Chronic PCP Treatment Research Articles

Allosteric Modulation of the Sigma-1 Receptor Elicits Antipsychotic-like Effects.

Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.

Chronic phencyclidine treatment impairs spatial working memory in rhesus monkeys.

Phencyclidine (PCP) could induce schizophrenia (Sz) like behavior in both humans and animals, therefore, has been widely utilized to establish Sz animal models. It induced cognitive deficits, the core symptom of Sz, mainly through influencing frontal dopaminergic function. Nonhuman primate (NHP) studies demonstrated impaired object retrieval detour (ORD) and spatial delayed response (SDR) task performance by acute or chronic PCP treatment. However, NHP investigations, continually monitoring SDR performance before, during and after PCP treatment, are lacking. Present study investigated the long-term influence of chronic PCP treatment on SDR performance and the possible increase of SDR deficit severity and duration by the incremental dosing procedure in rhesus monkeys. SDR task was performed repeatedly up to eight weeks after constant dosing procedure (i.m., 0.3 mg/kg, day 12-25), during which drug effects on locomotor activity and blood cortisol concentration were assessed. Incremental dosing procedure (starting dose 0.3 mg/kg, day 6-19) began five months later. Constant dosing procedure induced differential level of hyperactivity across testing days, without significant influence on blood cortisol concentration. It reduced SDR performance, until occurrence of the first and worst impairment on day 15 and 23 respectively. The impaired performance recovered to pretreatment level over one week after drug cessation. In contrast, incremental dosing procedure impaired SDR performance on the first treatment day, which recovered within treatment period. Results suggested increase of SDR deficit severity by repeated PCP administrations, whereas the incremental dosing procedure did not increase SDR deficit severity and duration.

Reduced expression of synapsin II in a chronic phencyclidine preclinical rat model of schizophrenia.

Schizophrenia is a mental disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. Phencyclidine (PCP)-a N-methyl-D-aspartate (NMDA) receptor antagonist-induces symptoms indistinguishable from those of schizophrenia. A reduction of the phosphoprotein synapsin II has also been implicated in schizophrenia and has a well-known role in the maintenance of the presynaptic reserve pool and vesicle mobilization. This study assessed the behavioral and biochemical outcomes of chronic NMDA receptor antagonism in rodents and its implications for the pathophysiology of schizophrenia. Sprague Dawley rats received saline or chronic PCP (5mg/kg/day) for 14days via surgically implanted Alzet® osmotic mini-pumps. Following the treatment period, rats were tested with a series of behavioral paradigms, including locomotor activity, social interaction, and sensorimotor gating. Following behavioral assessment, the medial prefrontal cortex (mPFC) of all rats was isolated for synapsin II protein analysis. Chronic PCP treatment yielded a hyper-locomotive state (p=0.0256), reduced social interaction (p=0.0005), and reduced pre-pulse inhibition (p<0.0001) in comparison to saline-treated controls. Synapsin IIa (p<0.0001) and IIb (p<0.0071) levels in the mPFC of chronically treated PCP rats were reduced in comparison to the saline group. Study results confirm that rats subject to chronic PCP treatment display behavioral phenotypes similar to established preclinical animal models of schizophrenia. Reduction of synapsin II expression in this context implicates the role of this protein in the pathophysiology of schizophrenia and sheds light on the longer-term consequences of NMDA receptor antagonism facilitated by chronic PCP treatment.

Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model

Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to both a broad range of symptoms and disease heterogeneity, current therapeutic approaches to treat schizophrenia fail to address all symptomatic manifestations of the disease. Therefore, disease models that reproduce core pathological features of schizophrenia are needed for the elucidation of pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatography-mass spectrometry proteomic (LC-MS(E)) and metabonomic (LC-MS) profiling analysis combined with the targeted proteomics (selected reaction monitoring and multiplex immunoassay) of serum and brain tissues to investigate a chronic phencyclidine (PCP) rat model in which glutamatergic hypofunction is induced through noncompetitive NMDAR-receptor antagonism. Using a multiplex immunoassay, we identified alterations in the levels of several cytokines (IL-5, IL-2, and IL-1β) and fibroblast growth factor-2. Extensive proteomic and metabonomic brain tissue profiling revealed a more prominent effect of chronic PCP treatment on both the hippocampal proteome and metabonome compared to the effect on the frontal cortex. Bioinformatic pathway analysis confirmed prominent abnormalities in NMDA-receptor-associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA, and GABAergic signaling in the hippocampus and in proteins associated with neurodegeneration. We further identified abundance changes in the level of the superoxide dismutase enzyme (SODC) in both the frontal cortex and hippocampus, which indicates alterations in oxidative stress and substantiates the apoptotic pathway alterations. The present study could lead to an increased understanding of how perturbed glutamate receptor signaling affects other relevant biological pathways in schizophrenia and, therefore, support drug discovery efforts for the improved treatment of patients suffering from this debilitating psychiatric disorder.

