Phencyclidine and related drugs bind to the activated N-methyl-d-aspartate receptor-channel complex in rat brain membranes

doi:10.1016/0304-3940(87)90719-1

Neuroscience Letters

Volume 76, Issue 2, 6 May 1987, Pages 221-227

https://doi.org/10.1016/0304-3940(87)90719-1 Get rights and content

Abstract

In functional studies, phencyclidine (PCP) and similar drugs non-competitively antagonize neuronal responses to the excitatory amino acid, $N- methyl- d -aspartate$ (NMDA). Here we show that, in crude postsynaptic densities from rat brain, the binding of [³H]TCP (a PCP analogue) was enhanced almost 4-fold by l-glutamate and NMDA, but not by quisqualate, kainate or γ-aminobutyric acid. The potencies of excitatory amino acid agonists and antagonists in the [³H]TCP binding assay closely paralleled their affinities for NMDA-sensitive l-[³H]glutamate binding sites. In contrast, dissociative anaesthetics and σ-opiates inhibited [³H]TCP binding (with a profile characteristic of PCP binding sites), but had no effect on l-[³H]glutamate binding. These data indicate that PCP binding sites are linked to NMDA receptors, and that PCP and related drugs bind preferentially to the activated configuration of the NMDA receptor channel complex.

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In Table 1 we also present the binding affinities of these compounds for the N-methyl-d-aspartate (NMDA) glutamate ion channel, determined by a radioligand binding assay using Wistar rat brain preparations.10 Many of the pharmacological effects of ketamine (anaesthetic, analgesic, psychomimetic, anti-depressant), have previously been linked to this property11,12 since ketamine has high binding affinity for the NMDA receptor, with its Ki reported in the literature to be 1.9 µM.13 However, our data clearly suggests that NMDA potency does not correlate at all with the anaesthetic or analgesic activity of the compounds discussed here.
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A calcium imaging technique combined with a confocal laser scanning microscope (CLSM) was applied to investigate the effects of phencyclidine (PCP) on glutamate-induced calcium increases in same group of primary cultured neocortical neurons. Non-N-methyl-d-aspartate (NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) alone did not significantly alter glutamate-induced changes of fluorescence (89.6%), while addition of PCP greatly blocked increases in fluorescence to 32.6% of the glutamate response. Competitive NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV) alone and the addition of PCP reduced glutamate responses to 30.5% and 21.2%, respectively. These data clearly demonstrate that the neuropharmacological properties of PCP may function through its blockade of the NMDA receptor.
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Exposing the developing brain to the N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) has been shown to cause deficits in neurobehavioral functions, particularly on learning and memory and seizure sensitivity. Besides acting as a noncompetitive NMDA antagonist, PCP at high doses is known to affect the dopaminergic system. The present study assessed the effect of postnatal PCP treatment on locomotor activity and striatal dopamine (DA) D₂ receptor. Male and female rat pups were injected intraperitoneally (ip) with one of three doses of PCP (1, 3 and 5 mg/kg) or saline from postnatal day (PD) 5 to PD 15. Control and PCP-treated rats were given a challenge dose of PCP (10 mg/kg) as adults, and their locomotor behaviors—locomotion, stereotypy and ataxia—were scored. Postnatal PCP treatment did not have any significant effect in either sex on any of the PCP-induced locomotor behavioral paradigms studied. Separate groups of male and female rats were treated daily with saline or PCP (5 mg/kg ip) from PD 5 to PD 15 and sacrificed either as juveniles (PD 21) or adults, and D₂ receptor binding was measured in their striata. Striatal D₂ receptor density in juvenile and adult male postnatal PCP-treated rats did not differ from saline-treated controls. Adult female PCP-treated rats showed a slight but significant reduction in the maximal binding of striatal D₂ receptors. There was no effect of postnatal PCP on striatal D₂ receptor binding in female juvenile rats. These results support the hypothesis that blocking the developing NMDA receptor minimally affects PCP-induced locomotor behavior and the striatal D₂ receptor.
