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 two most important afferent projections to the striatum contain glutamate and dopamine, respectively. Excitotoxic damage resulting from excessive stimulation of the N-methyl-D-aspartate subtype of glutamate receptor has been implicated in pathophysiology of ischaemic stroke, hypoglycaemic brain damage and Huntington's disease. We studied the ability of the dopamine system to modify the anatomical, neurochemical and behavioural consequences of glutamatergic toxicity in the striatum. In a first set of experiments, the specific N-methyl-D-aspartate receptor agonist quinolinate was injected unilaterally into the striatum of rats pretreated with one of (i) intraperitoneal (i.p.) saline (controls); (ii) i.p. haloperidol, a D2 dopamine receptor agonist; or (iii) 6-hydroxydopamine lesion of the ipsilateral nigrostriatal tract. Quinolinate-induced striatal damage, as assessed by morphometric and neurochemical criteria, was significantly attenuated in the animals with 6-hydroxydopamine lesions and in those pretreated with haloperidol, compared with saline-pretreated controls. There were no significant differences between the 6-OHDA and haloperidol groups. In a second set of experiments, animals received (i) bilateral intrastriatal quinolinate plus perioperative i.p. saline; (ii) bilateral intrastriatal quinolinate plus i.p. haloperidol; or (iii) bilateral intrastriatal saline. Again, the quinolinate-lesioned animals treated with perioperative haloperidol had significantly less striatal damage than the bilateral quinolinate rats. Behavioural assessment in the Morris Water Maze showed the bilateral quinolinate+haloperidol group to be significantly less impaired on a spatial acquisition task than the bilateral quinolinate animals. Measures of spontaneous daytime motor activity showed significant differences in average speed and rest time between the bilateral quinolinate+haloperidol rats and the bilateral quinolinate group. The performance of the bilateral quinolinate+haloperidol group was not significantly different from that of controls on any of the behavioural tasks. These results indicate an important role for D2 dopamine receptor-mediated mechanisms in striatal excitotoxicity. Since the excitotoxic process involves the same fundamental signalling mechanism that is involved in normal glutamatergic transmission, these findings imply an ability of D2 receptor blockade to modify glutamate signalling in the striatum. These results may have implications for treatment strategies in ischaemic stroke, hypoglycaemic brain damage and schizophrenia.
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PMID:Dopamine-glutamate interactions in the striatum: behaviourally relevant modification of excitotoxicity by dopamine receptor-mediated mechanisms. 893 42

Studies suggest age- and sex-dependent structural and functional patterns of human cerebral lateralization underlie hemisphere specialization and its alterations in schizophrenia. Recent works report sexual dimorphism of neurons in the hippocampal formation and specialization of hemispheres in rats. Our experiments indicate for the first time functional lateralization of the high-affinity choline uptake (HACU) system directly associated with a synthesis of acetylcholine in the hippocampus of Wistar rats. The markedly increased HACU activity was found in the left compared to the right hippocampus of adult male but not female animals. Lineweaver-Burk plot analysis revealed a statistically significant increase of Vmax in the left hippocampus of 14-day-old when compared to 7-day-old males. It appears that laterality of HACU occurs during late postnatal maturation, and its degree is markedly enhanced after puberty and attenuated during aging. Quinolinic acid (QUIN), an endogenous agonist of N-methyl-D-aspartate type glutamate receptors, was used in this study to evaluate the neurodevelopmental hypothesis of schizophrenia. It is known that elevated levels of QUIN accompany viral infections, increasing the risk of developing schizophrenia. Bilateral intracerebroventricular application of QUIN (250 nmoles/ventricle) to pups aged 12 days significantly impaired the cholinergic hippocampal system of adolescent male and female rats and reversed lateralization of male HACU. Morphological analysis indicated marked changes in brain lesion sizes (extensive 24 h and moderate 38 days after the operation). Asymmetry of lesions was observed in the majority of cases, but the left hemisphere was not generally more vulnerable to QUIN effects than the right side. Moreover, no lateral differences were found between lesioned hippocampi in the specific binding of [3H]hemicholinium-3 (10%-15% loss of binding sites when compared to sham-operated animals). In summary, our results indicate a symmetrical drop in the number of choline carriers of lesioned male rats but a asymmetrical decrease in the activity of remaing carriers, suggesting defects in processes of sexual brain differentiation, leading under normal conditions to the higher activity of carriers in the left hippocampus. The data demonstrate viral infection-mediated alterations in normal patterns of brain asymmetry and are discussed in relation to animal models of neurodevelopmental and neurodegenerative diseases.
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PMID:Age- and sex-dependent laterality of rat hippocampal cholinergic system in relation to animal models of neurodevelopmental and neurodegenerative disorders. 1509 28

