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Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

Despite advances in understanding the pathophysiology of Huntington’s disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect. This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.

The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-D-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.

NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. ? 2013 Published by Elsevier B.V. and ECNP.

A well established theory proposes that glutamate signalling via the NMDA receptor is compromised in patients with schizophrenia. Deficits related to NMDA receptor signalling can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). In addition, a number of studies suggest that normalizing of PFC function could constitute a treatment rationale for schizophrenia. To further study the role of PFC function we investigated the effect of local PFC NMDA receptor blockade on impaired prepulse inhibition (PPI) induced by systemic administration of PCP. Mice received prefrontal injections of PCP (0.01, 0.1 or 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. PCP induced deficits in PPI were ameliorated by prefrontal PCP (0.1 mM) treatment whereas PPI was not affected by prefrontal cortex PCP administration per se at any of the doses tested. Taken together, inhibition of NMDA receptors in the PFC does not seem to be enough to impair PPI per se but NMDA receptor mediated signalling in the PFC may be a key factor for the PPI-disruptive effects of global NMDA receptor inhibition. This indicates that targeting PFC NMDA receptor signalling may have potential as a treatment target for schizophrenia although further studies are needed to understand pharmacology and pathophysiological role of PFC NMDA receptors.

Rationale Schizophrenia-like cognitive deficits induced by phencyclidine (PCP), a drug commonly used to model schizophrenia in experimental animals, are attenuated by nitric oxide (NO) synthase inhibitors. Furthermore, PCP increases NO levels and sGC/cGMP signalling in the prefrontal cortex in rodents. Hence, a cortical NO/sGC/cGMP signalling pathway may constitute a target for novel pharmacological therapies in schizophrenia. Objectives The objective of this study was to further investigate the role of NO signalling for a PCP-induced deficit in pre-attentive information processing. Materials and methods Male Sprague–Dawley rats were surgically implanted with NO-selective amperometric microsensors aimed at the prefrontal cortex, ventral hippocampus or nucleus accumbens, and NO levels and prepulse inhibition (PPI) were simultaneously assessed. Results PCP treatment increased NO levels in the prefrontal cortex and ventral hippocampus, but not in the nucleus accumbens. The increase in NO levels was not temporally correlated to the deficit in PPI induced by PCP. Furthermore, pretreatment with the neuronal NO synthase inhibitor N-propyl-l-arginine dose-dependently attenuated both the increase in prefrontal cortex NO levels and the deficit in PPI. Conclusions These findings support a demonstrated role of NO in the behavioural and neurochemical effects of PCP. Furthermore, this effect is brain region-specific and mainly involves the neuronal isoform of NOS. However, a temporal correlation between a PCP-induced disruption of PPI and an increase in prefrontal cortex NO levels was not demonstrated, suggesting that the interaction between PCP and the NO system is more complex than previously thought.

Schizophrenia is a chronic disorder generally considered to encompass positive symptoms, negative symptoms and cognitive deficits. Increasing attention has been paid to the social cognitive deficits of the disorder as these dysfunctions are particularly handicapping, predictive of functional outcome and show poor treatment response. Phencyclidine (PCP) is a psychotomimetic drug used to model the different aspects of schizophrenia in experimental animal models. PCP-induced cognitive deficits and hyperlocomotion may be blocked by pretreatment with nitric oxide (NO) synthase inhibitors in rodents. The present study was carried out to evaluate the acute effects of PCP and NO synthase inhibition on social interaction in male Sprague–Dawley rats. The NO synthase inhibitor, l -NAME (10 mg/kg) and PCP (2 mg/kg) was injected subcutaneously to rats, which were then tested in pairs for social interactive behaviour. Twenty-four hours after the initial test a drug-free social interaction test was carried out to assess the rats’ memory of the previous social interaction. The results showed that PCP reduced the time of social interaction on Day 1 compared to controls, and that pretreatment with the NO synthase inhibitor, l -NAME, attenuated this reduction towards control levels. Neither locomotor activity, nor frequency of social interactions were affected by the PCP treatment, suggesting that the PCP-induced effects observed were not due to drug-induced stereotypies. In combination with increasing clinical evidence for the involvement of NO in the pathophysiology of schizophrenia, the present results indicate that NO synthase inhibition may be a potentially new treatment strategy for alleviating social dysfunction in schizophrenia.