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Conantokin-G (con-G) and conantokin-T (con-T) are small (17 and 21 amino acids, respectively) γ-carboxyglutamate (Gla) containing peptides derived from the venoms of marine cone snails that are potent and selective inhibitors of N-methyl-d-aspartate (NMDA) receptors. In this study, the effects of con-G and con-T on NMDA-evoked responses were evaluated in mouse primary hippocampal neuronal cultures using the whole-cell patch-clamp technique. Under equilibrium conditions, NMDA-induced currents were inhibited by con-G and con-T (10 nM–100 μM) in a dose-dependent manner while maintaining a holding potential of −70 mV. In the presence of saturating amounts of NMDA (100 μM) and glycine (1 μM), the IC₅₀ values obtained were 487±85 nM for con-G and 1030±130 nM for con-T. NMDA (10 μM–1 mM) dose-response curves produced in the presence of con-G or con-T (1 or 3 μM) resulted in a downward shift of the current response at saturation with NMDA, without affecting the EC₅₀. The maximum response obtainable in the absence of peptide could not be achieved by increasing concentrations of NMDA. The same effect was also observed for conantokin inhibition of spermine-potentiated responses. Association rate constants (k_on) for the peptides were determined in the presence of NMDA and glycine, with and without the addition of spermine. Using a single binding site bimolecular model, k_on values were 3.1±0.2×10³ M⁻¹ s⁻¹ for con-G and 3.2±0.1×10³ M⁻¹ s⁻¹ for con-T in the absence of spermine. The added presence of a saturating amount of spermine (300 μM) resulted in an approximate 60% increase in the k_on values for both con-G and con-T. These results demonstrate that con-T and con-G inhibit NMDA-evoked currents, as well as the potentiation by spermine, in what appears to be a noncompetitive manner, and that spermine increases the rate of conantokin inhibition.
A further study on asymmetric cross-sensitization between MK-801 and phencyclidine-induced ambulatory activity
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XU, X. AND E. F. DOMINO. A further study on asymmetric cross-sensitization between MK-801 and phencyclidine-induced ambulatory activity. PHARMACOL BIOCHEM BEHAV 63(3) 413–416, 1999.—Our previous study found that MK-801–sensitized rats showed cross-sensitization to the locomotor stimulant effects of phencyclidine, but phencyclidine sensitized rats did not show cross-sensitizaton to MK-801. This study was designed to determine whether the asymmetric cross-sensitization was due to injection–environment conditioning or possibly reduced phencyclidine-like effects following further repeated injections of phencyclidine. Adult female Sprague–Dawley rats were used in this study, and their activity was assessed with an automated photoelectric system. Results confirmed the early finding that four daily injections of phencyclidine (3.2 mg/kg) or MK-801 (0.32 mg/kg) produced locomotor sensitization, and that the two drugs showed asymmetric cross-sensitization. Moreover, injection–environment conditioning was ruled out as a possible cause for cross-sensitization from MK-801 to phencyclidine, and possibly reduced phencyclidine-like effects following further repeated injections was also ruled out as a cause for the failure of cross-sensitization from phencyclidine to MK-801. These additional results further confirm our previous finding, and indicate that there are significant differences in the neural mechanisms underlying phencyclidine- and MK-801–induced sensitization.

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Phencyclidine and related drugs bind to the activated N-methyl-d-aspartate receptor-channel complex in rat brain membranes

Abstract

Trends Pharmacol. Sci.

Neurosci. Lett.

Neuroscience

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Brain Res.

Brain Res.

The dissociative anaesthetics ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons by N-methyl-aspartate

Br. J. Pharmacol.

Selective depression of excitatory amino acid induced depolarizations by magnesium ions in isolated spinal cord preparations

J. Physiol. (London)

Structure-activity relationship studies of phencyclidine derivatives in the rat

J. Pharmacol. Exp. Ther.

Phencyclidine and related drugs bind to the activated $N- methyl- d -aspartate$ receptor-channel complex in rat brain membranes