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Phencyclidine in Low Doses Selectively Blocks a Presynaptic Voltage-Regulated Potassium Channel in Rat Brain (Nerve Terminals/Synaptosomes/Mrb Efflux) D

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Phencyclidine in Low Doses Selectively Blocks a Presynaptic Voltage-Regulated Potassium Channel in Rat Brain (Nerve Terminals/Synaptosomes/Mrb Efflux) D Proc. Nati. Acad. Sci. USA Vol. 83, pp. 189-192, January 1986 Neurobiology Phencyclidine in low doses selectively blocks a presynaptic voltage-regulated potassium channel in rat brain (nerve terminals/synaptosomes/MRb efflux) D. K. BARTSCHAT AND M. P. BLAUSTEIN Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD 21201 Communicated by Bernhard Witkop, September 5, 1985 ABSTRACT Phencylidine (PCP) is a major drug of abuse METHODS in the United States. It produces a toxic confusional psychosis in man. We show here that nanomolar to micromolar concen- Preparation of Synaptosomes. Synaptosomes prepared as trations of PCP and behaviorally active congeners selectively described (12, 14) were equilibrated with physiological salt block voltage-regulated noninactivating (or very slowly inac- solution (PSS; 5 mM KCI/145 mM NaCl/2 mM MgCl2/10 tivating) presynaptic K channels in the brain. The rank order mM glucose/0.5 mM Na2HPO4/0.1 mM unlabeled RbCl/10 of potency for blockage of these K channels parallels both the mM Hepes buffer titrated to pH 7.4 with NaOH) and were relative ability of these agents to produce characteristic behav- allowed to accumulate tracer IRb (20 ,Ci/ml of PSS; 1 Ci = ioral deficits in rats and their ability to displace [3H]PCP from 37 GBq) at 30'C for 30 min. its high-affinity binding sites in brain. In view of the enhanced Measurement of "Rb Efflux from Synaptosomes. Aliquots voltage-gated Ca influx that would be expected to accompany (30 1.l) of the 86Rb-loaded synaptosome suspension were blockage of presynaptic K channels, this mechanism could pipetted onto glass fiber filters, were washed free of extra- explain the excessive neurotransmitter release that is charac- cellular tracer with PSS, and were then exposed to efflux teristic of PCP intoxication. medium for various lengths of time (1-4 sec). Rb efflux was terminated by the rapid addition of "stopping solution" ion An understanding of the neuronal site(s) of action of containing the K-channel blockers tetraethylammonium phencyclidine [1-(l-phenylcyclohexyl)piperidine, PCP, "an- (145 mM), tetrabutylammonium ion (5 mM), and RbCl (0.1 gel dust"] is of major social importance, since PCP is widely mM) but no NaCl or KCl. Suction was rapidly applied, and abused in some areas of the United States. This drug the filters and filtrates were counted by liquid scintillation produces a toxic confusional psychosis in man that repro- spectroscopy; Rb efflux was expressed as: duces many ofthe primary symptoms of schizophrenia (1, 2). Rb efflux (%) = 86Rbffltrate x 100. The precise mechanism of action of this agent is not known, =6Rbfltrate + "Rbfilter but many studies suggest that the complex behavioral syn- The efflux medium was similar to the loading medium; in drome elicited by PCP is a consequence of altered central experiments involving increased external potassium concen- synaptic transmission (1, 2). While PCP binds with high tration, [K]0, K replaced Na mole-for-mole. When drugs affinity to brain membranes (3-5), the physiological activity were tested in the effiux medium, they also were added to the of these receptors has not been elucidated. wash medium to facilitate equilibration with the synapto- Several different mechanisms have been proposed to somes. See refs. 12 and 13 for additional details. account for the behavioral effects of PCP and its analogues: for example, they block the channels associated with nico- tinic cholinergic receptors (6, 7). However, many of the RESULTS analogues that display potent antinicotinic activity are be- Synaptosomes Possess Voltage-Regulated K Channels. Rb haviorally inactive (6, 7). Phencyclidines also block N- efflux from synaptosomes loaded with "Rb was used to methyl-D-aspartate (NMDA)-activated excitatory postsyn- assess the K permeability of the nerve terminals under aptic potentials in brain (8, 9), but this effect does not explain "resting" conditions and under conditions in which the the excess neurotransmitter release seen in PCP intoxication terminals were depolarized by increasing [K]0. 