Chronic Administration Of Phencyclidine Research Articles

The Ultimate Intra-/Extra-Dimensional Attentional Set-Shifting Task for Mice

Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set shifting in humans are the Wisconsin Card Sorting Test and the Cambridge Neuropsychological Test Automated Battery Intra-/Extra-Dimensional set-shift task (ID/ED). These tasks have proven clinical relevance and have been successfully adapted for monkeys. However, similar tasks currently available for rodents are limited, mainly because of their manual-based testing procedures. The current limitations of rodent attentional set-shifting tasks are hampering translational advances in psychiatric medicine. To closely mimic the Cambridge Neuropsychological Test Automated Battery ID/ED task in primates, we present the development of a novel operant-based two-chamber ID/ED "Operon" task for mice. We show the ability of this novel task to measure attentional set shifting in mice and the effects of genetic and pharmacologic manipulations of dopamine and glutamate. In genetically modified mice with reduced catechol-O-methyltransferase activity there was selective improvement on extradimensional shift abilities and impairment of serial reversal learning. Chronic administration of phencyclidine produced a selective impairment of extradimensional shift while producing a generalized decrease in latency to respond. We demonstrate that this novel ID/ED Operon task may be an effective preclinical tool for drug testing and large genetic screening relevant to the study of executive dysfunctions and cognitive symptoms of psychiatric disorders. These findings may help elucidate the biological validity of similar findings in humans.

Chronic administration of phencyclidine produces decreased sensitivity to mechanical stimulation in the absence of altered affective behavior: Implications for pain processing in schizophrenia

Patients with schizophrenia have been shown to display decreased sensitivity to pain, which can severely compound the impact of injuries and illnesses. Alterations in the sensory and affective systems of pain processing have been proposed as mechanisms, but the unique contribution of each of these systems has not been elucidated. The aim of this study was to investigate these two components of pain using the NMDA receptor antagonist, phencyclidine (PCP), an established animal model of schizophrenia. Animals underwent L5 spinal nerve ligation surgery in order to provoke a condition of ongoing pain responding, followed by treatment with 2.58 mg/kg of PCP, or saline, and 20 mg/kg of the atypical antipsychotic clozapine, or vehicle, in a block design. Responses to mechanical stimuli were assessed to determine changes in sensory processing, and affective pain processing was examined with the place escape avoidance paradigm. The results showed animals receiving PCP exhibited decreased sensitivity to mechanical stimulation and unaltered behavior in the avoidance paradigm. These findings corroborate and strengthen the human literature investigating schizophrenia and alterations in pain perception. More importantly, the differential findings between the tests of sensory and affective pain processing provide a novel means of understanding schizophrenia-related pain insensitivity.

Reduced activation of intracellular signaling pathways in rat prefrontal cortex after chronic phencyclidine administration

Evidence exists that schizophrenia is characterized by deficits in cell–cell communication and information processing. In the present study, we used the phencyclidine (PCP) animal model of schizophrenia to investigate possible defects in intracellular signaling proteins involved in neuroplasticity. Western Blot analysis has been performed to determine total and phospho-protein levels of extracellular signal-regulated kinases 1/2 (ERK1/2), type II calcium/calmodulin-dependent protein kinase (αCaMKII) and cAMP-response element binding protein (CREB) in prefrontal cortex (PFC) and hippocampus (HIP) of rat chronically treated with PCP, whereas their mRNA levels were determined by real time RT-PCR. We found reduced levels of P-ERK1/2, P-αCaMKII and P-CREB in prefrontal cortex of PCP-treated animals when compared to controls, whereas no effects were observed on total protein or mRNA levels. Conversely, no significant changes were detected on protein levels or mRNA expression in hippocampus. Given the role of ERK1/2, αCaMKII and CREB in neuroplastic mechanisms and cell communication, our data suggest that their decreased activation following chronic PCP administration can contribute to cortical defects occurring in schizophrenia, and may therefore represent potential targets for pharmacological intervention.