Chronic cannabinoid exposure reduces phencyclidine-induced schizophrenia-like positive symptoms in adult rats

Chronic cannabis use can induce psychotic states that resemble schizophrenia. Yet, schizophrenic patients often smoke cannabis as a form of self-medication to counter the aversive symptoms of schizophrenia. We recently demonstrated an ameliorating effect of cannabinoid self-administration (SA) on negative and cognitive schizophrenia-like symptoms induced experimentally by the non-competitive N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Whether cannabinoid SA alleviates or exacerbates schizophrenia-like positive symptoms is still unclear. This follow-up study aimed to evaluate the effect of self-administered cannabinoid on PCP-induced schizotypic positive symptoms in adult rats. Male rats were trained to self-administer either the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN; 12.5μg/kg/infusion) or its vehicle (Veh) intravenously. The effects of acute and chronic intermittent intraperitoneal administration of PCP (2.5mg/kg) on motor parameters were then tested in Veh-SA and WIN-SA. Cannabinoid SA significantly attenuated the psychotomimetic effects of PCP exposure observed in control rats. Following acute PCP administration, WIN-SA animals displayed more frequent rearing and lower anxiety-like profile than Veh-SA rats. WIN-SA rats also exhibited lower behavioural sensitisation to chronic PCP treatment as demonstrated by reduced hyperlocomotion in response to an acute PCP challenge. In addition, parallel experiments performed in experimenter-administered rats that received WIN at comparable SA doses confirmed the ameliorating effects of cannabinoid exposure on PCP-induced schizotypic behaviours, indicating that motivational effects were not responsible for the ameliorative effects of cannabinoids. Our results indicate that cannabis may exert protective effects on positive schizotypic symptoms in adult animals such as hypermotility and anxiety state.

Exposure to enriched environments during adolescence prevents abnormal behaviours associated with histone deacetylation in phencyclidine-treated mice

Enriched environments (EEs) during development have been shown to influence adult behaviour. Environmental conditions during childhood may contribute to the onset and/or pathology of schizophrenia; however, it remains unclear whether EE might prevent the development of schizophrenia. Herein, we investigated the effects of EE during adolescence on phencyclidine (PCP)-induced abnormal behaviour, a proposed schizophrenic endophenotype. Male ICR mice (3 wk old) were exposed to an EE for 4 wk and then treated with PCP for 2 wk. The EE potentiated the acute PCP treatment-induced hyperlocomotion in the locomotor test and prevented chronic PCP treatment-induced impairments of social behaviour and recognition memory in the social interaction and novel object recognition tests. It also prevented the PCP-induced decrease of acetylated Lys9 in histone H3-positive cells and increase of the histone deacetylase (HDAC)5 level in the prefrontal cortex. To investigate whether the histone modification during adolescence might be critical for the effect of EE, 3-wk-old mice were first treated with sodium butyrate (SB; an HDAC inhibitor) for 4 wk and then treated with PCP for 2 wk. Chronic SB treatment during adolescence mimicked the effects of EE, including potentiation of hyperlocomotion induced by acute PCP treatment and prevention of social and cognitive impairments, decrease of acetylated Lys9 in histone H3-positive cells and increase of the HDAC5 level in the prefrontal cortex associated with chronic PCP treatment. Our results suggest that EEs prevent PCP-induced abnormal behaviour associated with histone deacetylation. EEs during childhood might prove to be a novel strategy for prophylaxis against schizophrenia.

Ultrasonic vocalisations explain unexpected effects on pre-pulse inhibition responses in rats chronically pre-treated with phencyclidine

Deficits in pre-pulse inhibition (PPI-indicative of psychosis in humans) can be replicated in rats using the NMDA receptor antagonist phencyclidine (PCP). Ultrasonic vocalisations (USVs) produced by rats in response to acoustic startle are indicative of heightened anxiety; here we tested the predictive validity of USVs as an indicator of PPI. Male juvenile Sprague–Dawley rats ( n = 10) were treated for 14 days with either PCP (5 mg/kg i.p.) or saline controls (1 ml/kg i.p.). PPI responses and USVs were recorded on days 16 and 19. PCP-treated rats showed decreased PPI performance on day 16 compared to controls; an observation that was unexpectedly reversed on day 19. Call parameters indicated that both treatment groups experienced similar levels of anxiety in response to the PPI paradigm on day 16. On day 19, the controls showed increased call duration and latency to onset (LtO) of calling, but decreased in the total number of calls produced compared to day 16. The calling period was significantly reduced compared to PCP-treated animals on say 19, whilst the LtO and duration were significantly increased. These changes were considered indicative of heightened levels of anxiety, most likely due to inadvertent fear conditioning (supported by reduced PPI performance) acquired during PPI testing. In contrast, the stability of USV characteristics emitted by PCP treated animals likely signified the detrimental effects of chronic PCP treatment on working memory. These results suggest that USVs are a valuable additional measure during PPI testing, helping to explain the unexpected results from our control group.

