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PubMed2002

Acute administration of phencyclidine induces tonic activation of medial prefrontal cortex neurons in freely moving rats.

Recent studies have reported that acute administration of the psychotomimetic drug phencyclidine results in considerable increases in the amounts of both extracellular glutamate and dopamine in the medial prefrontal cortex (mPFC). However, the effect of phencyclidine on the firing activity of mPFC neurons remains unknown. Here, we report the first data on phencyclidine-induced activation of mPFC neurons in freely moving rats. Unanesthetized rats received an intraperitoneal injection of either phencyclidine (5 mg/kg) or physiological saline (0.5 ml/kg) in order to investigate the impulse activity of mPFC neurons and behavioral activity. The phencyclidine injection induced a remarkable increase (two-fold or more) in the spontaneous discharge rate of the majority of mPFC neurons (20/23), and this increase lasted for more than 70 min. In addition, a considerable augmentation of behavioral activity was observed that nearly paralleled that of the mPFC neuronal activation. In contrast, microiontophoretically applied phencyclidine exerted little influence on the spontaneous firing activity of most mPFC neurons (25/29) in anesthetized rats, although systemically applied phencyclidine produced activation of mPFC neurons even under general anesthesia. These results suggest that the behavioral abnormalities induced by acute administration of phencyclidine may be caused by hyperactivation of mPFC neurons, and that this hyperactivation is elicited through excitatory inputs from brain regions outside the mPFC.

Action Potentials↗
PubMed1998

Acute phencyclidine neurotoxicity in rat forebrain: induction of haem oxygenase-1 and attenuation by the antioxidant dimethylthiourea.

Phencyclidine and other N-methyl-D-aspartate receptor antagonists are toxic to pyramidal neurons in the posterior cingulate/retrosplenial cortex of rat brain. Previous studies have shown induction of heat shock protein 70 in affected neurons. In this study, expression of haem oxygenase-1, a heat shock protein induced by oxidative stress, was examined in rat forebrain after administration of a single intraperitoneal dose of phencyclidine (50 mg/kg). Northern and Western blot analyses of brain tissue extracts from phencyclidine-treated rats revealed a marked induction of haem oxygenase-1 mRNA and protein, respectively. Immunohistochemistry studies revealed that phencyclidine increased haem oxygenase-1 immunoreactivity primarily in posterior cingulate/retrosplenial, piriform and entorhinal cortices, striatum and hippocampus. Haem oxygenase-1 protein was induced in non-neuronal cells, mainly astrocytes. Some microglia expressing haem oxygenase-1 protein were also found in the posterior cingulate/retrosplenial cortex. Haem oxygenase-1 immunoreactive astrocytes and microglia were present in close proximity to the heat shock protein 70-positive neurons in the posterior cingulate/retrosplenial cortex following phencyclidine. Pretreatment of rats with 1,3-dimethylthiourea, an antioxidant, significantly reduced haem oxygenase-1 protein induction by phencyclidine. Thus, induction of haem oxygenase-1 in glia by phencyclidine appears to be mediated mostly by oxidative stress. Experiments with the amino cupric silver stain for neuronal degeneration revealed phencyclidine-induced neurotoxicity in the posterior cingulate/retrosplenial cortex. The number of affected neurons was significantly reduced after 1,3-dimethylthiourea pretreatment. This suggests that the neurotoxicity of N-methyl-D-aspartate antagonists is due in part to the oxidative stress and may be amenable to therapeutic interventions.

Animals↗
PubMedDate not supplied

Cardiac actions of phencyclidine in isolated guinea pig and rat heart: possible involvement of slow channels.

