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)

To determine the influence of neurons of the ventral hippocampus on dopamine (DA) turnover in other limbic areas, spontaneous and amphetamine-induced locomotion as well as DA and its metabolites were assayed in nucleus accumbens, medial prefrontal cortex and anteromedial striatum, 14 and 28 days after bilateral ibotenic acid (IA) or sham lesions of the ventral hippocampus in the rat. Spontaneous locomotion was increased 28 days postoperatively, while D-amphetamine induced locomotion was augmented both 14 and 28 days postoperatively in IA lesioned animals. DA levels in the nucleus accumbens were decreased on the 14th, but increased on the 28th day after the lesion. Dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and the DOPAC/DA ratio in the medial prefrontal cortex (MPFC) were reduced 28 days postoperatively. Moreover, there was a significant negative correlation between the DOPAC/DA ratio in the MPFC and DA levels in the nucleus accumbens at this time point. These data indicate that a lesion of the ventral hippocampus can produce differential changes in cortical and limbic DA activity. Implications for an animal model of schizophrenia are considered.
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PMID:Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens and prefrontal cortex in the rat. 151 Dec 95

In this study, we investigated whether risperidone, a serotonin-S2A (5-HT2A)/dopamine-D2 (D2)-receptor antagonist, inhibits phencyclidine (PCP)-induced stereotyped behaviors in comparison with haloperidol and ritanserin. Moreover, we also attempted to investigate the effects of these antipsychotics on the contents of dopamine, serotonin (5-HT) and their metabolites in rat striatum and frontal cortex. In rats, PCP (5 mg/kg, i.p.) caused hyperlocomotion and stereotyped behaviors, including sniffing, head-weaving, backpedalling and turning. Both resperidone (0.8-2.4 mg/kg, p.o.) and haloperidol (0.3-1.0 mg/kg, p.o.) inhibited these behaviors, except for backpedalling, in a dose-dependent manner. PCP (10 mg/kg, i.p.) produced hyperlocomotion and stereotyped behaviors, including rearing, sniffing head-twitch, backpedalling and turning. Risperidone (0.8-2.4 mg/kg, p.o.) inhibited both hyperlocomotion and PCP-induced behaviors, except for backpedalling, while ritanserin (3-10 mg/kg, p.o.) inhibited only the head-twitch. These results suggest that risperidone may have an antipsychotic effect on schizophrenia as well as PCP psychosis in humans by exerting a mixed 5-HT2A/D2 antagonism. Neurochemically, the increasing effects of risperidone on the content of DOPAC and the ratio of DOPAC to dopamine in the striatum were lower than those of haloperidol. These findings may support the view that the extrapyramidal side effects of risperidone are lower than those of haloperidol in clinical situations.
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PMID:Effects of risperidone on phencyclidine-induced behaviors: comparison with haloperidol and ritanserin. 753 32

The mesocortical dopamine system is thought to play an important role in the etiology of the stress response. Dopamine (DA) has been shown to accumulate in the rat frontal cortex in response to a wide variety of stressors. Diazepam, an anxiolytic benzodiazepine, can reverse the effects of stress on cortical DA. We investigated the effects of acute and chronic diazepam administration on immobilization stress-induced changes of the DA system in the frontal cortex of the rat. In the first study, 2.5 mg/kg diazepam was administered 20 min prior to 40 min of immobilization stress. Acute diazepam significantly reduced basal levels of extracellular DA and antagonized the stress-induced increase in cortical DA when compared to untreated stressed rats. Acute diazepam did not significantly effect extracellular DOPAC. In the second study, an experimental group of rats was given approximately 2 mg/kg/day diazepam in their drinking water for 3 weeks. This treatment significantly reduced anxiety as assessed by a staircase test for anxiety. Chronic diazepam had no effect on basal levels of cortical DA. However, chronic diazepam treatment also attenuated stress-induced increases in extracellular DA when compared to untreated stressed control rats. Chronic diazepam did not affect stress-induced changes in DOPAC but it did antagonize the effects of stress on HVA. Thus, acute and chronic diazepam treatment can antagonize stress-induced activation of the mesocortical DA system. It is proposed that this effect is produced through an enhancement of GABAergic neurotransmission by diazepam. The role of the dopaminergic system during stress, anxiety, and schizophrenia is discussed.
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PMID:The effect of acute and chronic diazepam treatment on stress-induced changes in cortical dopamine in the rat. 858 19