Chronic phencyclidine administration reduces the expression and editing of specific glutamate receptors in rat prefrontal cortex

Phencyclidine (PCP) induces a form of psychosis that mimics naturally occurring schizophrenia in the most relevant domains of the psychopathology. In this report, we investigated the effect of chronic treatment with PCP on expression and RNA editing of α-amino-propionic acid (AMPA) and kainate (KA) glutamate receptor (GluR), in the rat prefrontal cortex and the hippocampus. We found that chronic, but not acute, PCP treatment decreased GluRs expression in the rat prefrontal cortex but not in the hippocampus. In particular, the mRNA coding for GluR2 and GluR3 subunits were reduced by 50%, whereas those coding for KA GluR5 and GluR6 were decreased by 30%. In addition, we observed a decrease of the editing levels of the R/G site in the flop form of both GluR2 and GluR3 and a significant increase in the editing level of GluR6 Q/R site. The variation in the editing level of the R/G sites suggests that chronic PCP treatment induced the formation of glutamate receptor subunits with slower resensitization kinetics and, with respect to kainate receptors, an increase in the Q/R editing level might generate receptor channels with a lower permeability to cations. Combining all the data, it can be inferred that the PCP treatment induced a specific and site-selective reduction of glutamatergic neurotransmission in the prefrontal cortex but not in the hippocampus.

Social Interaction Deficits Caused by Chronic Phencyclidine Administration are Reversed by Oxytocin

Chronic administration of phencyclidine (PCP) has been advanced as a valid animal model of the social deficit symptoms of schizophrenia. In these studies, the cumulative time that male rats treated once a day for 14 days with PCP actively engaged in social behavior was decreased approximately 75% relative to saline-treated control animals. In addition, these socially impaired rats had an increase in the relative amount of noncontact interactions compared with saline-injected peers. Social behaviors were preferentially affected by PCP treatment because in two anxiety-related behavioral assays, the open field and light/dark emergence tests, there was a failure to differentiate between the PCP-treated rats and saline-injected control rats. Considering the general importance of the neuropeptides oxytocin and vasopressin in male social behaviors, studies of molecular markers related to these neuropeptides were performed. Hypothalamic oxytocin mRNA expression was significantly decreased while oxytocin receptor binding was increased in the central nucleus of the amygdala following chronic PCP treatment. Given the significance of central nucleus of the amygdala in social behavior, oxytocin was infused into the central nucleus of experimental and control male rats, and their postinfusion social interaction and open field behaviors were analyzed. A bilateral infusion of 1 mug of oxytocin into the central amygdala selectively restored the normal quantity and quality of social behavior in chronic PCP-treated male rats without altering open field behaviors. These findings suggest that deficits in the central oxytocinergic system may underlie the social impairment exhibited in this animal model of schizophrenia.

Chronic phencyclidine administration induces schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate in rat brain

Administration of phencyclidine (PCP) to both humans and animals models the symptoms of schizophrenia. Brain concentrations of N-acetylaspartate (NAA) are reduced in this disease, reflecting neuronal dysfunction. This study investigates the effects in rats of a chronic intermittent regime of PCP on NAA and its precursor N-acetylaspartylglutamate (NAAG) in rat frontal and temporal cortex, hippocampus and striatum, determined by HPLC. We found significant PCP-induced deficits of NAA and NAAG only in the temporal cortex; NAAG was significantly elevated in the hippocampus. These changes closely reflect postmortem findings reported in schizophrenia.

Differential and Region-Specific Activation of Mitogen-Activated Protein Kinases Following Chronic Administration of Phencyclidine in Rat Brain

We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.

Differential expression of GABA(A) receptor subunit mRNAs and ligand binding sites in rat brain following phencyclidine administration.

Recent biochemical observations have suggested the abnormalities in the gamma-amino-butyric acid (GABA)ergic system in schizophrenic brains. In the present study, we investigated the subunits gene expressions and ligand binding of the GABA(A) receptor following acute and chronic administration of phencyclidine (PCP), which induces schizophrenia-like symptoms, in rats using in situ hybridization and in vitro quantitative autoradiography. PCP i.p. administration at a daily dose of 7.5 mg/kg resulted in a significant decrease in expression of alpha 1 subunit mRNA in cerebral cortices (cingulate (-13%) and temporal cortex (-6%)) and hippocampal formation (CA1 (-11%), CA2 (-10%), CA3 (-11%) and dentate gyrus (-12%)) 1 h after a single treatment. In the repeated PCP administrations for 14 days, the expression of beta 2 mRNA in the cerebellum (-10%) and of beta 3 mRNA in the cerebral cortices (cingulate (-12%), parietal (-16%) and temporal cortex (-16%), caudate putamen (-18%), inferior colliculus (-18%), and cerebellum (-15%) were significantly decreased. In addition, [(35)S]t-butylbicyclophosphorothionate (TBPS) binding was also reduced in layer IV of the frontoparietal cortex (-14%), inferior colliculus (-17%), and cerebellum (-12%) following chronic PCP treatment, while no changes were observed following acute PCP treatment. These results indicate that single and repeated administrations of PCP independently regulate the expression of GABA(A)/benzodiazepine (BZD) receptor subunits mRNA and its receptor binding in the brain.

Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex.

In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist, would cause a long-lasting behavioral sensitization associated with neuronal toxicity. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP. Following assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microscopy or terminal dUTP nick-end labeling (TUNEL). In study I, PCP challenge produced a much more robust and long-lasting increase in locomotor activity in rats chronically treated with PCP than in those chronically treated with saline. In study II, clozapine pretreatment blunted the degree of sensitization caused by PCP. In study I, a marked increase in TUNEL-positive neurons was found in layer II of the olfactory tubercle and piriform cortex of rats chronically treated with PCP. Many of these neurons had crescent-shaped nuclei consistent with apoptotic condensation and margination of nuclear chromatin under the nuclear membrane. Acute PCP had no effect. Electron microscopy revealed that PCP caused nuclear condensation and neuronal degeneration consistent with apoptosis. Cell counts in layer II of the piriform cortex revealed that chronic PCP treatment resulted in the loss of almost 25% of the cells in this region. However, an increase in glial fibrillary acidic protein (GFAP)-positive cells in the molecular layer suggests that this neurotoxicity also may involve necrosis. In study II, the PCP-induced neuronal degeneration was essentially completely abolished by clozapine pretreatment. This pattern of degeneration was found to coincide with the distribution of the mRNA of the NR1 subunit of the NMDA receptor. The relevance of these data to a PCP model of chronic NMDA receptor hypofunction is discussed.

Changes in dopamine D2 and GluR-1 glutamate receptor mRNAs in the rat brain after treatment with phencyclidine.

In situ hybridization of slide-mounted brain sections from rats subjected to acute and chronic phencyclidine treatment was carried out using synthetic oligonucleotides complementary to dopamine D2-receptor and non-N-methyl-D-aspartate (NMDA) glutamate-receptor-subunit (GluR-1) mRNAs. There was no significant difference in either the D2-receptor or the GluR-1 mRNA levels in any brain region of the acute phencyclidine (10 mg/kg)-treated and control groups. However, chronic administration of phencyclidine (10 mg/kg/day, 14 days) significantly decreased the dopamine D2-receptor mRNA level in the caudate-putamen (by 27%, P < 0.01) and significantly increased the GluR-1 mRNA level in the prefrontal cortex (by 29%, P < 0.001). These results suggest that the chronic pharmaco-behavioral effects of phencyclidine may involve expression of both dopamine- and non-NMDA glutamate-receptor mRNAs.

Alterations in rat brain [ 3H]-TCP binding following chronic phencyclidine administration

Rats were chronically infused with phencyclidine (PCP, 13.3 mg PCP·HCl/kg/day) or saline, s.c., for 10 days using osmotic minipumps (n = 5 for each group). Twenty-four hours after the cessation of dosing, the rats were sacrificed, and brains were removed for analysis of PCP receptor binding. Saturation studies of the binding of [ 3H]-TCP to brain homogenates revealed statistically significant increases in the maximum binding capacity ( B max) and decreases in the affinity for [ 3H]-TCP in the PCP-treated group.

Changes in norepinephrine concentration following chronic administration of phencyclidine (PCP) to genetically hypertensive and normotensive rats

1. 1. Chronic treatment of genetically hypertensive and normotensive rats with phencyclidine (PCP) resulted in changes in norepinephrine (NE) concentration in regions of the brain and in the adrenal gland. 2. 2. Chronic PCP treatment resulted in an 18% increase in hypothalamic NE in hypertensive rats and a 20% increase in NE in the medial lower brainstem of normotensive rats. 3. 3. Hypertensive rats also showed a 28% decrease in adrenal NE after PCP treatment.