In order to examine the construct validity of rats with excitotoxic damage of the left entorhinal cortex (EC) as an animal model of schizophrenia, we measured dopamine (DA)-related behaviors and methamphetamine (MAP)-induced DA release in the accumbens nucleus (NAC) in these animals. Quinolinic acid (lesion group) or phosphate buffer (sham group) was infused into the left EC of adolescent (postnatal 7 weeks) male Wistar rats. On the 14th and 28th postoperative day, spontaneous and MAP (1 mg/kg, i.p.)-induced locomotor activities, as well as MAP-induced stereotypy, were measured. The lesioned rats exhibited significantly greater spontaneous or MAP-induced locomotor activity on both of the postoperative days than did sham-operated animals, while EC lesions did not affect MAP-induced stereotypy on either occasion. MAP (1 mg/kg, i.p.)-induced DA release in NAC was measured by in vivo microdialysis on the 28th postoperative day. Lesioned rats did not show a significant change in MAP (1 mg/kg, i.p.)-induced DA release in NAC compared to sham-operated animals. These results suggest that excitotoxic damage of the left EC produces behavioral changes consistent with altered mesolimbic dopaminergic transmissions, possibly mediated by postsynaptic supersensitivity.
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PMID:Enhanced locomotor activity in rats with excitotoxic lesions of the entorhinal cortex, a neurodevelopmental animal model of schizophrenia: behavioral and in vivo microdialysis studies. 1519 92

Morphological studies report reductions in the volume of medial temporal lobe structures and the prefrontal cortex in subjects with schizophrenia. The present study was performed to clarify the role of prefrontal-temporo-limbic system in the manifestation of psychosis, using entorhinal cortical lesion rats as a vulnerability animal model. Quinolinic acid (lesion group) or phosphate buffer (sham group) was infused into the left entorhinal cortex (EC) of male Wistar rats. On the 28th postoperative day, methamphetamine (MAP; 1 mg/kg, i.p.)-induced dopamine (DA) release in the nucleus accumbens (NAC) and the basolateral amygdala (BLA), as well as locomotor activity and prepulse inhibition (PPI), was measured following microinfusion of lidocaine or the cerebrospinal fluid (CSF) into the medial prefrontal cortex (mPFC). Lesions of the EC resulted in enhancement of MAP-induced DA release in the NAC and BLA. Further analysis revealed that the enhancement by EC lesions of MAP-induce DA release in the NAC was particularly evident in the lidocaine-infused rats. EC lesions also enhanced MAP-induced locomotor activity, especially in the lidocaine-treated animals. By contrast, infusion of lidocaine into mPFC attenuated MAP-induced DA release in the BLA, irrespective of the lesion status. Both EC lesions and lidocaine infusion disrupted PPI. These results indicate that inactivation of the mPFC, as well as structural abnormalities in the EC, leads to dysregulation of DAergic neurotransmissions in the limbic regions. The implications of these findings in relation to the neural basis for psychosis vulnerability are discussed.
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PMID:Effect of prefrontal cortex inactivation on behavioral and neurochemical abnormalities in rats with excitotoxic lesions of the entorhinal cortex. 1737 84

Quinolinic acid (QUIN), an endogenous metabolite of the kynurenine pathway, is involved in several neurological disorders, including Huntington's disease, Alzheimer's disease, schizophrenia, HIV associated dementia (HAD) etc. QUIN toxicity involves several mechanisms which trigger various metabolic pathways and transcription factors. The primary mechanism exerted by this excitotoxin in the central nervous system (CNS) has been largely related with the overactivation of N-methyl-D-aspartate receptors and increased cytosolic Ca(2+) concentrations, followed by mitochondrial dysfunction, cytochrome c release, ATP exhaustion, free radical formation and oxidative damage. As a result, this toxic pattern is responsible for selective loss of middle size striatal spiny GABAergic neurons and motor alterations in lesioned animals. This toxin has recently gained attention in biomedical research as, in addition to its proven excitotoxic profile, a considerable amount of evidence suggests that oxidative stress and energetic disturbances are major constituents of its toxic pattern in the CNS. Hence, this profile has changed our perception of how QUIN-related disorders combine different toxic mechanisms resulting in brain damage. This review will focus on the description and integration of recent evidence supporting old and suggesting new mechanisms to explain QUIN toxicity.
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PMID:Quinolinic Acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms. 2240 67