Modulation of [3H]MK-801 binding to NMDA receptors in vivo and in vitro

Murray, Fraser; Kennedy, Jeffrey D.; Hutson, Peter H.; Elliot, Jason; Huscroft, Ian T.; Mohnen, Kirsten; Russell, Michael G. N.; Grimwood, Sarah

doi:10.1016/s0014-2999(00)00263-6

Cited by 55 publications

(35 citation statements)

References 31 publications

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“…A similar situation exists for ketamine, where the psychotomimetic concentration in the serum is of the order of 100-500 nM, 8 a value that matches the ketamine action (100-500 nM) at D2 High (Figure 3, top), but not that at the NMDA receptor, which has a ketamine K i of 3100 nM for striatal tissue (Figure 3, bottom), 760-2270 nM for brain membranes 33,34 and 3150 nM 34 for cloned NMDA receptors ( Table 1).…”

Section: Discussionmentioning

confidence: 73%

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

2005

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Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2 High , their dissociation constants (K i ) were obtained on [ 3 H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2 High with a K i of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a K i of 313 nM, as labeled by [ 3 H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2 High with a K i of 55 nM, an affinity higher than its 3100 nM K i for the NMDA sites. Dizocilpine had a K i of 0.3 nM at D2 High , but a K d of 1.8 nM at the NMDA receptor. LSD had a K i of 2 nM at D2 High . Because the psychotomimetics had higher potency at D2 High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis. Keywords: dopamine receptor; phencyclidine; domperidone; ketamine; NMDA receptors; psychotomimetics While the clinical anti-dopaminergic actions of antipsychotic drugs are compatible with the hyperdopamine hypothesis of psychosis and schizophrenia, 1,2 the psychoses caused by glutamate antagonists such as phencyclidine or ketamine suggest a hypo-glutamate component in psychosis. [3][4][5] However, phencyclidine also lowers plasma prolactin 6 and elicits rotation, 7 suggesting a direct or indirect dopaminemimetic action of phencyclidine.Although phencyclidine and ketamine are not selective for glutamate NMDA receptors, 8 the precise affinities of these drugs for dopamine D2 receptors need to be clarified in order to determine their dopaminergic and non-dopaminergic components of action. More specifically, although phencyclidine had a dissociation constant of 37 000 nM at the D2 receptor in rat striatal homogenate, 8 phencyclidine had a dissociation constant of 1.3 nM for the functional high-affinity site of the cloned D2 receptor, or the D2 High receptor. 9 This apparent discrepancy may be resolved by the recent finding that dopamine itself has a dissociation constant of 3000 nM when competing vs [ 3 H]raclopride at striatal D2 receptors, but has a dissociation constant of 1.5 nM at the D2 High receptor when the link between dopamine D1 and D2 receptors is blocked by the D1 antagonist SCH23390. 10 The link between D1 and D2 receptors arises from several sources, including the colocalization of dopamine D1 and D2 receptors in at least 50% of the medium spiny neurons in the striatum, the cooperation and mutual potentiation of D1 and D2 agonists on various behaviors, and the biochemical conversion of D2 receptors from their functional high-affinity state, D2 High , into their low-affinity state, D2 Lo...

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Section: Discussionmentioning

confidence: 73%

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

2005

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“…However, low doses of MK-801 (0.2-0.3 mg/kg) have been reported to disrupt sensitization (Li et al, 1999;Haracz et al, 1995;Kalivas and Alesdatter, 1993;Stewart and Druhan, 1993;Wolf andJeziorski, 1993, Vanderschuren andKalivas, 2000;Wolf, 1998). At these doses in vivo, NMDA receptor occupancy and antagonism by MK-801 is only 40-50% (Price et al, 1988;Murray et al, 2000). Perhaps these results instead illustrate the points of difference and similarity between acute pharmacological NMDA receptor blockade and chronic genetic hypofunction of the NMDA receptor system.…”

Section: Discussionmentioning

confidence: 91%

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

Ramsey

Laakso

Cyr

et al. 2008

Neuropsychopharmacol

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NMDA receptor-mediated glutamate transmission is required for several forms of neuronal plasticity. Its role in the neuronal responses to addictive drugs is an ongoing subject of investigation. We report here that the acute locomotor-stimulating effect of cocaine is absent in NMDA receptor-deficient mice (NR1-KD). In contrast, their acute responses to amphetamine and to direct dopamine receptor agonists are not significantly altered. The striking attenuation of cocaine's acute effects is not likely explained by alterations in the dopaminergic system of NR1-KD mice, since most parameters of pre-and postsynaptic dopamine function are unchanged. Consistent with the behavioral findings, cocaine induces less c-Fos expression in the striatum of these mice, while amphetamine-induced c-Fos expression is intact. Furthermore, chronic cocaine-induced sensitization and conditioned place preference are attenuated and develop more slowly in mutant animals, but amphetamine's effects are not altered significantly. Our results highlight the importance of NMDA receptor-mediated glutamatergic transmission specifically in cocaine actions, and support a hypothesis that cocaine and amphetamine elicit their effects through differential actions on signaling pathways.

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“…Subsequent studies were conducted using an intravenous route of administration to increase the drug's access to the brain. The doses of L-701,324 selected for testing exhibit widely divergent effects on [ 3 H]MK-801 binding in vivo, ranging from o10% inhibition at 3 mg/kg to 480% inhibition at 30 mg/kg (Murray et al, 2000). At all doses tested, a nonsignificant trend toward an increase in T/C ratio was observed but there was no evidence of a dose dependency of the response.…”

Section: Discussionmentioning

confidence: 92%

“…Rats received a bolus injection of one of three doses of the drug (3, 10, or 30 mg/kg) administered intravenously to facilitate entry into the brain (Murray et al, 2000). The results of these experiments are illustrated in Figure 2.…”

Section: Experiments 2: Effect Of the Glycine B Site Antagonist L-701mentioning

confidence: 99%

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

Neuropsychopharmacol

127

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Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine B /NMDA and a-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine B site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine B receptor.

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Modulation of [3H]MK-801 binding to NMDA receptors in vivo and in vitro

Cited by 55 publications

References 31 publications

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

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