Subchronic and chronic PCP treatment produces temporally distinct deficits in attentional set shifting and prepulse inhibition in rats

We have previously demonstrated that subchronic (five daily administrations of 2.6 mg/kg PCP) and chronic intermittent administration of 2.6 mg/kg PCP to rats produces hypofrontality and other neurochemical changes akin to schizophrenia pathology (Cochran et al., Neuropsychopharmacology, 28:265-275, 2003). We sought to determine whether behavioral alterations related to discrete aspects of schizophrenia are also induced by these PCP treatment regimes. Following administration of vehicle or PCP according to the protocols described above, rats were assessed for attentional set shifting ability, prepulse inhibition (PPI), or social interaction and the locomotor response to a challenge dose of amphetamine. Ability to shift attentional set was impaired 72 h after the last PCP administration following the subchronic and chronic intermittent treatment regimes. PPI was disrupted after each acute administration of PCP in animals under the subchronic treatment regime. However, PPI deficits were not sustained 72 h after the last of five daily administrations. In subchronic and chronic PCP treated animals, no change was found in social interaction behavior, and there was little change in baseline or amphetamine-stimulated locomotor activity, employed as an indicator of dopaminergic hyperfunction. The temporally distinct behavioral effects of these PCP treatment regimes suggest that PPI deficits relate directly to acute NMDA receptor antagonism, whereas the more enduring set shifting deficits relate to the longer term consequences of NMDA receptor blockade. Therefore, these subchronic and chronic PCP treatment regimes produce hypofrontality (Cochran et al., Neuropsychopharmacology, 28:265-275, 2003) and associated prefrontal cortex-dependent deficits in behavioral flexibility which mirror core deficits in schizophrenia.

T-817MA, a novel neurotrophic compound, ameliorates phencyclidine-induced disruption of sensorimotor gating

Neurodegenerative changes have been suggested to provide a basis for the pathophysiology of schizophrenia. T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl} azetidin-3-ol maleate) is a novel compound with neuroprotective and neurite-outgrowth effects, as elicited in rat primary cultured neurons. We examined the effect of T-817MA on phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI), a measure of sensorimotor gating, in male Wistar rats. In chronic experiments, male Wistar rats were injected intermittently with PCP (2.0 mg/kg, i.p., three times per week) or vehicle (saline, 2.0 ml/kg) for 1 month. T-817MA (0.21 or 0.07 mg/ml, p.o.) or distilled water was administered throughout the study period. In an acute experiment, T-817MA (8.4 mg/kg, p.o.) or distilled water was administered, followed by treatment with PCP (2.0 mg/kg, i.p.) or vehicle (saline, 2.0 ml/kg), before PPI measurements. Intermittent administration of PCP for 1 month induced persistent disruption of PPI. Coadministration of T-817MA at 0.21 mg/ml but not 0.07 mg/ml completely blocked PCP-induced disruption of PPI, whereas T-817MA (0.21 mg/ml) by itself did not show a significant effect on PPI in control rats. On the other hand, single administration of T-817MA did not affect PPI disruption by acute treatment with PCP. These results suggest that T-817MA is effective in ameliorating sensorimotor gating deficits caused by chronic PCP treatment, possibly via neuroprotective actions. Our findings provide a novel therapeutic approach for patients with schizophrenia.

A Primate Model of Schizophrenia Using Chronic PCP Treatment

To establish a primate animal model of schizophrenia with negative symptoms, the behavioral effects of chronic phencyclidine (PCP) and additional acute methamphetamine (MAP) administration were investigated in six monkeys. The results indicate that chronic PCP treatment induced a significant decrease in all categories of social behaviors, and that the chronic PCP monkeys also spent less time in proximity to other monkeys than the control monkeys. Acute MAP injection to the chronic PCP monkeys exacerbated the behavioral effects of PCP. The results suggest that these monkeys can be used as a primate model of schizophrenia with negative symptoms.

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.

