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

The anterior cingulate cortex is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Previous studies suggest abnormalities in the glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia patients. In the present study we used quantitative autoradiography to investigate the binding of [3H]MK801, [3H]L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and [3H]kainate, which respectively label the N-methyl-D-aspartate (NMDA), AMPA, and kainate receptors of the ionotropic glutamate receptor family, in the left anterior cingulate cortex of 10 schizophrenia patients and 10 controls, matched for age, gender, and postmortem interval.AMPA receptor densities were higher in cortical layer II, whereas NMDA receptor densities were higher in cortical layers II-III in the anterior cingulate cortex of both control and schizophrenia group. In contrast, kainate receptors displayed the highest density in cortical layer V. [3H]AMPA binding was significantly increased by 25% in layer II in the schizophrenia group as compared with the control group. Similarly, a significant 17% increase of [3H]MK801 binding was observed in layers II-III in the schizophrenia group. No statistically significant difference was observed for [3H] kainate binding between the schizophrenia and control groups. These results suggest that ionotropic glutamate receptors are differentially altered in the anterior cingulate region in schizophrenia. The increase in [3H]AMPA and [3H]MK801 binding in the superficial layers suggests a postsynaptic compensation for impaired glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia. The findings add to a growing body of literature that supports a dysfunction of excitatory activity in the anterior cingulate cortex in schizophrenia.
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PMID:Selective alterations in ionotropic glutamate receptors in the anterior cingulate cortex in schizophrenia. 1243 56

Based on the glutamate dysfunction hypothesis for the pathophysiology of schizophrenia, MK801, a noncompetitive antagonist for the NMDA-type of glutamate receptors, was administered to mice by i.p. injection. We observed hyperlocomotion and stereotypy, two behavioral signs indicative of schizophrenic symptoms in human. Aided with automated movement measuring of locomotion and videotaping for off-line scoring of stereotypy, these two schizophrenia-like behaviors were readily evaluated. According to the result of dose-response measurements of serial MK801 dosages in the BALB/c inbred mice, 0.6 mg/kg MK801 was determined as the optimum dosage for these behaviors. Furthermore, the same experiments were performed in another inbred strain C57BL/6 and the outbred stock ICR, and similar results were obtained. These results show that MK801 induces schizophrenia-like symptoms in both inbred and outbred mice. Risperidone, an atypical antipsychotic drug for treating schizophrenia in human, was used in the schizophrenia models using BALB/c and C57BL/6 mice. The results indicated that risperidone dose-dependently inhibited the MK801-induced schizophrenia-like symptoms in BALB/c and C57BL/6 mice. Thus, our results indicate that the MK801-induced behaviors may serve as useful mouse models of schizophrenia.
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PMID:[Animal models of schizophrenia using different laboratory mouse strains]. 1293 15

Using a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs) distributed across the entire 1.5-Mb locus on chromosome 22q11 associated with susceptibilit to schizophrenia, we previously identified two subregions that were consistently associated with the disease. In the distal subregion, we detected an association signal with five neighboring SNPs distributed over a haplotypic block of 80 kb encompassing six known genes. One of these five SNPs, rs175174, had the strongest association of all 72 SNPs that we tested. Here we show that rs175174 regulates the level of the fully functional transcript by modulating the retention of intron 4 of the gene ZDHHC8, which encodes a putative transmembrane palmitoyltransferase. Zdhhc8-knockout mice had a sexually dimorphic deficit in prepulse inhibition, a gene dosage-dependent decrease in exploratory activity in a new environment and a decreased sensitivity to the locomotor stimulatory effects of the psychomimetic drug dizocilpine (MK801). SNP rs175174 shows differences in transmission distortion between sexes in individuals with schizophrenia. Our results indicate that there is an unexpected connection between impaired palmitate modification of neuronal proteins and the psychiatric phenotypes associated with microdeletions of chromosome 22q11.
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PMID:Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. 1522 48

Phencyclidine (PCP) is a psychotomimetic drug that elicits schizophrenia-like symptoms in healthy persons, and administration of PCP to animals is used as a pharmacological model of schizophrenia. We recently demonstrated that systemic administration of PCP to rats produces long-lasting activation of medial prefrontal cortex (mPFC) neurons with augmentation of locomotor activity, whereas direct application of PCP to mPFC neurons has little effect on their firing activity. These findings suggest that PCP-induced activation of mPFC neurons is elicited mainly via excitatory inputs from regions outside the mPFC. In the present study, we examined effects of local application of PCP to the ventral hippocampus (vHIP) on firing activity of PFC neurons in freely moving rats. PCP locally perfused into the vHIP increased spontaneous discharges of PFC neurons during perfusion with augmentation of locomotor activity. Local application of a more selective NMDA receptor antagonist, MK801, to vHIP neurons under anesthesia increased the spontaneous firing rates of most neurons directly projecting to the mPFC, whereas local application of MK801 to mPFC neurons did not induce excitatory responses in any of those neurons. The present results indicate that tonic excitatory inputs from the vHIP to the PFC may trigger development of behavioral abnormalities.
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PMID:Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway. 1534 31

