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PubMed1998

Phencyclidine and corticosteroids induce apoptosis of a subpopulation of striatal neurons: a neural substrate for psychosis?

Phencyclidine, a non-competitive N-methyl-D-aspartate receptor antagonist and indirect dopamine agonist, has neuroprotective properties. Phencyclidine, however, can also exert toxic effects and causes degeneration of neurons in the retrosplenial cortex. In this paper we demonstrate that acute administration of a high dose of phencyclidine to rats, (80 mg/kg), also causes death of a subpopulation of striatal neurons. The dying cells exhibited many of the morphological and biochemical features of cells undergoing apoptosis as revealed by a silver methenamine stain, propidium iodide fluorescence histochemistry and a TUNEL procedure. The majority of the dying cells tended to be clustered within the dorsomedial aspect of the striatum. The type of striatal cell undergoing apoptosis was determined by stereotaxically injecting a colloidal gold retrograde anatomical tracer into the major areas of striatal termination prior to the administration of phencyclidine. This procedure demonstrated that phencyclidine induced striatal apoptosis is almost exclusively limited to striatopallidal neurons. A similar series of experiments was conducted to determine whether the synthetic corticosteroid, dexamethasone, also induces apoptosis of striatal neurons. Corticosteroids are known to be toxic to hippocampal neurons and interact with striatal dopamine transmission. Acute administration of dexamethasone, (20 mg/kg), induced apoptosis of a subpopulation of striatal cells. As was the case with phencyclidine, most of the dexamethasone-induced apoptotic striatal cells were striatopallidal neurons located within the dorsomedial striatum. The pathology during the early stages of Huntington's disease is restricted to an equivalent subpopulation of striatal neurons. Many Huntington's patients are extremely psychotic during this stage in the progression of the disease. Psychosis is also associated with the acute administration of both phencyclidine and dexamethasone to humans. We accordingly speculate that the selective loss of striatopallidal neurons in the dorsomedial striatum may represent the neural substrate of many forms of psychosis.

Animals↗
PubMed1999

Mutation of structural determinants lining the N-methyl-D-aspartate receptor channel differentially affects phencyclidine block and spermine potentiation and block.

Spermine and other endogenous polyamines potentiate, block and permeate the N-methyl-D-aspartate receptor channel. To identify structural determinants of the N-methyl-D-aspartate channel that mediate spermine's actions, we generated mutant receptors with asparagine (N) to glutamine (Q) or arginine (R) substitutions in the selectivity filter of the channel. We demonstrate that mutation of the three critical asparagines in this domain differentially affects block by phencyclidine and both potentiation and block by spermine. N-to-Q and N-to-R mutations in the N site of the NR1 subunit (N598 in NR1(011), N619 in NR1(100)) and N-to-Q mutations in the N and N + 1 sites (N595 and N596 in NR2A, respectively) of the NR2 subunit (Q/NN, R/NN, N/QN, N/NQ, Q/QN and Q/NQ receptors) reduced affinity for phencyclidine. The Q/NN receptor showed markedly reduced potentiation by spermine, with little or no change in spermine block. The R/NN receptor showed markedly reduced spermine potentiation and affinity for spermine at its block site. The N/QN, N/NQ and Q/QN mutant receptors showed somewhat enhanced spermine block, while the Q/ NQ double mutant exhibited significantly more enhanced spermine block. Thus, the asparagine residues critical to Ca2+ permeability and Mg2+ block of N-methyl-D-aspartate channels are also critical to block by spermine and phencyclidine. To examine the interaction of spermine and phencyclidine within the channel, we performed competition studies. Spermine appeared to compete with phencyclidine for binding to the receptor; however, blocks by phencyclidine and by spermine were not additive. The findings suggest that spermine can bind to a site in the external vestibule of the channel to impede phencyclidine binding, but allow Na+ influx.