The mechanisms responsible for the positive inotropic effect of phencyclidine were studied in isolated preparations of guinea pig and rat heart. In electrically paced left atrial muscle preparations, phencyclidine increased the force of contraction; rat heart muscle preparations were more sensitive than guinea pig heart muscle preparations. The positive inotropic effect of phencyclidine was not significantly reduced by a combination of phentolamine and nadolol; however, the effect was competitively blocked by verapamil in the presence of phentolamine and nadolol. Inhibition of the outward K+ current by tetraethylammonium chloride also produced a positive inotropic effect; however, the effect of tetraethylammonium was reduced by phentolamine and nadolol, and was almost insensitive to verapamil. The inotropic effect of phencyclidine was associated with a marked prolongation of the action potential duration and a decrease in maximal upstroke velocity of the action potential, with no change in the resting membrane potential. In partially depolarized atrial muscle preparations, which were reactivated by elevation of the extracellular Ca2+ level and stimulation at a high voltage, phencyclidine markedly increased the amplitude and the duration of the slow action potentials. Rat heart muscle preparations had higher sensitivity to these effects of phencyclidine. The specific [3H]phencyclidine binding observed with membrane preparations from guinea pig ventricular muscle was saturable with a single class of high-affinity binding site. This binding was inhibited by verapamil, diltiazem, or nitrendipine, but not by ryanodine or tetrodotoxin. These results suggest that the positive inotropic effect of phencyclidine results from enhanced Ca2+ influx via slow channels, either by stimulation of the channels or secondary to inhibition of outward K+ currents.

Animals↗
PubMed1979

Some structure activity relationships of phencyclidine derivatives as anticholinergic agents in vitro and in vivo.

Phencylidine derivatives exhibit multiple interactions with cholinergic systems: they block nicotinic and muscarinic receptors,and inhibit both acetyl and butyrylcholinesterase. In peripheral tissue, the net pharmacological effects of the phencyclidines is antiacetylcholine activity. The dissociation constants measured in isolated smooth muscle and from competition experiments for the muscarinic high-affinity binding sites in brain homogenates (Kd = 10(-5) - 10(-6) M) are 3--4 orders of magnitude lower than those of anticholinergic glycolate esters. However, phencyclidines have comparable potency to that of d-tubocurarine in blocking the nicotinic receptor in the isolated frog rectus abdominis (Kd = 10(-6) M). Brain uptake experiments of (3H) labeled phencyclidine showed that during the time period in which central effects are observed with these drugs their concentration in brain reaches values close to the Kd (10(-5) - 10(-6) M). This finding, and the cross tolerance observed in vivo between phencyclidine and other centrally acting cholinergic drugs supports the possible involvement of cholinergic interactions in the psychotropic action of phenyclidine derivatives. Quantum chemical calculations of the interaction pharmacophores of drugs in the phencyclidine series have indicated the molecular determinants for the interaction of these drugs with the muscarinic receptor. The calculations revealed that these drugs can match the reactivity characteristics of ACh and the semi-rigid muscarinic agonist 3-acetoxyquinuclidine, but their rigid molecular frame will be conductive to antagonistic rather than agonistic activity when the drug-receptor complex is formed. The identification of a "cholinergic interaction pharmacophore" for these drugs by quantum mechanical calculations made possible the suggestion of other active phencyclidine derivatives, e.g. p-NH2 and p-OH analogs which proved to be equipotent to phencyclidine. The inactivity of the p-NO2 derivative was also predicted on this basis and served as an additional confirmation of the theoretical criterion for activity; the difference between the activities of the ethynyl and cyano derivatives was explained by the modification of the cholinergic interaction pharmacophore. On the basis of these theoretical predictions, electrophysiological studies were carried out by the others and the results prompted the suggestion that "physostigmine is of potential value in the treatment of post-operative patients emerging from ketamine anesthesia and in the treatment of phencyclidine overdosed patients".

Animals↗
PubMed1984

Mechanism of phencyclidine binding to the acetylcholine receptor from Torpedo electroplaque.

