, 1990a,b), to determine whether tiletamine interacts differentially with these two subpopulations of PCP recognition sites. We have also characterized tiletamine in several in vitro radioreceptor assays to determine the receptor specificity.…”

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confidence: 99%

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Contrasting Neurochemical Interactions of Tiletamine, a Potent Phencyclidine (PCP) Receptor Ligand, with the N‐Methyl‐D‐Aspartate‐Coupled and ‐Uncoupled PCP Recognition Sites

Rao¹,

Contreras²,

Cler³

et al. 1991

Journal of Neurochemistry

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Neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate (NMDA)-coupled and -uncoupled PCP recognition sites were examined. Tiletamine potently displaced the binding of [3H]1-(2-thienyl)cyclohexylpiperidine with an IC50 of 79 nM without affecting sigma-, glycine, glutamate, kainate, quisqualate, or dopamine (DA) receptors. Like other PCP ligands acting via the NMDA-coupled PCP recognition sites, tiletamine decreased basal, harmaline-, and D-serine-mediated increases in cyclic cGMP levels and induced stereotypy and ataxia. Tiletamine was nearly five times more potent than PCP at inhibiting the binding of 3-hydroxy[3H]PCP to its high-affinity NMDA-uncoupled PCP recognition sites. However, following parenteral administration, dizocilpine maleate (MK-801), ketamine, PCP, dexoxadrol, and 1-(2-thienyl)cyclohexylpiperidine HCl, but not tiletamine, increased rat pyriform cortical DA metabolism and/or release, a response modulated by the NMDA-uncoupled PCP recognition sites. Pretreatment with tiletamine did not attenuate the MK-801-induced increases in rat pyriform cortical DA metabolism, a result suggesting that tiletamine is not a partial agonist of the NMDA-uncoupled PCP recognition sites in this region. However, following intracerebroventricular administration (100-500 micrograms/rat), tiletamine increased pyriform cortical DA metabolism with a bell-shaped dose-response curve. These data indicate a differential interaction of tiletamine with the NMDA-coupled and -uncoupled PCP recognition sites. The paradoxical effects of tiletamine suggest that tiletamine might activate receptor(s) or neuronal pathways of unknown pharmacology.

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confidence: 99%

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Contrasting Neurochemical Interactions of Tiletamine, a Potent Phencyclidine (PCP) Receptor Ligand, with the N‐Methyl‐D‐Aspartate‐Coupled and ‐Uncoupled PCP Recognition Sites

Rao¹,

Contreras²,

Cler³

et al. 1991

Journal of Neurochemistry

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“…Numerous attempts have been made to identify drugs which might either (a) mimic PCP in blocking the neurotoxic effects of glutamate or (b) antagonize the effects of PCP and thus constitute potential antipsychotic agents [Bakshi and Geyer 1995;Corbett et al 1995;Deutsch et al 2002]. However, based upon the prevailing hypothesis that the PCP receptor is located within the N-methyl-D-aspartate (NMDA) receptor-gated ion channel (Wood et al 1987;Javitt et al 1994;O'Donnell and Grace 1998), it is difficult to conceptualize a drug able to exclude PCP from its receptor without itself blocking the channel and thus mimicking the behavioral effects of PCP. Nonetheless, numerous drugs have been reported to diminish psychomotor activation by PCP (Maurel-Remy et al 1995;Klamer et al 2005;Podhorna and Didriksen 2005).…”

Section: Discussionmentioning

confidence: 99%

Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs

2008

Pharmacology Biochemistry and Behavior

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It has been observed that agents with agonist activity at 5-HT 2A receptors prevent neurotoxicity induced by the non-competitive NMDA antagonist, dizocilpine (MK-801). Subsequent behavioral studies reported complete antagonism by LSD and DOM of the stimulus effects of the related NMDA antagonist, phencyclidine [PCP]. The present study sought to extend those observations to include other psychoactive drugs. Male F-344 rats were trained in a 2-lever, fixed ratio 10, food-reinforced task with PCP (3.0 mg/kg; IP; 30 min pretreatment) as a discriminative stimulus. Tests of generalization were then conducted using the training dose of PCP in combination with a range of doses of DOM, LSD, d-amphetamine, MDMA, psilocybin, buspirone, and GHB. All of the drugs tested in combination with PCP produced a statistically significant diminution of PCP-appropriate responding but for none was antagonism complete. These data, obtained using a stimulus control model of the hallucinogenic effects of PCP, fail to support the hypothesis that LSD and DOM completely antagonize stimulus control by PCP. Instead, the data suggest complex interactions between PCP-induced stimulus control and a variety of psychoactive drugs including GHB, an agent with no known affinity for serotonergic receptors.

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“…Irifune et al, have also demonstrated that ketamine has an indirect dopaminergic agonistic action [1]. The dopaminergic and NMDA systems have pivotal roles in the modulation of the presynaptic Ach release in the striatum [4,5]. In fact ketamine is known to inhibit Ach release in the striatum of rodents through the dopaminergic activating action and/or the antagonistic action on the NMDA receptors [5].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the anesthetic action of ketamine is believed to be antagonism of the N-methyl-D-aspartate (NMDA) receptors. Several classes of the NMDA antagonists are known to reduce Ach release [5]. Ketamine may alter the regulatory mechanisms of mAchRs by inhibiting presynaptic Ach release, especially if ketamine is chronically or repeatedly administered.…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent effects of repeated ketamine administration on muscarinic acetylcholine receptors in the mouse forebrain

Hitomi¹,

Morita

Saito

et al. 1995

J Anesth

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To study the effects of repeated ketamine administration (0: saline, 12.5, 25, and 50 mg·kg every 3 days for a total of five times, subcutaneously) on the central muscarinic acetylcholine receptors (mAchRs), receptor binding assays of mAchR were carried out in the forebrain of mice, using [H]quinuclidinyl benzilate ([H]QNB) as a ligand. We also examined whether repeated ketamine administration could modify the sensitivity to scopolamine (0.5 mg·kg) (a muscarinic antagonist). Repeated ketamine administration produced a significant increase in the receptor density values (Bmax) for [H]QNB (1520±51 fmol·mg protein for the control group, 1650±43 for the 12.5 mg·kg group, 1966±70 for the 25 mg·kg group and 2064±125 for the 50 mg·kg group) (P<0.05, when the 25 mg·kg and 50 mg·kg groups were compared to the control group) without any change in apparent affinity. Repeated ketamine reduced scopolamine-induced hyperlocomotion at 50 mg·kg (P<0.05). We conclude that repeated ketamine administration produces up-regulation of mAchRs, which is probably associated with the altered Ach transmission of the central nervous system.

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Antagonism of N-methyl-D-aspartate (NMDA) evoked increases in cerebellar cGMP and striatal ACh release by phencyclidine (PCP) receptor agonists; evidence for possible allosteric coupling of NMDA and PCP receptors

Cited by 44 publications

References 0 publications

Contrasting Neurochemical Interactions of Tiletamine, a Potent Phencyclidine (PCP) Receptor Ligand, with the N‐Methyl‐D‐Aspartate‐Coupled and ‐Uncoupled PCP Recognition Sites

Contrasting Neurochemical Interactions of Tiletamine, a Potent Phencyclidine (PCP) Receptor Ligand, with the N‐Methyl‐D‐Aspartate‐Coupled and ‐Uncoupled PCP Recognition Sites

Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs

Dose-dependent effects of repeated ketamine administration on muscarinic acetylcholine receptors in the mouse forebrain

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