Algorithms↗
PubMed1988

Synthesis, absolute configuration, and molecular modeling study of etoxadrol, a potent phencyclidine-like agonist.

Etoxadrol (2a), one of the eight possible optical isomers of 2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane, was synthesized from (S,S)-1-(2-piperidyl)-1,2-ethanediol, which was obtained from cleavage of dexoxadrol (1a, (S,S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane). The absolute configuration of etoxadrol hydrochloride, a phencyclidine-like compound biologically, was determined to be 2S, 4S, and 6S at its three chiral centers by single-crystal X-ray analysis. Epietoxadrol (2b), epimeric with etoxadrol at the C-2 center, was also obtained from the synthesis. This much less potent enantiomer has the 2R,4S,6S configuration. The affinity of etoxadrol to the phencyclidine binding site was found to be comparable to that of phencyclidine itself and was 35 times more potent than its epimer, epietoxadrol. Three diastereomeric mixtures were prepared that had low affinity for the phencyclidine site. In studies of the discriminative stimulus properties of these compounds, it was found that only etoxadrol substituted for the phencyclidine stimulus. With use of computer-assisted molecular modeling techniques, a hypothetical phencyclidine binding site model has been developed that, unlike our former hypothesis based on Dreiding models, correctly predicts the higher affinity of etoxadrol and the lesser affinity of epietoxadrol for the phencyclidine site.

Animals↗
PubMed1980

The effects of phencyclidine and three analogues on motor performance in mice.

A measure of motor impairment in which mice were required to climb to the top of an inverted screen was used to study the effects of phencyclidine. The time course of effects of phencyclidine after intravenous, intraperitoneal and per os administrations was compared. The intravenous route resulted in a rapid peak effect of activity and phencyclidine was most potent by this route. Peak effects of phencyclidine were seen by 30 min after intraperitoneal and per os administrations and the decline in activity was not very different with these two routes. However, greater peak effects were seen with intraperitoneal than per os administration. The effects of phencyclidine were also compared to ketamine, N-ethyl-phenylcyclohexylamine (PCE) and 1-[1-(2-thienyl)-cyclohexyl]-piperidine (TCP). The order of potency was PCE greater than phencyclidine greater than TCP greater than ketamine. PCE, phencyclidine and TCP had similar time courses of activity, whereas ketamine was shorter acting.

Animals↗
PubMed1985

Concurrent phencyclidine and saccharin access: presentation of an alternative reinforcer reduces drug intake.

Six monkeys self-administered orally delivered phencyclidine ("angel dust") and saccharin under concurrent fixed-ratio 16 schedules during daily three-hour sessions. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking spouts. Three saccharin concentrations (0.003%, 0.03% and 0.3%, wt/vol) were tested in a nonsystematic order. For each saccharin concentration, the following series of phencyclidine concentrations (mg/ml) was presented: 0.25, 0.5, 1, 0.25 (retest), 0.125, 0.0625, 0.0312, 0.25 (retest) and 0 (water with stimuli signaling phencyclidine). As the saccharin concentration increased, the number of drug deliveries decreased, and the peaks of the concentration-response functions were shifted to the right. The lowest saccharin concentration (0.003%, wt/vol) maintained responding in excess of phencyclidine levels in only one monkey. The two higher saccharin concentrations maintained behavior far in excess of phencyclidine, but saccharin deliveries decreased in some monkeys as phencyclidine concentration and intake (mg/kg) increased. The time course and patterns of phencyclidine-reinforced responding were also altered when saccharin was concurrently available. The results are discussed in terms of strategies to reduce drug-reinforced behavior, preference between different reinforcers, and measures of reinforcing efficacy.

Animals↗
PubMed1987

Phencyclidine detection during toxicology testing of a university medical center patient population.

