Chronic phencyclidine (PCP)-induced modulation of muscarinic receptor mRNAs in rat brain: impact of antipsychotic drug treatment

Many antipsychotics (APDs) have a high affinity for muscarinic receptors, which is thought to contribute to their therapeutic efficacy, or side effect profile. In order to define how muscarinic receptor gene expression is affected by atypical or typical APDs, rats were treated with chronic (2.58 mg/kg) PCP (a psychotomimetic) or vehicle, plus clozapine (20 mg/kg/day) or haloperidol (1 mg/kg/day), and M1, M2 and M3 receptor mRNA levels were determined in brain sections. Negligible changes in M2 or M3 muscarinic mRNA were detected in any region after clozapine or haloperidol. Chronic PCP administration increased M1 mRNA expression in the prefrontal cortex, which was not reversed by either chronic clozapine or haloperidol treatment. Chronic clozapine treatment in combination with PCP treatment decreased M1 receptor mRNA levels in the nucleus accumbens core, whereas chronic haloperidol in combination with PCP treatment increased M1 receptor mRNA levels in the ventromedial hypothalamus and medial amygdala. Thus M1 receptor gene expression is targeted by APDs, although the regions affected differ according to the APD treatment and whether PCP has been administered. The different brain circuitry modulated, may reflect the differing modes of action of typical and atypical APDs. These data provide support for the dysregulation of M1 receptors in schizophrenia, and furthermore, modulation by antipsychotic agents in the treatment of schizophrenia.     

MMPI subtypes for chronic phencyclidine (PCP) abusers

The present study applied empirical clustering procedures to the MMPI protocols of 196 chronic phencyclidine (PCP) abusers. Subjects were randomly divided into two groups, and two methods of cluster analysis, the average linkage method and Ward's hierarchical procedure, were performed. Both cluster methods produced highly comparable results within each group, and the MMPI profiles found in each group were quite similar. Cluster analytic studies of other substance abuse populations are needed in order to replicate the MMPI profile types found in the present study. These investigations would lead to an empirical typology across various substance abuse populations that would depict developmental stages.     

The effects of atypical antipsychotics and phencyclidine (PCP) on rotorod performance.

A series of six experiments were conducted to determine the effects of haloperidol, clozapine, olanzapine, and phencyclidine (PCP) on rotorod performance. Rodents were trained to walk on a rotorod to avoid a mild shock to a criterion of 20 rpm for 3 min. None of the vehicles of any of these drugs disrupted rotorod performance. Haloperidol disrupted rotorod performance at doses of 0.03, 0.1, and 0.3 mg/kg, and olanzapine disrupted rotorod performance at doses of 3.0 and 10.0 mg/kg. Clozapine produced a much milder disruption across all three doses (3.0, 10.0, and 30.0 mg/kg). PCP produced a consistent and severe disruption of rotorod performance at doses of 4.0 and 6.0 mg/kg, but not at a dose of 2.0 mg/kg. Twenty-four hours postinjection there were no residual PCP effects on rotorod performance. Coadministration of either haloperidol or olanzapine with PCP did not reverse PCP-induced disruption in rotorod performance, while clozapine produced a partial reversal at only one dose. These findings indicate that olanzapine functions similarly to classic antipsychotics with respect to their effects on locomotion and balance.     