Agmatine, a decarboxylation product of arginine, is thought to be an important neuromodulator in the mammalian brain. It is proposed to exert neuroprotective, anxiolytic and antidepressant effects. The receptor-binding profile of agmatine is complex and includes interaction with alpha(2)-adrenergic and imidazoline I(1) receptors. Furthermore, agmatine is an NMDA-receptor antagonist and inhibits nitric oxide synthase. Prepulse inhibition (PPI) of the acoustic startle response is used as a measure of the pre-attentive information processing. PPI is lowered in schizophrenia and this impairment can be mimicked in experimental animals using the psychotomimetic drug phencyclidine (PCP). The aim of the present study was to investigate the effects of agmatine per se on the PPI response and the effects of agmatine pre-treatment on a PCP-induced disruption of PPI. Agmatine administration (10, 20 and 40 mg/kg) did not change the PPI response or the acoustic startle response. However, pre-treatment with agmatine 20 mg/kg, but not agmatine 40 mg/kg, significantly attenuated a PCP (5 mg/kg)-induced disruption of the PPI response. These results emphasize the potential role of agmatine as a neuromodulator and potential target for novel treatments for brain disorders.

Deficits in prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, are characteristics of schizophrenia and related neuropsychiatric disorders. Previous studies in mice demonstrate a contribution of dopamine (DA) D(1)-family receptors in modulating PPI and DA D(2) receptors (D2R) in mediating the PPI-disruptive effects of amphetamine. To examine further the contributions of DA receptor subtypes in PPI, we used a combined pharmacological and genetic approach. In congenic C57BL/6 J wild-type mice, we tested whether the D1R antagonist SCH23390 or the D2/3R antagonist raclopride would attenuate the effects of the indirect DA agonist cocaine (40 mg/kg). Both the D1R and D2/3R antagonists attenuated the cocaine-induced PPI deficit. We also tested the effect of cocaine on PPI in wild-type and DA D1R, D2R, or D3R knockout mice. The cocaine-induced PPI deficit was influenced differently by the three DA receptor subtypes, being absent in D1R knockout mice, partially attenuated in D2R knockout mice, and exaggerated in D3R knockout mice. Thus, the D1R is necessary for the PPI-disruptive effects of cocaine, while the D2R partially contributes to these effects. Conversely, the D3R appears to inhibit the PPI-disruptive effects of cocaine. Uncovering neural mechanisms involved in PPI will further our understanding of substrates of sensorimotor gating and could lead to better therapeutics to treat complex cognitive disorders such as schizophrenia.

Latent inhibition (LI) is a behavioural procedure used to evaluate the potential propsychotic and antipsychotic properties of psychoactive drugs. In the present study, a conditioned taste aversion (CTA) procedure was used to investigate the effects of the nitric oxide (NO) synthase inhibitor, N G -nitro- l -arginine methyl ester (L-NAME), and the psychotomimetic drugs, phencyclidine (PCP) and d-amphetamine (d-AMP) on LI. PCP (2 mg/kg) and d-AMP (0.5 mg/kg) were both found to enhance LI in this procedure. The effect of d-AMP on LI was less pronounced and this drug also caused a weak disruption of taste aversion conditioning. Pretreatment with L -NAME (10 mg/kg) blocked the LI enhancing effect of PCP on LI but not that of d-AMP. L -NAME by itself caused an attenuation of LI. L -NAME has been shown to block also other behavioural and biochemical effects of PCP in previous studies and these results and the present findings suggest that at least some of the effects PCP are dependent on NO and possibly also that some NOS inhibitors may exert antipsychotic properties.

BACKGROUND The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission. OBJECTIVE To investigate pharmacological interactions between pridopidine and tetrabenazine. METHODS Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison. RESULTS Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine. CONCLUSIONS Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine-induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy.