The rate of detection of phencyclidine during toxicology testing of a university medical center patient population was studied by retrospective review of the results of 6,870 toxicology panels performed on urine during the period September 1, 1984 to September 1, 1987. The rate was compared with that noted in earlier studies of drug detection at this institution. For the three-year period, 91 panels (1.3%) involving 82 individuals were positive for phencyclidine: men, 49 cases; women, 15 cases; children, 10 cases; and neonates, 8 cases. The typical user was a 25 year old Hispanic or Black man who had ingested phencyclidine alone or in combination with at least one other drug (usually ethanol or cocaine) and who had been admitted to the trauma service. Despite use of the same analytical methodology and increased ordering of toxicology tests during the study period, the frequency of phencyclidine detection decreased during each year of the study (1984-85, 2.3% of 1,280 panels; 1985-86, 1.5% of 1,956 panels; and 1986-87, 0.9% of 3,634 panels). These figures are substantially lower than the 5% rate noted in our study of emergency room patients in 1979. These data suggest that the use of phencyclidine may be decreasing, possibly due to increase in abuse of other drugs such as cocaine and the amphetamines and to the more stringent restrictions placed upon phencyclidine synthesis. About half of the phencyclidine-positive findings occurred in trauma patients, suggesting the particular importance of searching for the drug in this population.

Adolescent↗
PubMed1985

Comparison between locomotor activity changes produced by phencyclidine and D-amphetamine in CD-1 male mice.

Comparative studies were pursued to investigate the locomotor activity induced by phencyclidine hydrochloride in CD-1 male mice. Horizontal, vertical, and rotational activity counts were quantitated using an infrared beam animal activity monitor. Five doses (1.5, 2.5, 3.5, 5.0, and 10.0 mg/kg, i.p.) of phencyclidine were compared. At the 1.5 mg/kg dose, no locomotor activity changes were observed when compared to a saline control group. Increased activity was observed at the 2.5, 3.5, and 5.0 mg/kg doses. Decreased activity was observed at the 10.0 mg/kg dose when compared to the 5.0 mg/kg dose possibly due to ataxia. In addition, the locomotor activity produced by acute d-amphetamine and acute phencyclidine was compared at doses of 2.5 mg/kg and 5.0 mg/kg respectively. The overall locomotor activity levels produced by acute d-amphetamine and phencyclidine were not significantly different at p less than 0.05. The time to peak activities and peak level activities were also similar and occurred at 20-25 minutes and 1100-1300 inches respectively after i.p. administration. Administration of apomorphine after phencyclidine did not change overall locomotor activity. The data implies that phencyclidine may act primarily as a dopamine reuptake inhibitor rather than a dopamine release stimulator. Phencyclidine also affects other activity (unlike amphetamine) as seen by the severe depression of vertical activity.

Animals↗
PubMed1982

Comparison of phencyclidine, etoxadrol and dexoxadrol in the pigeon.

The effects of phencyclidine, etoxadrol and dexoxadrol were compared in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-minute schedule of grain presentation. Etoxadrol was half as potent as phencyclidine in suppressing responding, and dexoxadrol was half as potent as etoxadrol. These three drugs, along with ketamine and cyclazocine, were also compared in pigeons trained to discriminate injections of 0.64 mg/kg of phencyclidine from injections of distilled water. All five drugs produced phencyclidine-like responding at the higher doses, with the order of potency being phencyclidine, etoxadrol, cyclazocine, dexoxadrol and ketamine. These data showed that a phencyclidine-like discriminative cue can be demonstrated across three classes of chemical compounds, as exemplified by phencyclidine and ketamine, etoxadrol and dexoxadrol, and cyclazocine.

Analgesics↗
PubMed1982

Stereoselective antagonism of phencyclidine's discriminative properties by adenosine receptor agonists.

Rats trained to discriminate between phencyclidine and saline vehicle were used to test various agents for their ability to mimic or block the phencyclidine cue. ketamine, dexoxadrol, tiletamine, and phencyclidine analogs were found to mimic phencyclidine's behavioral effects. Treatment with the adenosime receptor agonists N6-cyclohexyladenosine and L-phenylisopropyladenosine blocked the discriminative properties of phencyclidine. These results suggest that adenosine receptor agonists might be useful in treating phencyclidine-induced psychosis.