Abuse of phencyclidine (PCP) a laboratory experience

Emergency Room patients at Riverside General Hospital who are found by the attending physician to have depressed sensorium and altered personality are routinely subjected to urine tests for various drugs of abuse including phencyclidine (PCP). The findings of the laboratory analysis of these patients are presented in this paper. The toxicology laboratory of this hospital performs screening procedures for various drugs on urine specimens by thin layer chromatography. Drugs detected are confirmed by gas chromatography and a homogeneous enzyme immunoassay technique. In 1981, 1.6% of the urine specimens of patients in the above-mentioned category were found to be positive for PCP. This percentage increased sharply during 1982 (5.8%) and 1983 (5.6%). During 1984 and 1985 the percentage dropped to 4.2% and 4.6%. It is implied from data that the abuse of this drug in this area has leveled off. The data also indicated that PCP is predominantly used by young adults with ages ranging from 21 to 30 years. The abuse of this drug in people over 40 years of age is comparatively very small. Among users of this drug, 67.5% are men and 32.5% are women. Out of 68 women found to be abusing PCP, 5 delivered their babies in this hospital. PCP was detected in the urine specimens of each of these babies. Four out of the five infants showed withdrawal symptoms such as extreme irritability, jitteriness, hyperactivity with high pitched cries and a poor ability to take food.     

Metabolic interactions of phencyclidine (PCP) and delta 9-tetrahydrocannabinol (THC) in the rat

The in vitro effects of THC on the metabolism of PCP by rat liver were determined. Samples containing 1 mM PCP were incubated for 1 hr at 37 degrees C with an NADPH-generating system containing 10,000 X g supernatant or Ca++-precipitated rat liver microsomes. These incubations were carried out in the presence or absence of THC and at the end of 1 hr, PCP metabolites were determined by gas chromatography. In the presence of 0.1, 0.05, 0.025 and 0.0125 mM THC, the production of 1-(1-phenyl-4-hydroxycyclohexyl)piperidine (metabolite I) by the 10,000 X g supernatant was decreased by 46, 29, 23 and 16% respectively. Similarly, production of 1-(1-phenylcyclohexyl)-4-hydroxypiperidine (metabolite II) was reduced significantly by 58, 44, 34 and 23% with the respective concentrations of THC. However, the production of 1-phenylcyclohexylamine (metabolite III) was increased by 18, 32, 30 and 22% with 0.1, 0.05, 0.025 and 0.0125 mM THC. Incubations with Ca++-precipitated liver microsomes revealed similar trends in PCP metabolism in the presence or absence of THC. Metabolites I and II were reduced by 62 and 67% by 0.1 mM THC. Another concentration of THC (0.025 mM) caused a 50 and 62% decrease in I and II. These observations suggest that THC alters the in vitro microsomal metabolism of PCP.     

Social stimuli enhance phencyclidine (PCP) self-administration in rhesus monkeys

Environmental factors, including social interaction, can alter the effects of drugs of abuse on behavior. The present study was conducted to examine the effects of social stimuli on oral phencyclidine (PCP) self-administration by rhesus monkeys. Ten adult rhesus monkeys (M. mulatta) were housed side by side in modular cages that could be configured to provide visual, auditory, and olfactory stimuli provided by another monkey located in the other side of a paired unit. During the first experiment, monkeys self-administered PCP (0.25 mg/ml) and water under concurrent fixed ratio (FR) 16 schedules of reinforcement with either a solid or a grid (social) partition separating each pair of monkeys. In the second experiment, a PCP concentration-response relationship was determined under concurrent progressive ratio (PR) schedules of reinforcement during both the solid and grid partition conditions. Under the concurrent FR 16 schedules, PCP and water self-administration were significantly higher during exposure to a cage mate through a grid partition than when a solid partition separated the monkeys. The relative reinforcing strength of PCP, as measured by PR break points, was greater during the grid partition condition compared to the solid partition condition indicated by an upward shift in the concentration-response curve. To determine whether the social stimuli provided by another monkey led to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which may have evoked the increase of PCP self-administration during the grid partition condition, a third experiment was conducted to examine cortisol levels under the two housing conditions. A modest, but nonsignificant increase in cortisol levels was found upon switching from the solid to the grid partition condition. The results suggest that social stimulation among monkeys in adjoining cages leads to enhanced reinforcing strength of PCP.     