Short and long term changes in NMDA receptor binding in mouse brain following chronic phencyclidine treatment

Phencyclidine (PCP) is an antagonist of the NMDA subtype of glutamate receptor. PCP treatment induces psychosis in normal humans, which provides a valuable model of schizophrenia. PCP administration also models some of the symptoms of schizophrenia in experimental animals. NMDA hypofunction has been hypothesized to explain these schizophrenia-like symptoms. Acute or chronic administration of the NMDA receptor antagonist PCP has been shown to induce several short or long-term effects in both humans and experimental animals. In an attempt to clarify the neurochemical substrates of these effects in the present study, we used quantitative autoradiography to examine the effects of chronic (14 days) PCP treatment on NMDA receptor binding in mouse brain following both a short- (1 and 24 h) and long-term (14 days) delay after the last PCP treatment. NMDA receptors were targeted using [(3)H]MK801. Chronic PCP treatment increased [(3)H]MK801 binding consistently in the hippocampus in the short-term (p < 0.01). Conversely in the long-term, there were widespread reductions in NMDA receptor binding and this effect was most evident in the hippocampus where a 35% reduction of binding was found (p < 0.001). These results suggest that the hippocampus has a strong involvement in both the short and long-term effects of PCP treatment and that reduced NMDA receptor function might be one of the neurochemical substrates of the long lasting actions of PCP or PCP-induced psychosis. Importantly, this study shows that the long-term delay following chronic PCP treatment more accurately represents a state of NMDA hypofunction than the short-term PCP model.

Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine

Schizophrenia is a major mental disorder. Dissociative anesthetics such as phencyclidine (PCP) produce a syndrome in humans that is clinically indistinguishable from schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors in brain are modulated by the amino acid glycine (GLY), which reverses neurochemical and behavioral effects of PCP in rodents. The present study investigates GLY effects on PCP-induced behavior in primates. In primates, PCP induces characteristic behavioral symptoms that can be used to model positive and negative symptoms of schizophrenia. This study investigated the effects of GLY treatment in ten socially housed monkeys receiving chronically infused PCP. Ten monkeys received escalating then stable doses of continuously infused PCP through a series of subcutaneously implanted osmotic minipumps. During a segment of the highest PCP dose period, monkeys were concurrently treated with glycine (2 g kg(-1) day(-1) bid p.o.). Behavioral observations were recorded during baseline and treatment periods. Chronic PCP treatment was associated with a progressive decrease in stereotyped pacing and a progressive increase in scanning behavior. Eight of ten animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. GLY treatment significantly reversed the effects of PCP on stereotyped pacing but had no effect on scanning. The results support GLY treatment as beneficial for negative symptoms of schizophrenia. Although further validation is needed, the results also indicate that chronic PCP in primates may be an appropriate model system for development of drugs targeting positive and negative symptoms of schizophrenia.

Opposing short‐ and long‐term effects on muscarinic M1/4 receptor binding following chronic phencyclidine treatment

Phencyclidine (PCP) is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Several studies have demonstrated that chronic NMDA receptor antagonist treatment in humans and animals can cause long-term behavioral changes that are reminiscent of negative and cognitive schizophrenia-like symptoms. The muscarinic cholinergic system, which is associated with cognitive functions, has been hypothesized to contribute to PCP's mechanism of action. No study, however, has examined the status of M1/4 receptors in the PCP model of schizophrenia. The aim of the present study was to investigate the effects of chronic (14 day) PCP treatment on mouse brain M1/4 receptors in the short term (1 hr and 24 hr) and long term (14 days) after last PCP administration. [(3)H]pirenzepine was used to target M1/4 receptors. In the short term following chronic PCP treatment, M1/4 binding was significantly increased in regions of the limbic system, caudate-putamen, cortex, and thalamus (ranging from 56% to 368%), compared with saline-treated mice. There were no differences in binding between mice treated with PCP for 14 days and sacrificed 1 hr or 24 hr after the final PCP treatment. In the long term following chronic PCP treatment, M1/4 binding was significantly decreased in all of the above-mentioned brain regions (ranging from 31% to 72%), except in the thalamus, which showed no change. These findings in the long-term group are similar to those reported in post-mortem studies of patients suffering from schizophrenia.