The mechanism of phencyclidine binding to Torpedo acetylcholine receptor-rich membranes was investigated. The rate of [3H]phencyclidine association is 10(3)- to 10(4)-fold more rapid when phencyclidine and carbamoylcholine are added simultaneously to acetylcholine receptor-rich membranes than when phencyclidine is added to membranes previously equilibrated with carbamoylcholine or membranes in the absence of carbamoylcholine. The mechanism of binding under conditions in which the slower rate was observed was studied with thermodynamic, viscosity, and kinetic experiments. Association and dissociation rates were highly dependent on temperature with activation energies of 26-30 kcal/mole. Viscosity had no effect on the association rate but increased the dissociation rate. These studies suggest that the binding is not diffusion-controlled but rather is limited by a significant energy barrier. The association rate was determined as a function of the concentration of acetylcholine receptor-rich membranes and the concentration of phencyclidine. In the presence of carbamoylcholine, the association rate was highly dependent upon the concentration of acetylcholine receptor but virtually insensitive to the concentration of phencyclidine. In the absence of carbamoylcholine, the association rate seemed to be a hyperbolic function of both the phencyclidine and the acetylcholine receptor concentration. The minimal model capable of explaining the data is a mechanism by which phencyclidine binds to two conformations of the acetylcholine receptor, one conformation having a higher affinity and constituting a lower percentage of receptors and the other having a lower affinity and constituting a higher percentage. The data are consistent with the possibility that the high-affinity conformation is the open-channel state of the acetylcholine receptor.

Animals↗
PubMed1983

Tolerance to phencyclidine in pigeons: cross-tolerance to ketamine.

In order to determine whether tolerance developed to the behavioral effects of phencyclidine, pigeons were trained to respond under a multiple fixed-ratio 30, fixed-interval 600-sec schedule of food presentation. When rates and patterns of responding reached stability, dose-response curves for phencyclidine (0.1-10 mumol/kg i.m.), ketamine (3-56 mumol/kg i.m.) and pentobarbital (1-75 mumol/kg i.m.) were determined. Phencyclidine, ketamine and pentobarbital all decreased fixed-ratio 30 responding in a dose-related manner and increased fixed-internal 600-sec. responding at immediate doses. At higher doses, pentobarbital decreased responding. High doses of phencyclidine and ketamine suppressed responding in the early portions of the session, but when responding returned, it returned at a high rate. After 35 daily injections of phencyclidine (3 mumol/kg/day i.m.), dose-response curves were redetermined for all three drugs. A tolerance was observed for moderate doses of phencyclidine, and a moderate cross-tolerance was observed to ketamine. No tolerance was observed for the total suppression of responding produced by high doses of phencyclidine and ketamine early in the test sessions. No cross-tolerance to pentobarbital was observed. After 215 days of daily phencyclidine administration, no withdrawal signs were observed upon the discontinuation of daily injections.

Animals↗
PubMed1981

The effect of phencyclidine on the turnover rate of acetylcholine in various regions of rat brain.

Although the mechanism of action of phencyclidine is poorly understood, an interaction of phencyclidine with central cholinergic systems has been proposed. To test this hypothesis directly, we investigated the effects of this compound on the turnover rate of acetylcholine (TRACh) in various areas of the rat brain. In doses of 14.3 to 114.4 mumol/kg (i.p.), phencyclidine increased the TRACh in the frontal cortex, parietal cortex and diencephalon when rats were sacrificed 30 min after drug treatment. In contrast, these doses of phencyclidine had no effect on the TRACh in the hippocampus or striatum. The increases in cortical and diencephalic TRACh were temporally correlated with the behavioral activity elicited by phencyclidine. A 7 day chronic treatment regimen (28.6 mumol/kd/day) provided no further evidence for tolerance development to the effects of phencyclidine on the TRACh in the frontal cortex or diencephalon. These results demonstrate that phencyclidine differentially affects cholinergic dynamics in various areas of the rat brain. The neurochemical profile of phencyclidine reported herein is similar to those previously described for central stimulants such as d-amphetamine, nomifensine and cocaine.

Acetylcholine↗
PubMed1982

Biochemical properties of the brain phencyclidine receptor.