86Rb, with a (1, 2). In addition, PCP has been proposed to interact with a" half-life 36 times longer than 42K, is a suitable tracer for K (12) opiate receptors (4), but the existence of a distinct a opiate because (i) Rb, like K, is accumulated by synaptosomes via receptor subtype has been questioned recently (10). a metabolically active, ouabain-sensitive route; (it) Rb per- One effect of low concentrations of PCP is blockade of a meates most neuronal K channels nearly as well as does K portion of the K-stimulated 1Rb efflux from rat brain itself; and (iii) synaptosomes preloaded with both 42K and presynaptic nerve terminals (synaptosomes) (6, 11). We 86Rb have qualitatively similar K and Rb effluxes. recently examined the properties of "*Rb efflux from synap- K channel activity in synaptosomes was determined from tosomes and found four physiologically and pharmacologi- the Rb efflux as illustrated in Fig. 1. "Rb efflux under resting cally distinct K channels (12, 13). The experiments presented conditions (5 mM [K]o in Fig. 1) was about 0.3-0.4%/sec in this report were designed to determine whether PCP and (component R), which corresponds to a resting K permeabil- chemically related analogues selectively block a single class ity of 2.4 x 10-7 cm/sec (12). Rb efflux under these of nerve terminal K channels at concentrations relevant to conditions probably reflects the mechanism(s) responsible their behavioral effects. for the normal K permeability of the resting terminals. The publication costs of this article were defrayed in part by page charge Abbreviations: PCP, phencyclidine [1-(1-phenylcyclohexyl)piperi- payment. This article must therefore be hereby marked "advertisement" dine]; [K]0, external potassium concentration; TCP, 1-[1-(2-thienyl)- in accordance with 18 U.S.C. §1734 solely to indicate this fact. cyclohexyl]piperidine. 189 Downloaded by guest on September 29, 2021 190 Neurobiology: Bartschat and Blaustein Proc. NatL Acad Sci. USA 83 (1986) I15 PCP Selectively Blocks Voltage-Regulated Noninactivating K Channels. To determine if PCP affects presynaptic K channels, this drug was tested for its ability to block the various components of the Rb efflux. In the experiment of I Fig. 1 Upper, the effects of 10 and 100 ,M PCP were examined in nominally Ca-free solutions. In 100 mM [K]0 medium, 10 AuM PCP depressed the 'Rb efflux through S by 04. about 35% but had negligible effect on component T. Increas- 0~~~~ .0 ing PCP to 100 ,uM had little additional effect on S but blocked component T by about 45%. Although not shown here, Tome,soecs component R and the Ca-dependent component C (13) were virtually unchanged by 100 ,M PCP. The dose-response curves for the effects of PCP on components S and Tare illustrated in Fig. 1 Lower. Note that low doses of PCP selectively blocked about one-third of 0 1 2 3 4 component S (Sv); higher doses inhibited T as well, but with Time,.sec little additional effect on S. Therefore, at PCP concentrations similar to those that elicit behavioral effects (0.1-1.0 mg/kg, 120 r corresponding to about 0.1-1 AM; ref. 15), the voltage- I Component T regulated presynaptic K channels, reflected in the PCP- sensitive portion of component S, should be selectively \o \ blocked. 80p- Is-o I The biphasic PCP dose-response curve for component Sin 0 Fig. 1 Lower implies that component S represents more than one class of K channels with different sensitivities to PCP. 601- 4-i This view is supported by calculations (12) that indicate that .0 depolarization of the terminals with 100 mM [K]0 should 401- Component S increase the driving force for unidirectional 'Rb efflux SR through the resting K permeability (component R), even with 20 no increase in conductance. Assuming ohmic behavior for R, about two-thirds ofthe increased Rb efflux observed between 0 1 and 4 sec in 100 mM [K]O (i.e., two-thirds of component S) can be accounted for by this electrodiffusion mechanism 0 -7 -5 (component SR in Fig. 1 Lower). The remaining Rb effiux PCP, log M through S (Sv) may be mediated by a class of voltage- regulated, noninactivating K channels that is uniquely sen- FIG. 1. Time course of 'Rb efflux from synaptosomes; the effect sitive to PCP. This view is supported by pharmacological of PCP. (Upper) 86Rb efflux in S mM K (o), 100 mM K (control) (o), experiments in which the inhibition of component S by 100 mM K/10 AtM PCP (*), or 100 mM K/100 AuM PCP (n). The data are means of six determinations. (Lower) PCP dose-response curves tetraalkylamines is evidently biphasic (12). for the inhibition of components S (o) and T(e). The data are means The possibility that component S consists of both Rb effiux offour determinations ± SEM. Similar results were obtained in three through PCP-sensitive voltage-regulated K channels (Sv) and other experiments. The components of 86Rb efflux indicated in the electrically driven efflux through voltage-independent com- figure are: R, Rb efflux in 5 mM K media (expressed in %/sec); S, ponent R (SR) was examined further in the experiments Rb efflux between 1 and 4 sec (%/sec) in K-rich medium minus represented in Fig. 2. The rate of "Rb efflux in nominally component R; T, K-dependent increment (%) in Rb efflux when the Ca-free media was measured at various [K]0 (see Fig. 1 efflux is extrapolated back to time zero; Sv = component of S that Upper) and figure 6 in ref. 12); the Rb efflux between 2 and is blocked by PCP; and SR = PCP-insensitive portion of component 4 sec (component 5) is plotted as a function of in Fig.
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