Nitric oxide is a ubiquitous messenger molecule, which at elevated concentrations has been implicated in the pathogenesis of several neurological disorders. Its role in oxidative stress, attributed in particular to the formation of peroxynitrite, proceeds through its high affinity for the superoxide radical. Alcoholism has recently been associated with the induction of oxidative stress, which is generally defined as a shift in equilibrium between pro-oxidant and anti-oxidant species in the direction of the former. Furthermore, its primary metabolite acetaldehyde, has been extensively associated with oxidative damage related toxic effects following alcohol ingestion. The principal objective of this study was the application of long term in vivo electrochemistry (LIVE) to investigate the effect of ethanol (0.125, 0.5 and 2.0 g kg(-1)) and acetaldehyde (12.5, 50 and 200 mg kg(-1)) on NO levels in the nucleus accumbens of freely moving rats. Systemic administrations of ethanol and acetaldehyde resulted in a dose-dependent increases in NO levels, albeit with very differing time courses. Subsequent to this the effect on accumbal NO levels, of subjecting the animal to different drug combinations, was also elucidated. The nitric oxide synthase inhibitor L-NAME (20 mg kg(-1)) and acetaldehyde sequestering agent D-penicillamine (50 mg kg(-1)) both attenuated the increase in NO levels following ethanol (1 g kg(-1)) administration. Conversely, the alcohol dehydrogenase inhibitor 4-methylpyrazole (25 mg kg(-1)) and catalase inhibitor sodium azide (10 mg kg(-1)) potentiated the increase in NO levels following ethanol administration. Finally, dual inhibition of aldehyde dehydrogenase and catalase by cyanamide (25 mg kg(-1)) caused an attenuation of ethanol effects on NO levels. Taken together these data highlight a robust increase in brain NO levels following systemic alcohol administration which is dependent on NO synthase activity and may involve both alcohol- and acetaldehyde-dependent mechanisms.

Under some conditions, external sensory noise enhances cognitive functions, a phenomenon possibly involving stochastic resonance and/or enhanced central dopamine transmission. Prepulse inhibition (PPI) of the startle reflex is a robust measure of sensorimotor gating and can be modulated by activity in the cortex and basal ganglia, including the central dopamine pathways.Previous empirical studies suggest a differential effect of acoustic noise in normal children and children with attention-deficit hyperactivity disorder (ADHD). This study investigated the effect of acoustic noise on PPI and if dopamine transmission interacts with acoustic noise effects in a rat ADHD model.The effect of background acoustic noise on acoustic startle response and PPI were measured with a constant prepulse to background noise ratio of 9 dB(A). Spontaneously hypertensive (SH) rats were used as the ADHD model and compared with Wistar and Sprague-Dawley rats. Microdialysis, methylphenidate treatment and 6-OHDA lesions were used to investigate interaction with dopamine transmission.Background noise facilitated PPI differently in SH rats and controls. The prefrontal cortex in SH rats had low basal dopamine concentrations, a high DOPAC/dopamine ratio and blunted dopamine release during PPI testing. Methylphenidate had small, but strain-specific, effects on startle and PPI. Bilateral 6-hydroxydopamine lesions did not alter startle or PPI.Prefrontal dopamine transmission is altered in SH rats during the sensorimotor gating task of PPI of the acoustic startle, indicating increased dopamine reuptake in this ADHD rat model. We propose that noise benefit could be explored as a non-pharmacological alternative for treating neuropsychiatric disorders.