This paper gives a detailed account of techniques which can be used to measure [3H]phencyclidine binding to its receptor. The main properties of the binding component are the following: (i) It is rapidly heat-inactivated at temperatures over 50 degrees C. (ii) It is destroyed by proteases like trypsin, pronase or papain suggesting that it is of a protein nature. The receptor structure is resistant to chymotrypsin. (iii) A good correlation was found between the pharmacological activity of 30 different analogs as measured by the rotarod assay and the affinity of these different molecules for the phencyclidine receptor. (iv) Monovalent and divalent cations antagonize [3H]phencyclidine binding to its receptor. The dissociation constant is 15 mM, the same for Na+, Li+, K+, cholinium or Tris. Na+ (and other monovalent cations) and phencyclidines bind to distinct sites. The saturation of the Na+ site by Na+ modulates the affinity of phencyclidine for its receptor. Divalent cations antagonize [3H]phencyclidine binding in the absence of Na+. This antagonism is of the non-competitive type. (v) [3H]phencyclidine binding is also antagonized by histrionicotoxin and by local anaesthetics.

Amphibian Venoms↗
PubMed1990

A comparison of the psychopharmacological profiles of phencyclidine, ketamine and (+) SKF 10,047 in the trimethyltin rat model.

The potential neuroprotective effects of phencyclidine, ketamine and (+) SKF 10,047 were investigated in the trimethyltin (TMT)-treated rat. Of the three drugs used in this study, only phencyclidine (5 mg/kg i.p.) reversed the behavioral hyperactivity and deficits in spatial localization of TMT-treated rats. Neurochemically, phencyclidine and (+) SKF 10,047 were without effect on the neurotransmitters (e.g. noradrenaline, dopamine, serotonin and 5-hydroxindole 3-acetic acid), examined in the amygdaloid cortex and hippocampal regions, while ketamine increased the steady state concentrations of 5-HIAA in the amygdaloid cortex. These results suggest the involvement of the phencyclidine receptor in reversal of the behavioural impairments produced by TMT in rats. The significance of these results with respect to phencyclidine and sigma receptors is discussed. The lack of effect of (+) SKF 10,047 in this model may reflect behavioural differences between phencyclidine and sigma ligands. It may be concluded that the TMT model can be exploited for studying the mechanism of action of molecules liable to have an effect at the phencyclidine receptor site, as opposed to the sigma receptor.

Animals↗
PubMed1978

Plasma phencyclidine pharmacokinetics in dog and monkey using a gas chromatography selected ion monitoring assay.

Phencyclidine was determined by gas chromatography selected ion monitoring in six dogs and seven monkeys. Aliquots of venous blood were taken over 4 h in the monkey after 1.1 mg kg-1 and over 24 h in the dog after 1.0 mg kg-1 of phencyclidine i.v. Pentadeuterated phencyclidine was used as the internal standard. In the electron impact mode the most abundant fragments in the mass spectrum of phencyclidine were m/e 91 and 200, and 96 and 205 in the [2H5]phencyclidine spectrum. These fragments were used to quantitate the amount of phencyclidine present. In both species, a complex exponential decline of plasma phencyclidine was found in most animals that fit a two compartment open model. In monkeys, the mean half-life (beta phase) was 2.36 h and in the dog it was 2.86 h. Compared with the monkey, the dog considerable emergence delirium. The two species had rather different pharmacokinetics which may be relevant to the observed differences in degree of anesthesia and recovery.

Animals↗
PubMed1981

Quantification of phencyclidine in mainstream smoke and identification of phenylcyclohex-1-ene as pyrolysis product.

Parsley cigarettes containing [3H]phencyclidine were machine smoked, and the mainstream smoke was trapped in glass wool filters. Radioactivity was extracted from these filters with chloroform. The average recoveries of radioactivity were 76, 85, 70, and 69% for cigarettes containing 3, 10, 30, and 50 mg of [3H]phencyclidine hydrochloride, respectively. TLC and GLC-mass spectrometry were employed to identify and quantify compounds in the filter extracts. Approximately one-half of the recovered radioactivity represented a pyrolysis product, phenylcyclohex-1-ene. Formation of this product involved loss of piperidine from phencyclidine. Piperidine, which was not radiolabeled, also may appear in smoke intact. The remainder of the radiolabeled material represented unchanged phencyclidine. Therefore, the percentage of [3H]phencyclidine delivered was approximately 40% of the amount smoked. This result was independent of puff frequency and quantity of phencyclidine hydrochloride smoked over the range tested. The [3H]phencyclidine delivery was compared to the quantities of [3H]-delta 9-tetrahydrocannabinol and [3H]nicotine delivered in mainstream smoke. The recovery of unchanged [3H]-delta 9-tetrahydrocannabinol from placebo marijuana cigarettes injected with a solution containing 3 mg of delta 9-tetrahydrocannabinol was 60%. Tobacco cigarettes injected with [3H]nicotine yielded 70% unchanged nicotine in mainstream smoke.

