Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nitric oxide-arginine pathway is intimately connected to the release of dopamine and glutamate, two neurotransmitter systems that may be dysfunctional in schizophrenia. In addition, nitric oxide synthase inhibitors share several behavioral effects with the psychotomimetic drug, phencyclidine. Previous research has found that phencyclidine-like drugs disrupt prepulse inhibition of the acoustic startle response, an animal model of sensorimotor gating, an attentional process that is disrupted in certain neuropsychiatric disorders in humans (e.g., acute schizophrenia). The purpose of the present study was to examine the effects of nitric oxide modulators in this model. Following injection with a nitric oxide modulator or phencyclidine, rats were placed in startle chambers in which they were exposed to acoustic pulses presented alone or preceded by a prepulse. As in previous reports, phencyclidine disrupted prepulse inhibition at doses that did not affect startle during pulse alone trials. In contrast, the nitric oxide synthase inhibitors, N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester (L-NAME), dose-dependently decreased startle during pulse alone trials, but neither drug affected prepulse inhibition. A nitric oxide precursor, L-arginine, produced similar results. Sodium nitroprusside (a nitric oxide releaser) and 7-nitroindazole (a third nitric oxide synthase inhibitor) did not affect startle amplitudes during pulse alone or prepulse + pulse trials. The present results suggest that modulation of nitric oxide synthesis or availability does not disrupt sensorimotor gating of the acoustic startle response and is probably not involved in mediation of this type of attentional deficit in humans.
 ...
PMID:Effects of modulation of nitric oxide on acoustic startle responding and prepulse inhibition in rats. 921 93

1. The neurodevelopmental hypothesis of schizophrenia postulates that disturbed nitric oxide (NO) function during neuronal development is one of premorbid factors for schizophrenia in later life. 2. The aim of present study is to investigate behaviorally whether neonatal inhibition of nitric oxide synthase (NOS) affects dopaminergic function, the abnormality of which may be ascribed to a major pathophysiology of schizophrenia. 3. Male rat pups were injected daily with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), from postnatal day (PD) 1 to 14. 4. When methamphetamine (MAP) was challenged on PD42, MAP-induced stereotypy was significantly attenuated in the L-NAME treated rats. The development of sensitization to the stereotypy-inducing effect of MAP, however, was not prevented with neonatal L-NAME. 5. These results suggest that decreased NO production during neonatal period may disturb normal maturation of dopaminergic system and result in impaired dopaminergic function in adult period.
 ...
PMID:Neonatal treatment with L-name (NG-nitro-L-arginine methyl ester) attenuates stereotyped behavior induced by acute methamphetamine but not development of behavioral sensitization to methamphetamine. 1104 41

Phencyclidine (PCP) is widely used as an animal model of schizophrenia. In rats, acute PCP treatment increased locomotor activity and induced stereotyped behaviours consisting of head weaving, turning and backpedalling. PCP had differential regional effects on c-fos expression in rat brain, suggesting different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. To elucidate the role of nitric oxide, an important intracellular messenger, in the mechanism of action of PCP the effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) were studied in PCP-treated animals. L-NAME potentiated PCP-induced behaviours and c-fos expression in many brain regions. The greatest increases were observed in the frontal, retrosplenial granular cortex, cerebellum, thalamic and subthalamic nuclei. While PCP alone induced low c-fos expression in the entorhinal cortex, with almost no expression in the rostral part of caudate putamen, animals pretreated with L-NAME showed marked activation in these brain areas. These results strongly indicate the involvement of the nitric oxide system in the mechanism of action of PCP.
 ...
PMID:Effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester on phencyclidine-induced effects in rats. 1109

The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31.
 ...
PMID:Investigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia. 1192 Aug 55

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.
 ...
PMID:Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat. 1579 2

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.
 ...
PMID:Effects of phencyclidine on spatial learning and memory: nitric oxide-dependent mechanisms. 1667 24

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.
 ...
PMID:Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive alpha2 adrenoceptor blockade: experimental evidence. 1670 32

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.
 ...
PMID:Phencyclidine affects memory in a nitric oxide-dependent manner: working and reference memory. 1693 57

CP-809,101 is a potent, functionally selective 5-HT(2C) agonist that displays approximately 100% efficacy in vitro. The aim of the present studies was to assess the efficacy of a selective 5-HT(2C) agonist in animal models predictive of antipsychotic-like efficacy and side-effect liability. Similar to currently available antipsychotic drugs, CP-809,101 dose-dependently inhibited conditioned avoidance responding (CAR, ED(50)=4.8 mg/kg, sc). The efficacy of CP-809,101 in CAR was completely antagonized by the concurrent administration of the 5-HT(2C) receptor antagonist, SB-224,282. CP-809,101 antagonized both PCP- and d-amphetamine-induced hyperactivity with ED(50) values of 2.4 and 2.9 mg/kg (sc), respectively and also reversed an apomorphine induced-deficit in prepulse inhibition. At doses up to 56 mg/kg, CP-809,101 did not produce catalepsy. Thus, the present results demonstrate that the 5-HT(2C) agonist, CP-809,101, has a pharmacological profile similar to that of the atypical antipsychotics with low extrapyramidal symptom liability. CP-809,101 was inactive in two animal models of antidepressant-like activity, the forced swim test and learned helplessness. However, CP-809,101 was active in novel object recognition, an animal model of cognitive function. These data suggest that 5-HT(2C) agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia.
 ...
PMID:CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. 1694 22

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.
 ...
PMID:Nitric oxide signaling in the medial prefrontal cortex is involved in the biochemical and behavioral effects of phencyclidine. 1789 15


1 2 3 Next >>