Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent biochemical observations have suggested the abnormalities in the gamma-amino-butyric acid (GABA)ergic system in schizophrenic brains. In the present study, we investigated the subunits gene expressions and ligand binding of the GABA(A) receptor following acute and chronic administration of phencyclidine (PCP), which induces schizophrenia-like symptoms, in rats using in situ hybridization and in vitro quantitative autoradiography. PCP i.p. administration at a daily dose of 7.5 mg/kg resulted in a significant decrease in expression of alpha 1 subunit mRNA in cerebral cortices (cingulate (-13%) and temporal cortex (-6%)) and hippocampal formation (CA1 (-11%), CA2 (-10%), CA3 (-11%) and dentate gyrus (-12%)) 1 h after a single treatment. In the repeated PCP administrations for 14 days, the expression of beta 2 mRNA in the cerebellum (-10%) and of beta 3 mRNA in the cerebral cortices (cingulate (-12%), parietal (-16%) and temporal cortex (-16%), caudate putamen (-18%), inferior colliculus (-18%), and cerebellum (-15%) were significantly decreased. In addition, [(35)S]t-butylbicyclophosphorothionate (TBPS) binding was also reduced in layer IV of the frontoparietal cortex (-14%), inferior colliculus (-17%), and cerebellum (-12%) following chronic PCP treatment, while no changes were observed following acute PCP treatment. These results indicate that single and repeated administrations of PCP independently regulate the expression of GABA(A)/benzodiazepine (BZD) receptor subunits mRNA and its receptor binding in the brain.
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PMID:Differential expression of GABA(A) receptor subunit mRNAs and ligand binding sites in rat brain following phencyclidine administration. 1094 Nov 40

Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABA(A) receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABA(A) receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.
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PMID:Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABA(A) synaptic receptors. 1212 79

The involvement of the septohippocampal system on the impaired sensorimotor gating induced by phencyclidine (PCP) or by an electrically induced hippocampal seizure was examined in behaving rats. An impaired sensorimotor gating, measured by prepulse inhibition (PPI) of the acoustic startle response, was observed following a hippocampal afterdischarge (AD) or systemic injection of PCP and was accompanied with an increase in hippocampal gamma waves (30-70 Hz). The medial septum infusion with muscimol (0.25 microg), a GABA(A) receptor agonist, 15 min prior to PCP or a hippocampal AD, prevented the impairment of sensorimotor gating and the increase in gamma waves. By itself, muscimol (0.25 microg) injection into the medial septum did not affect PPI, although it significantly suppressed spontaneous gamma waves. In order to identify subpopulations of neurons mediating the sensorimotor gating deficit and the hippocampal gamma wave increase, 0.14-0.21 microg of p75 antibody conjugated to saporin (192 IgG-saporin) was injected into the medial septum to selectively lesion the septohippocampal cholinergic neurons. Neither the PPI deficit nor the gamma wave increase induced by PCP or a hippocampal AD was affected by 192 IgG-saporin lesion of the medial septum. It is concluded that increase in neural activity in the medial septum participates in the impairment of sensorimotor gating and the increase in hippocampal gamma waves induced by PCP or a hippocampal AD. It is suggested that the GABAergic but not the cholinergic septohippocampal neurons mediate the sensorimotor gating deficit.
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PMID:The medial septum mediates impairment of prepulse inhibition of acoustic startle induced by a hippocampal seizure or phencyclidine. 1532 89