Cannabis↗
PubMed1998

Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence.

Acute administration of phencyclidine to rats potently activates mesocorticolimbic dopaminergic neurons. The activation of dopamine release and utilization in the prefrontal cortex and nucleus accumbens are associated with profound cognitive impairment and hyperlocomotion, respectively. This dopaminergic activation by phencyclidine is not mediated by direct effects on the cell body regions of the dopamine neurons; however, phencyclidine augments dopamine release locally in the terminal fields. In the present study, the possible involvement of the prefrontal cortex in mediating activation of the mesolimbic dopamine system by phencyclidine was examined. Ibotenic acid lesions of the prefrontal cortex attenuated the biochemical activation of the mesolimbic dopamine neurons by PCP, and prefrontal lesions sharply blunted phencyclidine-, but not amphetamine- or novelty-, induced hyperlocomotion. In addition, injection of phencyclidine directly into the prefrontal cortex increased dopamine utilization in the nucleus accumbens and induced hyperlocomotion. In summary, these studies show that phencyclidine activates the mesolimbic pathway through a mechanism in the prefrontal cortex, possibly by disinhibiting the cortical circuit and activating corticofugal glutamatergic release in the ventral tegmental area.

Animals↗
PubMed1985

A comparison of the discriminative stimulus properties of phencyclidine, given intraperitoneally or intraventricularly in rats.

Rats trained to discriminate intraperitoneally injected phencyclidine (PCP) from saline in a two-lever operant procedure distributed most of their responses on the phencyclidine lever after administration of 150 or 300 micrograms of phencyclidine into a lateral ventricle. This demonstrated that the discriminative stimulus properties of phencyclidine were centrally mediated. On the other hand, the potency of phencyclidine was increased by no more than about 7-fold from intraperitoneal to intraventricular administration. This suggests that either periventricular sites are not involved in mediating the discriminative stimulus properties of phencyclidine or that absorption of phencyclidine to relevant sites in the brain is not markedly enhanced by intraventricular administration.

Animals↗
PubMed1987

Electrophysiological actions of phencyclidine in hippocampal slices from the rat.

The electrophysiological effects of phencyclidine were examined in the CA region of slice preparations of the hippocampus of the rat. The only direct effects of phencyclidine on monosynaptic transmission in the Schaffer collateral/commissural input to the CA region were local anesthetic-like actions, that were observed at concentration greater than or equal to 50 microM, and were characterized by decreases in the amplitude of both orthodromically- and antidromically-evoked potentials. However, phencyclidine, at concentrations greater than 0.5 microM, increased the apparent sensitivity of slices to perfusion with norepinephrine (NE), such that a previously subthreshold concentration of NE significantly increased the magnitude of the population spike response through an action at beta-adrenergic receptors. This action of phencyclidine appears to reflect its ability to block the high affinity uptake of NE into nerve terminals in the slice preparation. Because these responses were observed at concentrations of phencyclidine which are found in the brains of abusers of phencyclidine, they may play a significant role in the overall neuropharmacological response to phencyclidine.

Animals↗
PubMed1989

Effects of self-administered phencyclidine on regional uptake of 2-deoxy-D-[1-14C]glucose in brain.