Systemic exposure to N-methyl-d-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)-dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.
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PMID:Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. 1559 Jul 30

1. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists produce behavioral responses that closely resemble both positive and negative symptoms of schizophrenia. These drugs also induce excitatory and neurotoxic effects in limbic cortical areas. 2. We have here mapped the brain areas which show increased activity in response to noncompetitive NMDA-receptor antagonist administration concentrating especially to those brain areas that have been suggested to be relevant in the pathophysiology of schizophrenia. 3. Rats were treated intraperitoneally with a NMDA-receptor antagonist MK801 and activation of brain areas was detected by monitoring the expression of c-fos mRNA by using in situ hybridization. 4. MK801 induced c-fos mRNA expression of in the retrosplenial, entorhinal, and prefrontal cortices. Lower c-fos expression was observed in the layer IV of the parietal and frontal cortex. In the thalamus, c-fos mRNA expression was detected in the midline nuclei and in the reticular nucleus but not in the dorsomedial nucleus. In addition, c-fos mRNA was expressed in the anterior olfactory nucleus, the ventral tegmental area, and in cerebellar granule neurons. 5. NMDA-receptor antagonist ketamine increased dopamine release in the parietal cortex, in the region where NMDA-receptor antagonist increased c-fos mRNA expression. 6. Thus, the psychotropic NMDA-receptor antagonist induced c-fos mRNA expression in most, but not all, brain areas implicated in the pathophysiology of schizophrenia. The high spatial resolution of in situ hybridization may help to define regions of interest for human imaging studies.
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PMID:Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia. 1567 79

Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2High, their dissociation constants (Ki) were obtained on [3H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2High with a Ki of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a Ki of 313 nM, as labeled by [3H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2High with a Ki of 55 nM, an affinity higher than its 3100 nM Ki for the NMDA sites. Dizocilpine had a Ki of 0.3 nM at D2High, but a Kd of 1.8 nM at the NMDA receptor. LSD had a Ki of 2 nM at D2High. Because the psychotomimetics had higher potency at D2High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis.
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PMID:Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. 1585 61

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling stimulus is inhibited by a preceding stimulus of a lower intensity. Most often this is tested in the auditory mode. PPI is impaired in a variety of clinical states, most notably schizophrenia. PPI is easily modeled in experimental animals and serves as a useful basis for determining the neural bases for behavioral plasticity. In the current study we examined the interactions of N-methyl-D-aspartate (NMDA) glutamate and nicotinic cholinergic receptor systems in the expression of PPI. Female Sprague-Dawley rats were tested for auditory PPI after s.c. injections of the NMDA antagonist dizocilpine (also known as MK-801), the prototypic nicotinic agonist nicotine or both. Vehicle (saline) injections served as the control. Nicotine (0.2-0.8 mg/kg) by itself caused a modest but significant dose-related improvement in PPI. Dizocilpine (25-100 microg/kg) caused a dramatic dose-related impairment in PPI. Interestingly, the low to moderate doses of nicotine potentiated the PPI impairment by dizocilpine. In a second experiment nicotine and dizocilpine interactions with the atypical antipsychotic drug clozapine were assessed. As in the first experiment, nicotine potentiated the adverse effects of dizocilpine on PPI. The combination of nicotine with clozapine effectively attenuated the PPI impairment caused by dizocilpine when neither alone was effective. Inasmuch as PPI is impaired in schizophrenia, its reversal by the antipsychotic drug clozapine may depend on co-administration of nicotine by smoking in the patients. Development of nicotinic-based co-treatments for schizophrenia may achieve this benefit of nicotine without the hazards of smoking. Sensory modulation deficit, which is a syndrome of sensory over-responsiveness may also benefit from such combination therapy.
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PMID:Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade. 1586 61

Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-(13)C]glucose and [1,2-(13)C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by (13)C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-(13)C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-(13)C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.
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PMID:Glial-neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure. 1639 97

A single 24 h period of maternal deprivation (MD) in rats has been shown to induce, in adulthood, a number of abnormalities in brain and behaviour that also occur in patients with schizophrenia. However, the short-term behavioural effects of MD have not been studied in detail. Since patients with schizophrenia are characterized by a retardation of normal development, we aimed in the present study to investigate the development of control rats and rats that were exposed to MD on postnatal day 9. Compared to control animals, MD rats showed (1) a reduction in body weight, (2) an increased in reversal latency in negative geotaxis, (3) a delayed eye opening, (4) a delayed emergence of walking and rearing; and (5) a delayed emergence of the behavioural response to amphetamine (amph). On the other hand, MD and control rats responded similarly to the non-competitive NMDA antagonist MK801. These data clearly show that early MD delays development, especially of the dopaminergic system and confirm our hypothesis that MD may represent an interesting animal model for the neurodevelopmental hypothesis of schizophrenia.
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PMID:Early maternal deprivation retards neurodevelopment in Wistar rats. 1642 13


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