Recent studies have implicated the thalamus as a possible site for neuroanatomical and neurochemical changes in schizophrenia. In the present study, we investigated thalamic neurochemical correlates of behaviors potentially linked to schizophrenia. Whole thalamic DOPAC levels were elevated in rats that had poor extinction of the acoustic startle response. The dopamine agonist apomorphine microinjected into the ventromedial thalamus (VmT) disrupted prepulse inhibition of startle. Catalepsy was induced by VmT microinjections of the GABA-A agonist muscimol. A previous study revealed attentional disturbances and suppression of frontal cortical metabolic activity after muscimol microinjections into the mediodorsal thalamic nucleus. Together with recent findings of neuron cell loss and elevated DA levels in the thalamus of schizophrenics, these data suggest the involvement of disturbances of thalamic neurotransmission in schizophrenia.
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PMID:Startle and sensorimotor correlates of ventral thalamic dopamine and GABA in rodents. 874 49

Viruses have been proposed to play a role in the pathogenesis of schizophrenia; however, the mechanisms by which infection could cause the affective, cognitive, and movement disorders of schizophrenia are not understood. The neurotropic RNA virus, Borna disease (BD) virus, linked to schizophrenia by serologic studies, causes movement and behavior disorders in a wide variety of mammalian and bird hosts. BD rats have hyperactivity and stereotyped behaviors similar to those that follow neurotoxic or electrolytic lesions in frontal cortex or its catecholamine afferents in rats. BD rats have high levels of viral nucleic acid in the prefrontal cortex (PFC), abnormal mesocortical dopamine activity (elevated levels of DOPAC in PFC), yet no alteration in specific binding of D1 or D2 receptor radioligands in PFC. Since frontal lobe dysfunction is frequently reported in schizophrenia, the BD rat model may provide insights into pathogenesis and management of this debilitating psychiatric disease.
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PMID:Prefrontal cortex dysfunction in Borna disease virus (BDV)--infected rats. 888 96

Changes in extracellular levels of dopamine (DA), DA metabolites DOPAC and HVA, and the serotonin metabolite 5-HIAA, were measured by microdialysis in the rat nucleus accumbens (n. acc) after treatments with serotonin (5-HT)1A (8-OH-DPAT) or 5-HT1B (RU 24969 and S-CM-GTNH2) receptor agonists. Subcutaneous injections of RU 24969 (0.02-2 mg/kg) dose-dependently decreased 5-HIAA levels (0 to -38%), and also induced long-lasting increases in DA levels (0 to +37%) and DOPAC (+11% at the dose 0.5 mg/kg) in the shell of the n. acc, whereas 8-OH-DPAT (0.25 and 0.5 mg/kg) reduced 5-HIAA levels (-25%) and very slightly increased DOPAC at the lower dose (+4%), but had no effect on DA levels. Three weeks after interruption of the subicular efferent projections, the increase in DA levels previously observed after systemic injections of RU 24969 was abolished. Microinjections of RU 24969 (10 micrograms/microliter) or S-CM-GTNH2 (3 micrograms/microliter) into the ventral subicular area reproduced the effects of systemic injections of RU 24969 cn DA levels and increased DOPAC (+13%; +19%, respectively) and HVA levels (+23%; +24%), with no significant change in 5-HIAA. It is concluded that: (1) serotonin interacts with the mesolimbic dopaminergic system through 5-HT1B, but not 5-HT1A, receptors: and (2) serotonin interaction with the mesolimbic dopaminergic system involves postjunctional 5-HT1B heteroreceptors located in the ventral subicular area, which modulate the activity of glutamatergic hippocampo-accumbens pathways and only secondarily alter DA levels in the n. acc. The possible relevance of these results for schizophrenia is discussed.
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PMID:Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway. 902 99