Lacosamide (LCM) is anticonvulsant in animal models and is in phase 3 assessment for epilepsy and neuropathic pain. Here we seek to identify cellular actions for the new drug and effects on recognised target sites for anticonvulsant drugs. Radioligand binding and electrophysiology were used to study the effects of LCM at well-established mammalian targets for clinical anticonvulsants. 10 microM LCM did not bind with high affinity to a plethora of rodent, guinea pig or human receptor sites including: AMPA; Kainate; NMDA (glycine/PCP/MK801); GABA(A) (muscimol/benzodiazepine); GABA(B); adenosine A1,2,3; alpha1, alpha2; beta1, beta2; M1,2,3,4,5; H1,2,3; CB1,2; D1,2,3,4,5; 5HT1A,1B,2A,2C,3,5A,6,7 and KATP. Weak displacement (25%) was evident at batrachotoxin site 2 on voltage gated Na+ channels. LCM did not inhibit neurotransmitter transport mechanisms for norepinephrine, dopamine, 5-HT or GABA, nor did it inhibit GABA transaminase. LCM at 100 microM produced a significant reduction in the incidence of excitatory postsynaptic currents (EPSC's) and inhibitory postsynaptic currents (IPSC's) in cultured cortical cells and blocked spontaneous action potentials (EC50 61 microM). LCM did not alter resting membrane potential or passive membrane properties following application of voltage ramps between -70 to +20 mV. The voltage-gated sodium channel (VGSC) blocker phenytoin potently blocked sustained repetitive firing (SRF) but, in contrast, 100 microM LCM failed to block SRF. No effect was observed on voltage-clamped Ca2+ channels (T-, L-, N- or P-type). Delayed-rectifier or A-type potassium currents were not modulated by LCM (100 microM). LCM did not mimic the effects of diazepam as an allosteric modulator of GABA(A) receptor currents, nor did it significantly modulate evoked excitatory neurotransmission mediated by NMDA or AMPA receptors (n > or = 5). Evidently LCM perturbs excitability in primary cortical cultures but does not appear to do so via a high-affinity interaction with an acknowledged recognition site on a target for existing antiepileptic drugs.
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PMID:Seeking a mechanism of action for the novel anticonvulsant lacosamide. 1662 Aug 82

Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABA(A) receptors, the primary target of most anesthetics. alpha6beta2/3delta receptors are subtypes of the GABA(A) receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates alpha6beta2delta and alpha6beta3delta receptors. Additionally, at higher concentrations, ketamine directly activates these GABA(A) receptors. Comparatively, dizocilpine (MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on alpha6beta2delta receptors. Of the recombinant GABA(A) receptor subtypes examined (alpha1beta2, alpha1beta2gamma2, alpha1beta2delta, alpha4beta2gamma2, alpha4beta2delta, alpha6beta2gamma2, alpha6beta2delta, and alpha6beta3delta), the actions of ketamine were unique to alpha6beta2delta and alpha6beta3delta receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from alpha6-containing GABA(A) receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null alpha6(-/-) and delta(-/-)mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on alpha6beta2/3delta receptors.
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PMID:Ketamine, but not phencyclidine, selectively modulates cerebellar GABA(A) receptors containing alpha6 and delta subunits. 1848 Feb 94

One of the most consistent findings in schizophrenia is the decreased expression of the GABA synthesizing enzymes GAD(67) and GAD(65) in specific interneuron populations. This dysfunction is observed in distributed brain regions including the prefrontal cortex, hippocampus, and cerebellum. In an effort to understand the mechanisms for this GABA deficit, we investigated the effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP), which elicits schizophrenia-like symptoms in both humans and animal models, in a chronic, low-dose exposure paradigm. Adult rats were given PCP at a dose of 2.58 mg/kg/day i.p. for a month, after which levels of various GABAergic cell mRNAs and other neuromodulators were examined in the cerebellum by qRT-PCR. Administration of PCP decreased the expression of GAD(67), GAD(65), and the presynaptic GABA transporter GAT-1, and increased GABA(A) receptor subunits similar to those seen in patients with schizophrenia. Additionally, we found that the mRNA levels of two Golgi cell selective NMDAR subunits, NR2B and NR2D, were decreased in PCP-treated rats. Furthermore, we localized the deficits in GAD(67) expression solely to these interneurons. Slice electrophysiological studies showed that spontaneous firing of Golgi cells was reduced by acute exposure to low-dose PCP, suggesting that these neurons are particularly vulnerable to NMDA receptor antagonism. In conclusion, our results demonstrate that chronic exposure to low levels of PCP in rats mimics the GABAergic alterations reported in the cerebellum of patients with schizophrenia (Bullock et al., 2008. Am. J. Psychiatry 165, 1594-1603), further supporting the validity of this animal model.
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PMID:Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine. 1965 Nov 69