Adenosine↗
PubMed1982

Radioimmunoassay for phencyclidine (PCP) in serum.

This accurate, sensitive radioimmunoassay for determining phencyclidine concentrations in serum specimens involves the use of anti-phencyclidine sera, 0.1 mL of serum specimen, an iodinated tracer, and a solid-phase separation. Phencyclidine metabolites do not show significant cross reactivity, but several phencyclidine analogs do cross react. Within-run coefficients of variation for human and dog serum ranged from 2.5 to 13% for concentrations from 2.0 to 500 micrograms/L. Day-to-day coefficients of variation for human and dog serum ranged from 4.3 to 16.7% for concentrations ranging from 2.0 to 90.0 micrograms/L. The sensitivity of the radioimmunoassay is less than 0.5 micrograms/L. Thirty serum specimens from two dogs given 1 mg of phencyclidine per kilogram body weight were analyzed by radioimmunoassay and a gas-chromatographic method. Nonparametric statistical comparison and linear regression showed that results from the two procedures correlate well (r2 = 0.952). Concentration-time data from the two dogs are presented to illustrate the utility of the radioimmunoassay for examining phencyclidine disposition.

Animals↗
PubMed1982

Nitrogen-phosphorous detection of phencyclidine in blood serum.

A method for quantitating phencyclidine in the blood serum of rhesus monkeys with a solvent extraction procedure followed by gas chromatography with nitrogen-phosphorous detection is reported. Phencyclidine was extracted with ether from 0.5 ml of serum (pH 13.5) made basic with 2M NaOH, followed by back-extraction into 0.5 M sulfuric acid. After the addition of 2 M sodium hydroxide, phencyclidine was extracted into a small volume of ether for concentration and injection into the gas chromatograph. The limit of quantitation of phencyclidine in serum was 5 ng/ml. Recovery averaged 51.9 +/- 4.3%. Standard curves were linear between 5-50 ng/ml and 100-2000 ng/ml. Comparison between serum and aqueous standards indicated no interference by serum components in the extraction procedure. Pentobarbital, caffeine, and the monohydroxy metabolites of phencyclidine did not interfere with the analysis. This procedure is a rapid and sensitive method for determination of serum phencyclidine levels in animal studies requiring analysis of large numbers of samples.

Animals↗
PubMed2005

Dopamine agonist action of phencyclidine.

Although the psychotomimetic action of phencyclidine is often used to model a hypoglutamate theory of psychosis or schizophrenia, work also exists showing that phencyclidine has a significant affinity for the dopamine D2 receptor. The present study was done to determine whether phencyclidine has a direct functional dopamine-like action on cells. The effect of phencyclidine was tested on the release of prolactin from rat cultured anterior pituitary cells. It was found that the release of prolactin was 50% inhibited by 4 nM phencyclidine. This strong dopamine-like agonist action at the functional high-affinity state of the dopamine D2 receptor by the phencyclidine psychotomimetic is consistent with the dopamine hypothesis of psychosis.

Animals↗
PubMed1975

Phencyclidine and ketamine: comparison with the effect of cocaine on the noradrenergic neurones of the rat brain cortex.