Recent theories propose that both GABA and glutamate signaling are compromised in patients with schizophrenia. These deficits can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). We have previously demonstrated that inhibition of the nitric oxide (NO) pathways in the brain, particularly in the PFC, prevents a wide range of PCP-induced behavioral deficits including disruption of prepulse inhibition (PPI). This study investigated the role of GABA(B) receptor signaling and NO in the effects of PCP on PPI. Mice received systemic or prefrontal injections of the GABA(B) receptor agonist baclofen (2.5-5 mg/kg and 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. GABA/NO interactions were studied by combining baclofen and the NO synthase inhibitor L-NAME (20 mg/kg) in subthreshold doses. The role of GABA(B) receptors for NO production in vivo was assessed using NO-sensors implanted into the rat PFC. PCP-induced PPI deficits were attenuated in an additive manner by systemic baclofen treatment, whereas prefrontal microinjections of baclofen completely blocked the effects of PCP, without affecting PPI per se. The combination of baclofen and L-NAME was more effective in preventing the effects of PCP than any compound by itself. Additionally, baclofen decreased NO release in the PFC in a dose-related manner. This study proposes a role for GABA(B) receptor signaling in the effects of PCP, with altered NO levels as a downstream consequence. Thus, prefrontal NO signaling mirrors an altered level of cortical inhibition that may be of importance for information processing deficits in schizophrenia.

Phencyclidine exerts psychotomimetic effects in humans and is used as a pharmacological animal model for schizophrenia. We, and others, have demonstrated that phencyclidine induces cognitive deficits in rats that are associated with schizophrenia. These cognitive deficits can be normalized by inhibition of nitric oxide synthase. The development of selective microelectrochemical nitric oxide sensors may provide direct evidence for the involvement of nitric oxide in these effects. The aim of the present study was to use LIVE (long term in vivo electrochemistry) to investigate the effect of phencyclidine, alone or in combination with the nitric oxide synthase inhibitor L-NAME, on nitric oxide levels in the medial prefrontal cortex of freely moving rats. Phencyclidine (2 mg kg(-1)) produced an increase in cortical nitric oxide levels and this increase was ameliorated by L-NAME (10 mg kg(-1)). Tentatively, the results from the present study provide a biochemical rationale for the involvement of nitric oxide in the phencyclidine model of schizophrenia.

The prefrontal cortex (PFC) is believed to play an important role in the cognitive impairments observed in schizophrenia and has also been shown to be involved in the modulation of prepulse inhibition (PPI), a measure of preattentive information processing that is impaired in schizophrenic individuals. Phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor, exerts psychotomimetic effects in humans, disrupts PPI, and causes hypofrontality in rodents and monkeys. We have previously demonstrated that interfering with the production of nitric oxide (NO) can prevent a wide range of PCP-induced behavioral deficits, including PPI disruption. In the present study, the role of NO signaling for the behavioral and biochemical effects of PCP was further investigated. Dialysate from the medial PFC of mice receiving systemic treatment with PCP and/or the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg), was analyzed for cGMP content. Furthermore, a specific inhibitor of NO-sensitive soluble guanylyl cyclase (sGC), 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ, 0.01-1 mM), was administered into the medial PFC of mice in combination with systemic injections of PCP, followed by PPI and locomotor activity testing. PCP (5 mg/kg) caused an increase in prefrontal cGMP that could be attenuated by pretreatment with the NO synthase inhibitor, L-NAME. Moreover, bilateral microinjection of the sGC inhibitor, ODQ, into the medial PFC of mice attenuated the disruption of PPI, but not the hyperlocomotion, caused by PCP. The present study shows that NO/sGC/cGMP signaling pathway in the medial PFC is involved in specific behavioral effects of PCP that may have relevance for the disabling cognitive dysfunction found in patients with schizophrenia.

Schizophrenia encompasses, amongst other symptoms, a heavy load of cognitive dysfunctionality. Using the psychotomimetic agent, phencyclidine (PCP), we have previously found that PCP-induced disruptions of cognitive function in translational rodent models of schizophrenia are dependent on nitric oxide (NO) production. In the present study, male Sprague-Dawley rats were subjected to a Morris water maze task designed to assess cognitive flexibility (i.e. the ability to cope with an increasingly demanding cognitive task) by means of a "constant reversal learning paradigm". Experiments were conducted to evaluate the effects of the NO synthase inhibitor, L-NAME (10 mg/kg), on PCP-induced (2 mg/kg) impairments. Control animals significantly improved their learning over the first 3 consecutive days, whereas PCP-treated animals failed to show any significant learning. Pretreatment with L-NAME normalized the PCP-induced disruption of learning to control levels. These findings suggest that PCP-induced disruptions of cognitive flexibility (i.e. ability to modify behaviour according to an increasingly demanding cognitive task) are dependent upon NO production. These observations, together with accumulated clinical findings, suggest that the NO system is a potential treatment target for cognitive dysfunctions in schizophrenia.