Effects of acute and chronic administration of phencyclidine on the A 10 dopaminergic mesolimbic system: Electrophysiological and behavioral correlates

Electrophysiological and behavioral methods were used to evaluate the effects of chronic exposure to phencyclidine (PCP, 5 mg/kg/day for 30 days) on ventral tegmental A 10 dopaminergic neurons and locomotor and ataxic behavior in the rat. Extracellular recordings from single neurons in the ventral tegmentum showed only minimal differences between rats chronically treated with either saline or PCP. A comparison of the rising portion of the cumulative dose-response curves indicated that the animals treated chronically with the drug required only 0.4 times more PCP than the controls to produce equivalent changes in neuronal firing rates. Also, the average maximum increase in activity in A 10 neurons, induced by PCP, was 43% in the drug-treated rats compared to 60% in the controls. Although these were moderate quantitative changes, a marked qualitative difference in the response of A 10 neurons to PCP was seen. Whereas PCP elicited a characteristic dose-dependent biphasic effect on the firing rates in the control group, the declining (inhibitory) component of the response was not present in the animals chronically treated with PCP. In parallel with the minimal electfophysiological changes, measurements of gross locomotor activity showed that the response to the thirtieth (30th) injection of PCP was virtually identical to that measured in the same animals following the first exposure. In contrast, however, the ataxia which accompanied the hyperactivity rapidly diminished over the course of treatment. It would appear, therefore, that chronic exposure to PCP did not substantially diminish the ability of PCP to activate the A 10 neurons, comprising the mesocorticolimbic dopaminergic systems. In fact, with long-term chronic use of PCP, larger doses may actually result in a greater degree of stimulation of midbrain dopaminergic neurons. This effect may partially underly the neurobiological mechanism by which chronic abuse of PCP can eventually lead to psychotic-like personality changes.

Phencyclidine (PCP): Effects of acute and chronic administration on egg activities in the rhesus monkey

Les effets de l'administration aigüe et chronique de phencyclidine (PCP) sur l'EEG et le comportement général ont été étudiés chez le singe au moyen d'électrodes implantées dans le cerveau. L'administration de PCP (2,0 ou 4,0 mg.kg i.v.) au singe, produit un pattern biphasique d'inhibition et d'excitation du comportement pendant une période d'observation de 6 à 8 h. La phase inhibitrice apparaît 1 à 3 min après injection de PCP, elle est caractérisée uniquement par des ondes lentes de haute amplitude, avec ondes delta (0,6–0,8 c/sec) dans le lobe pariétal et ondes thêta (4–5 c/sec) dans le lobe occipital ainsi que dans l'hippocampe pendant la phase d'immobilité comportementale. Cette phase d'inhibition dure de 1 h a 1,5 h, elle est suivie par des ondes rapides de grande amplitude avec composante thêta plus importante et apparition de nystagmus pendant la phase d'excitation. Dans le cas de l'administration chronique de PCP, l'intensité et la durée de la phase inhibitrice diminuent progressivement alors que les effets de la phase excitatrice augmentent. Ces résultats suggèrent que chez le single, l'administration de PCP produit un pattern biphasique d'inhibition et d'excitation, et qu'une administration chronique développe une tolérance aux effets inhibiteurs alors que l'effet excitateur commence à augmenter.

Acute and chronic phencyclidine administration changes serotonin receptors in rat brain

Acute and chronic phencyclidine administration changes serotonin receptors in rat brain

Effects of phencyclidine (PCP) on cardiorespiratory functions in the rhesus monkey

Effects of acute and chronic administration of phencyclidine (PCP) on heart rate (HR) and respiratory rate (RR) were studied in rhesus monkey. Acute administration of PCP (2.0 and 4.0 mg/kg i.v.) produced decrements in both HR and RR within 15 and 30 min after drug administration. Simultaneously, with this cardiorespiratory slowing, EEG tracings evidenced High-Voltage Slow-Waves (HVSW) and delta-waves. As HR and RR began to recover, High-Voltage Fast-Waves (HVFW) along with theta-waves developed in EEG recordings and persisted for 2–6 h, while both HR and RR were gradually returning to their respective pre-drug control levels. The intensity and duration of these PCP-induced effects were directly related to dosage level. Following chronic administration of PCP (daily dose of 2.0 or 4.0 mg/kg i.v.), its ability to produce cardiorespiratory alterations was significantly diminished along with a decrease in PCP-induced depression of EEG and behavioral activities. These results suggest that chronic PCP administration produces a tolerance to its depressant effect on HR, RR, EEG and behavioral activities in rhesus monkeys.