In slices of rat occipital cortex, the influence of phencyclidine and ketamine on the accumulation of 3H-noradrenaline and the subsequent outflow of tritium was investigated, and was compared with the effect of cocaine.--All three drugs inhibited the accumulation of tritium during incubation of the slices with 3H-noradrenaline. Phencyclidine was slightly, whereas ketamine was much less effective than cocaine.--All three drugs accelerated the spontaneous outflow of tritium from slices preincubated with 3H-noradrenaline. The acceleration caused by low concentrations probably reflects an inhibition of the re-uptake of spontaneously released 3H-noradrenaline; in addition, high concentrations (10(-4) M phencyclidine, 3 X 10(-4)-10(-3) M cocaine and 10(-3)-3 X 10(-3) M ketamine) appear to release tritiated compounds from the neurones. The distance between uptake-inhibiting and releasing concentrations was much greater for cocaine than for phencyclidine and ketamine.--All three drugs enhanced the overflow of tritium evoked by electrical field stimulation. The increase probably reflects an inhibition of the re-uptake of released 3H-noradrenaline; in addition, phencyclidine appears to enhance the release of noradrenaline per pulse.--The actions of phencyclidine and ketamine on central noradrenergic neurones may contribute to the characteristic psychotropic side-effects of these general anaesthetics.

Animals↗
PubMed1984

Increased phencyclidine self-administration due to food deprivation: interaction with concentration and training conditions.

Six monkeys were trained to self-administer orally delivered phencyclidine (0.25 mg/ml) under a fixed-ratio 16 (FR-16) schedule. Water was concurrently available under an FF-16 schedule. During initial phencyclidine training, three monkeys were allowed free access to food (food satiation) and three were maintained at 85% of their free-feeding body weights (food deprivation). At the end of the training phase, the food-satiated monkeys were food-deprived. After behavior was stable for ten sessions, all monkeys were food-satiated and tested with a range of phencyclidine concentrations (0.0625-1 mg/ml). They were subsequently food-deprived and tested with concentrations of 0.0312-1 mg/ml, and then they were again food-satiated and tested with 0.0312 and 0.25 mg/ml. The monkeys that were trained to self-administer phencyclidine while food-satiated showed substantial phencyclidine-maintained responding at lower drug concentrations when later tested while food-satiated. In contrast, monkeys that were trained while food-deprived did not respond for phencyclidine in excess of water at the lower concentrations when later tested while food-satiated. Drug-maintained performance during food deprivation did not change systematically as a function of training condition (food deprivation versus food satiation). These results illustrated a marked interaction between drug concentration and the feeding condition and this interaction was modified by training history.

Animals↗
PubMed1999

Quadazocine decreases responding reinforced by ethanol, sucrose, and phencyclidine fluid deliveries in rhesus monkeys: comparison to naltrexone's effects.

RATIONALE: The endogenous opioid system may mediate the reinforcing effects of ethanol as well as sweet-tasting solutions. For example, opioid antagonists, such as naltrexone, reduce ethanol- and sucrose-reinforced responding in rhesus monkeys. If these effects are due to blockade of the mu-receptor, then an opioid antagonist such as quadazocine with a receptor selectivity profile similar to that of naltrexone should reduce responding at doses correlated with its mu-selectivity. OBJECTIVES: To determine whether quadazocine would reduce responding for ethanol and sucrose at mu-selective doses, and whether quadazocine and naltrexone would reduce responding for a bitter-tasting drug solution such as phencyclidine. METHODS: Rhesus monkeys were given access to ethanol, sucrose, or phencyclidine concurrently with water. Prior to the drinking sessions, quadazocine (0.032-3.2 mg/kg) or saline was injected intramuscularly. During the phencyclidine experiment, naltrexone (0.1 and 0.32 mg/kg) was also tested. RESULTS: The highest quadazocine doses (1 and 3.2 mg/kg) reduced ethanol and sucrose fluid deliveries without affecting the concurrently available water. Quadazocine reduced the fluid deliveries of both phencyclidine and water when concurrently available. Naltrexone reduced only phencyclidine fluid deliveries. CONCLUSIONS: The opioid antagonist effect on oral-reinforced responding is not selective for ethanol or sweet-tasting solutions; responding for phencyclidine was reduced as well. Quadazocine and NTX may reduce responding by blocking the mu-receptor because the relative potency of these antagonists to reduce oral self-administration was similar to their relative potency to produce withdrawal in morphine-dependent monkeys. However, water responding was low in these experiments, and thus we cannot rule out rate-dependent effects of the antagonists.