PRECLINICAL STUDY: Different effects of chronic phencyclidine on brain‐derived neurotrophic factor in neonatal and adult rat brains

The N-methyl-D-aspartate (NMDA) receptor and brain-derived neurotrophic factor (BDNF) are both known to play major roles in the normal development of the brain. We have hypothesized that the chronic blockade of NMDA with phencyclidine (PCP) may have a different effect on BDNF synthesis at different stages of development. In an acute experiment, rat pups and adult rats were injected with PCP (2.5, 5 or 10 mg/kg) at postnatal day (PD) 15 or 49, respectively. In a chronic experiment, rat pups were injected daily from PD 5 to PD 14 with PCP (2.5, 5 or 10 mg/kg), while adult rats were injected daily with the same dose from PD 39 to PD 48. BDNF levels in the hippocampus, striatum and frontal cortex were determined by ELISA assay 24 hours after the last injection. Chronic PCP treatment of neonatal rats induced a dose-dependent decrease in BDNF in the hippocampus but not in the frontal cortex and striatum. Single injection of PCP to rat pups showed a slight reduction of BDNF in the hippocampus but only at higher doses. In contrast to neonatal brain, neither acute nor chronic injection of PCP influenced BDNF in adult brain. These findings suggest that chronic blockade of NMDA receptor in the early neonatal period has an inhibitory effect on BDNF synthesis in the hippocampus and may impair normal neurodevelopment in rat pups.

Effects of alpha7-type nicotinic receptor agonist on cortical D1 receptor binding and PDE-IV activity modulated by chronic PCP treatment in conscious monkey brain

Effects of alpha7-type nicotinic receptor agonist on cortical D1 receptor binding and PDE-IV activity modulated by chronic PCP treatment in conscious monkey brain

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.

The atypical antipsychotic drug clozapine enhances chronic PCP-induced regulation of prefrontal cortex 5-HT2 A receptors

The ability of antipsychotic drugs to affect 5-HT 2A receptor function has been widely suggested to contribute to their therapeutic properties. We have compared the ability of the antipsychotic drugs clozapine and haloperidol, alone and in combination with chronic phencyclidine (PCP), to modulate 5-HT 2A receptor binding and mRNA. Acute (i.p. 45 min) and chronic (21-day) clozapine (osmotic minipump (OMP); 20 mg/kg/day) produced widespread decreases in 5-HT 2A receptor binding (−60%–80%), measured using [ 3H]ketanserin autoradiography. Conversely, 5-HT 2A mRNA levels, determined using in-situ hybridisation, were modestly increased by chronic clozapine treatment (+10%–30%). Chronic PCP treatment, at a dose (2.58 mg/kg i.p. intermittently for 28 days) that reproduces many of the neurochemical deficits of schizophrenia, decreased 5-HT 2A receptor binding in the prefrontal cortex (PFC; −16%), consistent with the changes in post-mortem brain tissue from schizophrenic patients. Combined chronic PCP (i.p.) and clozapine (OMP) treatment down-regulated 5-HT 2A receptor binding in many areas, similar to the effects of clozapine treatment alone and clozapine further enhanced the effects of PCP in the prefrontal cortex. In contrast 5-HT 2A mRNA was not altered. Haloperidol treatment alone (1 mg/kg/day; OMP) and in combination with PCP (i.p.), generally produced no changes in 5-HT 2A receptor protein or mRNA. Hence chronic PCP treatment, as employed here, mimics the decreased 5-HT 2A receptor binding observed in the PFC of schizophrenic patients. Clozapine’s enhancement of the natural response of PCP to down-regulate PFC 5-HT 2A receptors may contribute to it’s improved therapeutic profile against negative symptoms and cognitive deficits.

Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs.

Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg(-1) i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.

Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function.

Phencyclidine (PCP) is a drug of abuse that has rewarding and dysphoric effects in humans. The complex actions of PCP, and PCP withdrawal in particular, on brain reward function remain unclear. The purpose of the present study was to characterize the effects of withdrawal from acute and chronic PCP treatment on brain reward function in rats. A brain stimulation reward procedure was used to evaluate the effects of acute PCP injection (0, 5, or 10 mg/kg) or chronic PCP treatment (0, 10, 15, or 20 mg/kg/day for 14 days delivered via subcutaneous osmotic minipumps) on brain reward function. Withdrawal from acute administration of 5 and 10 mg/kg PCP produced a decrease in brain reward function as indicated by a sustained elevation in brain reward thresholds. When administered chronically, 10, 15, or 20 mg/kg/day PCP induced a progressive dose-dependent potentiation of brain stimulation reward, while cessation of the treatment resulted in significant elevations in reward thresholds reflecting diminished reward. Specifically, withdrawal from 15 or 20 mg/kg/day PCP induced a depression in brain reward function that lasted for the entire month of observation. These results indicate that prolonged continuous administration of high PCP doses facilitates brain stimulation reward, while withdrawal from acute high PCP doses or chronic PCP treatment results in a protracted depression of brain reward function that may be analogous to the dysphoric and anhedonic symptoms observed in PCP dependence, depression, and schizophrenia.