Effects of phencyclidine on [3HJcate-cholamine and [3H]serotonin uptake in synaptosomal preparations from rat brain

Department of Psychiatry, University of Chicago, Chicago, IL (H.Y.M., R.C.A. and J.M.D.) U.S.A.
Biochemical Pharmacology (Impact Factor: 5.01). 09/1977; 26(15):1435-1439. DOI: 10.1016/0006-2952(77)90370-7


Phencyclidine inhibited uptake in vitro of [3H]norepinephrine (ic50 0.52 μM), [3H]dopamine (ic50 0.73 μM) and [3H]serotonin (ic50 0.80 μM) in crude synaptosomal preparations from rat brain through a competitive mechanism. Phencyclidine was fairly similar in potency to d-amphetamine and methylphenidate in inhibiting catecholamine uptake but was 8 times more potent than d-amphetamine and 34 times more potent than methylphenidate in inhibiting [3H]serotonin uptake.

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    • "Phencyclidine inhibits dopamine uptake and enhances dopamine release (Garey and Heath, 1976; Smith et al., 1977; Vickroy and Johnson, 1980; 1982), and the behavioural actions of phencyclidine could be reversed by functional antagonists of dopaminergic transmission (Freeman and Bunney, 1984). Similar effects of phencyclidine on noradrenaline and 5-hydroxytryptamine (5-HT) transport were also reported (Taube et al., 1975; Garey and Heath, 1976; Smith et al., 1977). The cholinergic system also provided potential targets for phencyclidine, which has modest affinity for nicotinic and muscarinic receptors as well as for cholinesterases (Kloog et al., 1977; Vincent et al., 1978; Albuquerque et al., 1980). "
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    ABSTRACT: The history of ketamine and phencyclidine from their development as potential clinical anaesthetics, through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The finding of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; 172(17). DOI:10.1111/bph.13222 · 4.84 Impact Factor
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    • "M100907, with PCP will not prevent the development of the NOR deficit in Long–Evans rats or C57Bl mice given sc PCP (Horiguchi et al., Rajagapol et al., unpublished data). The basis for this increase in extracellular 5-HT levels by NMDAR antagonists may be activation of dorsal and medial raphe 5-HT neurons as well as inhibition of the reuptake of 5-HT by a direct effect on the 5-HT transporter (Smith et al., 1977; Hori et al., 2000). Nabeshima et al. (1988) have reported that PCP, in vitro, like the 5-HT 2A/2C inverse agonist, ritanserin, protected 5-HT 2A/2C receptors from inactivation by sulfhydryl-modifying-agent, N-ethylmaleimide, suggesting that PCP due to its ability to enhance the extracellular concentrations of 5-HT as shown in Fig. 2. Sub-chronic treatment with PCP increased 5-HT 1A receptor binding in the medial–prefrontal and dorsolateral–frontal cortex but had no effect on the density of cortical 5-HT 2A receptors (Choi et al., 2009). "
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    ABSTRACT: The N-methyl-d-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT1A, and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT1A partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5–10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.
    The International Journal of Neuropsychopharmacology 11/2013; 16(10):2181-2194. DOI:10.1017/S1461145713000928 · 4.01 Impact Factor
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    • "PCP acts as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor [6]–[8]. Additionally, high doses of PCP block dopamine (DA) reuptake [1], [9]–[11]. Similar to PCP, amphetamine (AMPH) and its derivative methamphetamine (METH) produce behavioral sensitization to locomotor activity, rearing, and stereotypy when they are repeatedly administered [12], [13]. "
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    ABSTRACT: Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex)) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.
    PLoS ONE 10/2010; 5(10):e13722. DOI:10.1371/journal.pone.0013722 · 3.23 Impact Factor
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