The psychotomimetic drug, phencyclidine, induces schizophrenia-like behavioural changes in both humans and animals. Phencyclidine-induced disruption of sensory motor gating mechanisms, as assessed by prepulse inhibition of the acoustic startle, is widely used in research animals as a screening model for antipsychotic properties in general and may predict effects on negative and cognitive deficits in particular. Dopamine (DA) stabilizers comprise a new generation of antipsychotics characterized by a partial DA receptor agonist or antagonist action and have been suggested to have a more favourable clinical profile.The aim of the present study was to investigate the ability of first, second and third generation antipsychotics to interfere with the disruptive effect of phencyclidine on prepulse inhibition in mice.Aripiprazole blocked the phencyclidine-induced disruption of prepulse inhibition. The atypical antipsychotic clozapine was less effective, whereas olanzapine, and the typical antipsychotic haloperidol, failed to alter the effects of phencyclidine on prepulse inhibition.The somewhat superior efficacy of clozapine compared to haloperidol may be explained by its lower affinity and faster dissociation rate for DA D2 receptors possibly combined with an interaction with other receptor systems. Aripiprazole was found to be more effective than clozapine or olanzapine, which may be explained by a partial agonist activity of aripiprazole at DA D2 receptors. In conclusion, the present findings suggest that partial DA agonism leading to DA stabilizing properties may have favourable effects on sensorimotor gating and thus tentatively on cognitive dysfunctions in schizophrenia.

The cognitive and attentional deficits observed in schizophrenic patients are now considered central to the pathophysiology of the disorder. These deficits include an inability to filter sensory input as measured by, e.g., prepulse inhibition (PPI) reflex. Administration of phencyclidine (PCP), a drug that can induce a schizophrenia-like psychosis in humans, disrupts PPI in experimental animals. In rodents, this PCP-induced deficit can be blocked by pretreatment with nitric oxide (NO) synthase inhibitors. This suggests that some of the behavioral effects of PCP are mediated via NO. The substrate for in vivo NO production is l-arginine, and active transport of l-arginine via the cationic amino acid transporter may serve as a regulatory mechanism in NO production. The aim of the present study was to study the effects of l-arginine transport inhibition, using acute and repeated l-lysine treatment, on PCP-induced disruption of PPI in mice. Subchronic, and to some extent acute, pretreatment with l-lysine blocked a PCP-induced deficit in PPI without affecting basal PPI. l-lysine has been shown to block l-arginine transport in vitro, most likely via a competitive blockade and down regulation of cationic amino acid transporters. However, the importance of l-arginine transport as a regulatory mechanism in NO production in vivo is still not clear. The present results lend further support to the notion that some of the effects of PCP in the central nervous system are mediated via NO and that l-arginine transport may play a role in the regulation of NO production in the brain.

Phencyclidine (PCP), a non-competitive NMDA receptor antagonist, was used to model schizophrenia-like cognitive dysfunctions of learning and memory in rats using the Morris water maze model for spatial memory. A protocol introduced by Baldi and co-workers was used to distinguish working memory from reference memory. Male Sprague-Dawley rats were administered PCP (2.0 mg/kg) before the first swimming trial on each of five spatial memory acquisition days, either alone or after pre-treatment with the nitric oxide synthase inhibitor, L-NAME (10 mg/kg). Probe tests for memory were conducted before and after each acquisition session. The results showed that PCP disrupted the acquisition of both working and reference memory. Pre-treatment with L-NAME reversed both these effects of PCP. L-NAME treatment by itself did not significantly alter either acquisition or retention of spatial memory.