Phencyclidine (PCP): Effects on auditory evoked potentials in the rhesus monkey

Effects of acute and chronic administration of phencyclidine (PCP) on auditory evoked potentials (AEPs) were studied in rhesus monkeys with encephalic electrodes permanently implanted. AEPs were evoked by single clicks (1.0 pps in frequency) generated by an externally triggered audiomonitor. Single PCP injections (dose, 2.0 or 4.0 mg/kg IV) in monkeys produced a striking distortion in the amplitudes of major AEP components. This AEP distortion was manifested in superior temporal cortex (ST) by a complex pattern of amplitude reduction and enhancement, and was manifested in the medial geniculate body (MGB) by amplitude reduction. These effects persisted for 4 to 5 hours. Upon chronic administration (dose, 4.0 mg/kg IV daily), the effects of PCP on AEP components in ST were enhanced while little change was noted in its effect on AEP components in MGB. These results suggest that PCP administration in rhesus monkeys causes a significant disturbance of AEPs within central nervous system structures associated with auditory processing (i.e., ST and MGB), and that chronic PCP administration enhances its effects on AEPs predominantly in the primary auditory cortex while having little additional effects on AEPs from the subcortical auditory pathways.

Effects of phencyclidine (PCP) on the visual evoked potentials in the rhesus monkey

Effects of acute and chronic administration of phencyclidine (PCP) on both neocortical and subcortical visual potentials (VEPs) and on spontaneous EEGs were studied in the rhesus monkeys with permanently implanted brain electrodes. VEPs were evoked by brief single photo-stimulator flashes (0.8 pps, 10 μsec duration). Injection of PCP (0.5 to 4.0 mg/kg doses, IV) in monkeys produced a significant inhibition on the peak-amplitude of major VEP components predominantly in the occipital lobe and hippocampus. The PCP-induced VEP inhibition persisted in the presence of occipital and hippocampal theta-activities. Nystagmus persisted throughout the 6 to 8 hours course of PCP-induced behavior. A biphasic pattern of inhibitory and excitatory effects on EEGs and behavior was also observed during the 6 to 8 hours observation period. Chronic administration of PCP (2.0 and 4.0 mg/kg dose IV daily) produced a significant decrease in its inhibitory effects on VEPs, suggesting tolerance development to the inhibitory effect on VEPs. The results suggest that the hippocampus has important implications in the modulation of PCP effects on CNS activities related to the visual function of the rhesus monkey.

Behavioral effects of chronic phencyclidine administration in rats.

The development of tolerance to phencyclidine (PCP) was examined in rats using behavioral rating scales with simultaneous measurements of locomotor activity, stereotyped behaviors, and ataxia. Significant tolerance to the stereotyped behaviors and ataxia induced by 5 or 10 mg/kg PCP was found on day 5 of chronic drug treatment. Because ataxia interferes with PCP-induced locomotor activity (Sturgeon et al. 1979), tolerance to PCP-induced ataxia produced an increase in locomotor activity on day 5. Tolerance to the ataxia, but not to the stereotyped behaviors induced by PCP, was more prominent after day 15 of PCP administration than after day 5. Administration of PCP for 15 days resulted in significant decrease in locomotor activity for the 5 mg/kg group but not for the 10 mg/kg group. These results suggest that behavioral tolerance, rather than supersensitivity, develops after chronic PCP administration. The effects of PCP returned to baseline over a 14-day withdrawal period for rats treated with 5 mg/kg PCP for 15 days. Rats treated with 10 mg/kg PCP for 15 days still had not returned to baseline when tested 28 days after cessation of PCP treatment.

Behavioral effects of phencyclidine in the developing cat

The behavioral effects of chronic administration of phencyclidine (PCP) (1 or 2 mg/kg, i.p., injected every other day) were assessed in kittens which were 5–39 days old. The type of behavioral response produced was age-related. Under 21 days the major drug-induced response consisted of rostrocaudal forelimb movements. After this age the major responses were ataxic locomotion (consisting of walking, staggering and falling) and waxy rigidity.