Influence of enkephalin on K+-evoked efflux of putative neurotransmitters in rat brain

Summary In rat brain slices preincubated with various radiolabelled putative neurotransmitters, methionine-enkephalin diminished the potassium-evoked release of dopamine and acetylcholine. The effect was antagonised by naloxone. The potassium-induced efflux of three other neurotransmitters, histamine, 5-hydroxytryptamine and -aminobutyric acid, were unaffected by methionine-enkephalin. A probable physiological function for the endogenous ligands in specifically affecting the catecholaminergic and cholinergic transmission is suggested.     

A novel opener of large-conductance Ca2+ -activated K+ (BK) channel reduces ischemic injury in rat cardiac myocytes by activating mitochondrial K(Ca) channel

It has been suggested that a new type of large-conductance Ca(2+)-activated K(+) (BK) channel is distributed in the inner mitochondrial membrane (mitoK(Ca) channel) and that its opening may attenuate ischemic cardiac injury. We examined effects of 12,14-dichlorodehydroabietic acid (diCl-DHAA), a novel BK-channel opener, on rat cardiac myocytes and mitochondria. Application of diCl-DHAA concentration-dependently reduced Ca(2+) overload in isolated mitochondria, activated mitoK(Ca) channels in inside-out patches of mitochondrial membrane, facilitated flavoprotein-oxidization in myocytes, and increased cellular viability under simulated ischemia. In conclusion, diCl-DHAA directly opens mitoK(Ca) channels, prevents Ca(2+) influx into matrix, and reduces ischemic injury in cardiac myocytes.     

Neuropharmacological studies of phencyclidine (PCP)-induced behavioral stimulation in mice

A variety of drugs were screened to determine which were capable of blocking the behavioral stimulation produced in mice by acute administration of phencyclidine (PCP). Chlorpromazine and clozapine blocked PCP-induced stimulation, while haloperidol, reserpine, and alpha-methyl-p-tyrosine did not. The GABA receptor agonists imidazole acetic acid and muscimol blocked PCP, but other drugs that influence GABA, such as dipropylacetic acid, baclofen, and diazepam, were ineffective. Yohimbine and methysergide also blocked PCP in high dosages, but other drugs with comparable alpha-noradrenergic and serotonergic blocking properties (phentolamine, cyproheptadine, and cinnanserin) were ineffective. Cholinergic and anticholinergic drugs, beta-noradrenergic and opiate antagonists, and nonspecific sedatives and convulsants were also ineffective. These finding suggest that chlorpromazine, clozapine, yohimbine, and methysergide may share a property that is unlike their primary known modes of action on dopaminergic, alphanoradrenergic, and serotonergic neurotransmitter systems, and that this property accounts for their ability to block PCP. However, the effectiveness of GABA agonists appears to be mediated through direct activation of GABA receptors. It is suggested that chlorpromazine and imidazole acetic acid should be considered as possible drug treatments for PCP toxicity.     

Interaction between phencyclidine (PCP) and Gaba-ergic drugs: Clinical implications

Pretreatment (IP) of mice with (?) baclofen, muscimol, 4,5,6,7-tetrahydroisoxazolo (S,4-c) pyridin-3-ol hydrate (THIP), aminooxyacetic acid (AOAA) or γ-acetylenic GABA caused a dose-dependent inhibition of the locomotor stimulant effect of phencyclidine (PCP, 8 mg/kg). Although (?) baclofen was found to be the most effective PCP antagonist, its (+) isomer was inactive. The maximum blocking effect of AOAA was seen in animals treated 3 and 6 hr earlier. Except for γ-acetylenic GABA, none of these drugs significantly blocked the locomotor stimulant effect of d-amphetamine (3 mg/kg, IP). Diazepam reduced d-amphetamine response, but failed to influence PCP-induced stimulation. The locomotor stimulant effect of PCP, unlike that of d-amphetamine, may be the result of a specific GABA antagonistic effect at certain dopamine-rich areas of the brain. It seems that (?) baclofen may prove to be useful in the management of PCP intoxication.Administration of higher doses of PCP (20 and 50 mg/kg) in mice pretreated with (?) baclofen resulted in the development of surgical anesthesia manifested as the loss of a) righting reflex, b) pain sensation and c) corneal reflex. The duration of the general anesthetic response was found to be a function of the doses of both (?) baclofen and PCP. The possible use of (?) baclofen as an adjuvant to general anesthetic is discussed.     