Cognitive deficits of schizophrenia constitute a disabling part of the disease predicting treatment success as well as functional outcome. Phencyclidine (PCP), a non-competitive NMDA receptor antagonist was used to model schizophrenic cognitive dysfunctions of learning and memory using the Morris water maze paradigm for reference memory. In experiment 1 male Sprauge-Dawley rats were acutely administered PCP (0.5, 1.0 and 2.0 mg/kg s.c.) before the first swim session on each of the four acquisition days. Probe test for reference memory was performed 2 days after the last acquisition day; the first probe without drug treatment to assess reference memory and a second probe with prior drug treatment to control for state dependency effects of PCP. In experiment 2 the effects of pre-treatment (10 min before PCP) with the nitric oxide synthase inhibitor, L-NAME (10 mg/kg s.c.), on the PCP (2 mg/kg)-induced spatial memory deficit was evaluated in the Morris water maze paradigm for reference memory. The results showed that PCP in a dose of 2 mg/kg disrupts spatial learning as estimated by prolonged search time to find platform during acquisition as well as the reference memory test as measured by less time spent in target quadrant during probe trial. No state dependency effects of PCP were found. Pre-treatment with L-NAME completely reversed the PCP-induced disruption of acquisition learning. The reference memory disruption was, however, not completely restored as measured by probe trial.

The psychotomimetic drugs, phencyclidine (PCP) and MK-801, are non-competitive antagonists of the N-methyl-d-aspartate (NMDA) receptor and used as pharmacological tools to mimic a possible NMDA receptor hypofunction in schizophrenia. These drugs were tested in two behavioural paradigms in the present study: prepulse inhibition (PPI) of acoustic startle and locomotor activity (LMA) in an open field. Recent studies show that several behavioural and biochemical effects of PCP are blocked by nitric oxide synthase (NOS) inhibition. Hence, it is likely that some effects of PCP are mediated via an increase in NO production, an assumption not in accordance with the NMDA receptor antagonistic effect of PCP. Experiments were conducted in rats to further elucidate the involvement of NO-dependent mechanisms in the effects of PCP and MK-801, and how these effects may involve the NMDA receptor. The NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg) normalised the disruptive effect of PCP (2 mg/kg) on PPI and the stimulatory effect of PCP (4 mg/kg) on LMA. In contrast to these observations, the deficit in PPI induced by MK-801 (0.1 mg/kg) was not affected by L-NAME (10, 20 or 40 mg/kg). MK-801 (0.15 mg/kg)-induced hyperlocomotion was not affected by L-NAME (10 mg/kg), but attenuated by L-NAME (40 mg/kg). Furthermore, receptor binding studies aimed at investigating the influence of L-NAME on the binding of PCP to the MK-801-sensitive NMDA receptor binding site failed to show such an influence. These results suggest that the NO-sensitive effects of PCP are not sufficiently explained by its antagonistic effect at the NMDA receptor channel complex.

Phencyclidine has frequently been used to model schizophrenia in animals. In the present study, the ability of the neuronal selective nitric oxide synthase (NOS) inhibitor, Nomega-propyl-L-arginine, to block the behavioural effects of phencyclidine in mice was investigated. N(omega)-propyl-L-arginine (20 mg/kg) was found to block both phencyclidine (4 mg/kg)-induced disruption of prepulse inhibition and phencyclidine-induced stimulation of locomotor activity in the mice tested. It is concluded that the NOS-sensitive behavioural effects of phencyclidine in rodents is dependent on neuronal NOS and that NO may play a role in the psychotomimetic effects of phencyclidine.

Schizophrenic patients show deficits in pre-attentive information processing as evidenced, for example, by disrupted prepulse inhibition, a measure of sensorimotor gating. A similar disruption can be observed in animals treated with the psychotomimetic agent, phencyclidine (PCP). However, the mechanism by which PCP alters brain function has not been fully elucidated. Recent studies have demonstrated that certain behavioural and neurochemical effects of PCP in rats and mice are blocked by nitric oxide (NO) synthase inhibition, suggesting an important role for NO in the effects of PCP.The aim of the present study was to investigate the effects of PCP on cAMP production in the ventral hippocampus and the role of NO in these effects using in vivo microdialysis in rats. Furthermore, the effects of PCP on acoustic startle reactivity and prepulse inhibition of acoustic startle were compared with changes in cAMP levels in the ventral hippocampus.Significant increases in cAMP levels were observed in the ventral hippocampus following both local infusion (10(-4) mol/l and 10(-3) mol/l) and systemic administration (2 mg/kg) of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in cAMP levels in the hippocampus. Furthermore, systemic administration of the NO synthase inhibitor, L: -NAME (10 mg/kg), blocked both the changes in cAMP levels and the behavioural responses induced by PCP.These findings indicate that the effects of PCP on prepulse inhibition and startle reactivity are associated with an increase in cAMP levels in the ventral hippocampus, and that this change in cAMP response may be linked to the production of NO.