Phencyclidine profoundly alters cerebral metabolism in the rat. This study explored whether cerebral metabolic effects of phencyclidine differed when the drug was self-administered by trained rats, compared with when it was given acutely to naive rats. The regional cerebral uptake of 2-deoxy-D-[1-(D14C] glucose (DG) was examined following two injections of phencyclidine (0.5 mg/kg/injection, i.v.) or saline in freely-moving, drug-experienced rats. Naive controls received phencyclidine or saline according to an identical dose regimen. In self-administering and naive rats, phencyclidine produced many of the same effects on uptake of DG, including the following: decreases in the habenula, inferior colliculus, sensory cortical areas and corresponding thalamic relay nuclei; and increases in limbic areas (entorhinal and retrosplenial cortices, subicular areas). Some regions (auditory and motor cortices, medial geniculate body, globus pallidus) showed different effects in self-administering and naive rats. Another study, in which rats were not self-administering phencyclidine, but had histories of treatment with drugs similar to those of the self-administering rats, indicated that chronic exposure to drug accounted for some of the differences. Furthermore, differences between the effects of phencyclidine in self-administering, versus non-self-administering rats with similar histories suggested that activity in some regions of the brain may relate to training in drug self-administration and/or behavior.

Animals↗
PubMed1982

Effects of chronic phencyclidine on fixed-ratio responding: no relation to neurotransmitter receptor binding in rat cerebral cortex.

The effects of chronic phencyclidine (3.2 mg/kg for 25 days) on responding maintained under a fixed-ratio 30 schedule of food presentation were studied in rats. Initially phencyclidine produced large decreases in the overall rate of responding. This decrease was due primarily to long pauses in responding and secondarily to a decrease in local rates of responding. Although tolerance developed to the rate-decreasing effects of phencyclidine in each subject, the extent and pattern of its development differed among the subjects. After the chronic drug regimen, the rats were sacrificed. Ligand binding to muscarinic cholinergic, opiate, adrenergic, and serotonergic receptors in cortex was then compared to that in rats which received saline with operant training, phencyclidine alone, or saline alone. Neither operant behavior alone, phencyclidine alone, nor the interaction of phencyclidine and operant behavior was found to alter binding to these receptors. These results indicate that behavioral tolerance develops to phencyclidine, but it is not accompanied by changes in binding to the receptors studied.

Animals↗
PubMed2005

Effects of phencyclidine on schedule-controlled responding following neurotoxic lesions of the striatum.

The effects of phencyclidine on an operant task were evaluated prior to and after neurotoxic lesions of the striatum in rats. Subjects were trained to respond on a fixed-interval 90-second schedule for water presentation. The degree to which phencyclidine disrupted responding was first evaluated (dose range 1.0-4.0 mg/kg). The subjects were then divided into three matched groups and received bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) (100 microg), kainic acid (0.25 microg), or vehicle delivered stereotaxically. 6-OHDA was used to destroy the presynaptic neurons of the nigro-striatal pathway and kainic acid was employed to destroy the postsynaptic neurons whose cell bodies are located in the striatum. Following recovery, the phencyclidine dose-response curve was repeated in the fixed-interval paradigm. It was observed that 6-OHDA-induced damage resulted in a rightward shift of the dose-response curve indicating tolerance to phencyclidine and caused a significant depletion of striatal dopamine and gamma-aminobutyric acid (GABA). Kainic acid-induced damage resulted in a leftward shift in the dose-response curve indicating sensitivity to the schedule-disruptive effects of phencyclidine and produced a significant GABA depletion. The vehicle-treated rats exhibited no shift in their sensitivity to phencyclidine. These observations indicate that the effects of phencyclidine are mediated, at least in part, by striatal dopaminergic neurons.

Animals↗
PubMed1984

Phencyclidine use during pregnancy.

Phencyclidine, a frequently abused drug, has been shown to cross the placenta and may cause harmful effects in the fetus. Therefore, a prospective study was undertaken to determine the extent of phencyclidine use during pregnancy. Two thousand three hundred twenty-seven pregnant women were screened for phencyclidine use by questionnaire and enzyme-mediated immunoassay technique urine testing. Nineteen women were identified as using phencyclidine during pregnancy and 149 were past users. Women with a history of phencyclidine use were compared with a population sample of nonusers. Phencyclidine users were more likely to be white; they were also younger and of lesser parity than nonusers. The majority had a history of multiple drug abuse. Although 7.3% of the population gave a history of phencyclidine use and 0.8% were found to use the drug during pregnancy, these figures are believed to underestimate the problem.

Female↗