Effect of acute and chronic ethanol pre-treatment on the disposition of phencyclidine (PCP) in the rat

Disposition of [³H] Phencyclidine in brain, plasma and adipose tissue of rats acutely and chronically-treated with ethanol was studied using a method possessing high sensitivity and specificity for PCP. In rats acutely-treated with ethanol (5 g/kg PO dose) and PCP (10 mg/kg IP dose), dispositional factors did not play a role in the intensified pharmacological and behavioral effects of PCP. However in rats chronically-treated with 2.5 g/kg PO dose of ethanol twice a day for 19 days, the disposition of PCP (5 mg/kg IP dose) was significantly altered and the values of PCP in brain, plasma and adipose tissue were significantly higher than those in the control group. Although inhibition of PCP metabolism and a comparatively slower rate of its elimination appear to account for the potentiation of drug effects in animals chronically-treated with ethanol, interaction of drugs at the level of the central nervous system cannot be ruled out.     

Anaesthetic properties of phencyclidine (PCP) and analogues may be related to their interaction with Na+ channels

Among other properties, phencyclidine (PCP) and analogues display anaesthetic and anticonvulsant properties. Interaction of PCP and some analogues with the voltage-sensitive Na+ channels have been investigated and compared with their interaction with the PCP receptor. PCP and TCP inhibit apparently in a competitive manner the veratridine stimulated 22Na+ synaptosomal uptake with Ki values of 8.6 and 12.7 microM, respectively, close to those obtained in the inhibition of [3H]BTX-B binding (IC50 = 4.1 and 3.8 microM, respectively). The specific [3H]TCP binding to synaptosomes in ionic near physiological conditions is inhibited by PCP and TCP with IC50 values of 1.25 and 0.29 microM, respectively. Other PCP derivatives (GK3 and GK4) and PCP-like drugs (ketamine and MK801) inhibit 22Na+ uptake in an order of potency (GK3 greater than GK4 greater than PCP greater than TCP greater than MK801 greater than ketamine) which is different from that obtained in the inhibition of [3H]TCP binding (MK801 greater than TCP greater than PCP greater than ketamine greater than GK4 greater than GK3). Ketamine inhibits the veratridine-stimulated Na+ uptake at a concentration where its anesthetic effect occurs. It was concluded that the interaction of these drugs with the Na+ channel may reflect their anaesthetic properties while the interaction with the PCP receptors may be mainly related to their anticonvulsant and ataxic properties.     

Effects of acute and chronic antidepressant administration on phencyclidine (PCP) induced locomotor hyperactivity.

Previously it was found that both acute and chronic antidepressant pre-treatment enhanced the locomotor hyperactivity induced by a challenge injection of the non-competitive NMDA receptor antagonist, dizocilpine (MK-801). In the present study the effects of acute and chronic antidepressant administration on phencyclidine (PCP)-induced locomotor hyperactivity were examined. Phencyclidine (PCP), a non-competitive NMDA receptor antagonist increased locomotor activity in rats. Fluoxetine given acutely increased and prolonged the PCP-induced locomotor hyperactivity, while citalopram, sertraline and paroxetine had no effect on the PCP-induced behavioural effect. Repeated treatment with fluoxetine, citalopram and paroxetine increased the PCP-induced locomotor hyperactivity. In contrast, chronic sertraline administration attenuated the locomotor response to a PCP challenge. These results indicate that these antidepressants which are presumed to have a similar pharmacological profile, differ in their ability to alter PCP-induced hyperactivity. Whether these differences have any bearing on the therapeutic or adverse effects of these drugs remains to be shown.