Interaction of phencyclidine ("angel dust") with a specific receptor in rat brain membranes.

Abstract

I3H]Phencyclidine binds to synaptic membranes from rat brain in a saturable, reversible, and selective fashion, with a dissociation constant Kd of 0.25 jiM and a maximal binding capacity of 2.4 pmol/mg of membrane protein-i.e., 250 pmol/g of brain. The binding activity is concentrated in synaptosomal fractions, is higher in cerebral cortex and corpus striatum than in other parts of the rat brain, and is not detectable in the spinal cord. Only molecules of the phencyclidine series and ketamine are able to bind to the phencyclidine receptor.[3H]Phencyclidine bound to its receptor is not displaced by the classical neurotransmitters or neuromodulators. There is a good correlation between the apparent affinities of a series of phencyclidine analogs for the phencyclidine receptor and the pharmacological activities of these analogs as measured by the rotarod assay.Phencyclidine [N-(l-phenylcyclohexyl)piperidine] was introduced in the late 1950s as an intravenous general anesthetic that was nontoxic and nonflammable and produced minimal cardiorespiratory depression (1, 2). These clinical advantages were unfortunately offset by its prolonged duration of action and psychotomimetic effects (3), properties that have contributed to the emergence of phencyclidine as a major drug of abuse in the United States (4, 5). Phencyclidine produces long-lasting psychosis thought to resemble schizophrenia more than does the psychosis produced by any other psychotomimetic (3). Phencyclidine exaggerates psychopathology. Schizophrenics experience severe thought disorders and behavioral problems as long as 1 month after a single injection. Quiet mental patients become catatonic, and reactive ones become overreactive and restless (6, 7). In this paper we investigate the characterization of the phencyclidine receptor in mammalian brain. The data presented here show that a component present in rat brain membranes binds [3H]phencyclidine specifically and with a fairly high affinity. This component may be the physiologically important receptor that mediates the effects of phencyclidine in the central nervous system. MATERIALS AND METHODSMaterials. Molecules in the phencyclidine series were synthesized as previously described (8). The structures of these drugs are shown in Table 1. [3H]Phencyclidine was prepared on request at New England Nuclear by catalytic reduction at room temperature with tritium gas and purification of the reaction mixture on a silica gel column by high-pressure liquid chromatography. The purity of the product was established by thin-layer chromatography on silica gel in either methanol or 1-butanol/acetic acid/water, 25:4:10 vol/vol/vol. The specific radioactivity of the pure [3H]phencyclidine was 60 Ci/mmol (1 Ci = 3.7 x 1010 becquerels). Trans -r2OMt * Ph, phenyl; Th, 2-thienyl. 4678The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

Localization of phencyclidine binding sites on alpha and beta subunits of the nicotinic acetylcholine receptor from Torpedo ocellata electric organ using azido phencyclidine

“…These membranes have been shown to possess high affinity binding sites for PCP (Vincent et al, 1979;Zukin and Zukin, 1979). If AZ-PCP binds like PCP to the high affinity PCP binding sites in brain membranes, it will be able to serve as a potent photoaffinity probe for these sites.…”

“…With the development of sensitive binding assays for receptors, studies have indicated that PCP interferes with the binding of several drugs to their muscarinic (Kloog et al, 1977;Gabrielevitz et al, 1980;Vincent et al, 1978;Aronstam et al, 1980), opiate (Vincent et al, 1978), and other receptors. The existence ' of specific high affinity binding sites of PCP in rat brain tissue has also been demonstrated (Vincent et al, 1979;Zukin and Zukin, 1979). It is not known whether the anticholinergic activity of PCP Paster et al, 1974;Kloog et al, 1977;Kalir et al, 1978) contributes to its psychotic activity.…”

Ketamine-Induced NMDA Receptor Hypofunction as a Model of Memory Impairment and Psychosis

“…An important element of several of these theoretical positions is that NMDA receptor hypofunction (NRH) produced by any mechanism can be psychotogenic. This has renewed interest in the clinical effects of NMDA glutamate receptor antagonists.Ketamine and phencyclidine (PCP) are non-competitive NMDA glutamate receptor antagonists (Zukin and Zukin 1979;Vincent et al 1979;Lodge and Anis 1982;Lodge et al 1987) which can produce a transient state of NRH in the brain. Early investigators characterized a PCP-induced clinical syndrome of schizophrenia-like Received March 18, 1998; revised June 19, 1998; accepted June 29, 1998.…”

“…Ketamine and phencyclidine (PCP) are non-competitive NMDA glutamate receptor antagonists (Zukin and Zukin 1979;Vincent et al 1979;Lodge and Anis 1982;Lodge et al 1987) which can produce a transient state of NRH in the brain. Early investigators characterized a PCP-induced clinical syndrome of schizophrenia-like symptoms, including hallucinations, delusions, idiosyncratic and illogical thinking, poverty of speech and thought, agitation, disturbances of emotion, affect, withdrawal, decreased motivation, and dissociation (Johnstone et al 1959;Luby et al 1959;Rosenbaum et al 1959;Luby et al 1962;Corssen and Domino 1966;Bakker and Amini 1961;Davies and Beech 1960;Domino and Luby 1981).…”

Glutamate Modulation of Dopamine Measured in Vivo with Positron Emission Tomography (PET) and 11C-Raclopride in Normal Human Subjects

“…These agents bind to a site within the N-methyl-D-aspartate (NMDA) receptor complex, a glutamate receptor subtype (Corssen and Domino 1966;Zukin and Zukin 1976;Vincent et al 1979). At anesthetic doses (1.0 mg/kg and higher), ketamine has multiple neurochemical effects including the inhibition of monoamine transport and acetylcholinesterase and the blockade of sigma receptors (e.g., Smith et al 1981;Oye et al 1991;Cohen et al 1974).…”