A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP. The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation. PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801. The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.

Schizophrenia is a major public health problem that affects approximately 1% of the population worldwide. Schizophrenia-like symptoms can be induced in humans by phencyclidine (PCP), a drug with marked psychotomimetic properties. Phencyclidine disrupts prepulse inhibition of acoustic startle in rodents, a measure which has also been shown to be disrupted in schizophrenic patients. This effect is blocked by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide plays an important role in this effect of phencyclidine. Methylene blue, a guanylate cyclase and nitric oxide syntase inhibitor, has shown therapeutic value as an adjuvant to conventional antipsychotics in the therapy of schizophrenia. The aim of the present study was to investigate if phencyclidine-(4 mg/kg)induced disruption of prepulse inhibition could be affected by methylene blue (50 or 100 mg/kg) in mice. Furthermore, the effect of methylene blue (50 mg/kg) on phencyclidine-(4 mg/kg)induced hyperlocomotion was investigated. The present study shows that phencyclidine readily disrupts prepulse inhibition in mice without affecting pulse-alone trials. It was also found that methylene blue prevents the decrease in prepulse inhibition caused by phencyclidine in a dose-related manner. Furthermore, the increase in locomotor activity caused by phencyclidine was reduced by pretreatment with methylene blue. The results from the present study further support the suggestion that the nitric oxide synthase/guanylate cyclase pathway is involved in pharmacological and behavioural effects of phencyclidine. Since phencyclidine as well exerts psychotomimetic characteristics, agents that interfere with the nitric oxide synthase/guanylate cyclase pathway may be of therapeutic value also in the treatment of schizophrenia.

Latent inhibition (LI) is a behavioural procedure in which preexposure to a stimulus not followed by reinforcement retards subsequent conditioning to this stimulus when it is paired with reinforcement. Changes in LI thus reflect greater or lesser retardation of learning which essentially implies a potentiation or an attenuation of the LI effect. LI has proved sensitive to psychotomimetic and antipsychotic treatment, which has encouraged its use to model learning and attention deficits in schizophrenia. In the present study, experiments were conducted to evaluate the effects of the psychotomimetic drug, phencyclidine (PCP, 2 mg/kg), and compare it with D-amphetamine (D-AMP, 0.33 and 1 mg/kg), on LI using a conditioned taste aversion procedure. PCP was found to potentiate LI when administered acutely prior to the conditioning trails, while no such effect was observed when administered prior to the preexposure trials. D-AMP, on the other hand, disrupted LI possibly due to a failure to induce a persistent taste aversion conditioning.

Rationale: Schizophrenia is a major public health problem that affects approximately 1% of the population worldwide. Schizophrenia-like syndromes can be induced in humans by phencyclidine (PCP), a drug with marked psychomimetic properties. Recent studies show that the behavioural and biochemical effects of PCP in rats are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in the pharmacological effects of PCP. Objective: The aim of this study was to investigate if PCP-induced disruption of prepulse inhibition of acoustic startle could be blocked by the NOS inhibitor, L-NAME, in mice. Results: The present study shows that PCP readily disrupts prepulse inhibition in mice normally without affecting pulse-alone trials. Furthermore, L-NAME blocked the PCP-induced disruption of prepulse inhibition in a dose-related manner. Conclusions: The PCP-induced disruption of prepulse inhibition and the ability of L-NAME to block this effect in both rats and mice suggest that this is a general and not a species-specific effect. The results of the present study further suggest that PCP exerts at least some of its actions in the central nervous system by a NO-dependent mechanism.