Alcohol Drinking↗
PubMed1987

Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response.

The effects of acute administration of phencyclidine, an indirect dopamine agonist, on biochemical indices of dopaminergic activation were examined in mesocortical, mesolimbic and nigrostriatal regions of the rat. High doses (10 mg/kg) of phencyclidine resulted in a marked increase in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in all mesolimbic and mesocortical sites examined, as well as in the ventral tegmental area, source of the dopaminergic innervation of mesolimbic/cortical sites. In contrast, levels of both metabolites decreased in the striatum and tended to decrease in the substantia nigra, source of the striatal dopaminergic innervation. The metabolite response to phencyclidine was dose-related. These data indicate that the mesolimbic and mesocortical dopaminergic neurons are activated by phencyclidine. Since the firing rate of both A10 (ventral tegmental area) and A9 (substantia nigra) dopamine neurons has previously been shown to be increased by phencyclidine, these data suggest that phencyclidine results in a differential regulation of presynaptic release of dopamine in mesolimbic/cortical as opposed to nigrostriatal dopaminergic regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of sigma-type and phencyclidine receptors.

Brain sigma-type receptors and phencyclidine receptors are thought to mediate the psychotomimetic effects of benzomorphans and phencyclidine in humans. Recently, we reported the characterization of a selective sigma receptor ligand, 1,3-di-o-tolyl-guanidine (DTG), that shows negligible crossreactivity with phencyclidine receptors. Here we describe the synthesis and characterization of an isothiocyanate derivative of DTG, di-o-tolyl-guanidine-isothiocyanate (DIGIT). Guinea pig brain membranes treated with nanomolar doses of DIGIT followed by extensive washing exhibit a dose dependent reduction of [3H]DTG and (+)[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)[3H]3-PPP) binding to sigma receptors. Binding of radiolabelled ligands for phencyclidine, mu-opioid, benzodiazepine and dopamine-D2 receptors is not affected by membrane treatment with DIGIT, indicating specificity of the affinity label for sigma-type receptors. Treatment of DIGIT-derivatized membranes with 2 M NaCl does not result in recovery of sigma binding activity, suggesting that DIGIT's interaction with sigma receptors is not of an ionic nature. Equilibrium saturation binding experiments show that the inhibition of [3H]DTG binding to sigma receptors by DIGIT pretreatment of membranes is attributable to an irreversible reduction in the affinity (increase in Kd) of sigma receptors for DTG. The finding that sigma receptors are irreversibly modified by DIGIT whereas phencyclidine receptors are not affected suggests that sigma receptors are physically separate from phencyclidine receptors. The availability of a selective affinity label for the sigma receptor should facilitate the purification of the receptors and the characterization of sigma-type pharmacological effects in vivo and in vitro.

Affinity Labels↗
PubMed1984

Ethanol inhibition of phencyclidine percutaneous absorption.

The effect of parenterally administered ethanol on the percutaneous absorption of phencyclidine hydrochloride was investigated using the intact hairless (SKH, hr-1/hr-1) mouse as a model. Four hours after topical application of phencyclidine hydrochloride, the mean phencyclidine concentration (129.2 ng/g) in excised liver was significantly lower in mice that had received ethanol by intraperitoneal injection than in mice injected intraperitoneally with water (1730.1 ng/g) (p less than 0.01). When phencyclidine hydrochloride was administered by intraperitoneal injection there was no statistically significant difference between the mean concentration in liver (3442.5 ng/g) for ethanol-treated mice and that (3030.3 ng/g) for the control mice (p greater than 0.10), indicating that the observed difference was not due to enhancement of phencyclidine metabolism by ethanol. These findings suggest that ethanol inhibits the percutaneous absorption of phencyclidine hydrochloride.

Administration, Topical↗