Schizophrenia is a devastating mental disease that affects the human population worldwide with an incidence of about 1%. Over the last decades basic and clinical research has considerably increased our understanding of the pathophysiology of schizophrenia, as well as the mechanism of action of antipsychotic compounds (neuroleptics), and new atypical neuroleptics with equipotent or improved antipsychotic effects and fewer motoric side effects have been developed. However, the pharmacological intervention does not effectively treat all the symptoms of the disease, and there is still a need for new, more effective antipsychotic compounds. Studies of brain function have demonstrated a reduced activation of prefrontal cortical areas during cognitive tasks in schizophrenics. It is hypothesized, that this hypofrontality is associated with a reduced dopaminergic tonus in the prefrontal cortex, which subsequently causes the negative symptoms of schizophrenia, such as apathy and social withdraw. It has also been suggested, that increased dopaminergic activity in striatal areas is related to the wellknown positive schizophrenic symptoms, such as delusions and hallucinations. The present thesis addresses the regional effects of prototypical and atypical neuroleptics on nerve cell activity and dopaminergic tonus in three rat brain areas with special relevance for the pharmacological effects of neuroleptics. Finally, new pharmacological approaches to the medical treatment of schizophrenia are suggested based on our experimental results. Initially, the effects of the prototypical neuroleptic haloperidol and the atypical neuroleptic clozapine on nerve cell activity in the rat forebrain were investigated by measuring the regional expression of the Fos protein. The Fos protein is regarded as a marker of cellular activity and was measured by use of immunohistochemical techniques i) in the medial prefrontal cortex (PFC), probably involved in the negative symptoms of schizophrenia, ii) in the nucleus accumbens (NAc), probably involved in the positive symptoms of schizophrenia and iii) in the dorsolateral striatum (DLSt), most likely involved in the motoric side effects of neuroleptics. Clozapine increases Fos protein immunoreactivity in the PFC with no or minimal effects in the DLSt. In contrast, haloperidol increases Fos protein immunoreactivity in the DLSt with minor effect in the PFC. Other atypical neuroleptics (risperidone, sertindole and NNC 22-0031) induced a Fos protein expression pattern different from haloperidol: The atypical compounds exhibit a larger ratio between Fos protein expression in PFC and DLSt than measured for haloperidol. These results are in accordance with the reported beneficial effects of clozapine, risperidone and sertindole on negative symptoms of schizophrenia and their lower degree of motoric side effects compared to haloperidol. All neuroleptics induced Fos protein immunoreactivity in the NAc, in accordance with their ability to reduce positive psychotic symptoms in schizophrenics. The microdialysis technique was used to investigate the regional dopaminergic effects of the above mentioned antipsychotic compounds by measuring interstitial levels of the dopamine metabolite dihydroxyphenylacetic acid ([DOPAC]i) in PFC, NAc and DLSt. All antipsychotics tested increased [DOPAC]i in the NAc, whereas the atypical antipsychotics clozapine, risperidone, sertindole and NNC 22-0031--in contrast to haloperidol--preferentially increased [DOPAC]i in PFC compared to DLSt. Also these results are in concordance with the clinical effects of clozapine, risperidone, sertindole and haloperidol and support the hypothesis that reduced dopaminergic tone in the prefrontal cortex relates to the negative symptoms of schizophrenia. All clinically efficacious neuroleptics block central dopamine D2 receptors, which include the dopamine D2, D3 and D4 receptor subtypes. The present thesis characterizes a dopamine D3 receptor agonist, cis-OH-PBZI.
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PMID:Novel pharmacological approaches to the treatment of schizophrenia. 1091 83

Microinjection of a serotonergic 5-HT1B agonist (S-CM-GTNH2, 3 microg/l) into the dorsal subiculum (DS) induced long-lasting increases in dopamine (DA; +58%), dihydroxyphenylacetic acid (DOPAC; +15%) and homovanillic acid (HVA; +31%), without changing extracellular levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), measured by microdialysis in freely moving rats in the shell area of the nucleus accumbens (n. acc). Perfusion of a glutamate-N-methyl-D-aspartate (NMDA) receptor antagonist (MK 801, dizocilpine, 10 microM) through the dialysis probe in the n. acc induced similar long-lasting increases in DA and DOPAC, whereas the glutamate-quisqualate/kainate receptor antagonist (CNQX, 50 microM) had no effect. In the presence of dizocilpine in the n. acc, microinjection of S-CM-GTNH2 into the DS could still increase DOPAC and HVA, but DA levels were not further changed, whereas in the presence of CNQX, microinjection of S-CM-GTNH2 into the DS still increased not only DOPAC and HVA, but also DA levels in a way similar to that in the absence of glutamate antagonist. Therefore, activation of 5-HT1B receptors located in the DS increases the release of DA in the n. acc, presumably via the glutamatergic projection to this structure and acting through NMDA receptors in it. This implies either the suppression of a tonic indirect inhibitory influence and/or stimulation of a phasic excitatory effect of glutamate. Disruption of latent inhibition (LI) has been suggested as a model for a cognitive deficit in schizophrenia (hyperattention to irrelevant stimuli) and is usually associated with an increase in DA release in the n. acc. However, s.c. injection of RU 24 969 (0.5 mg/kg), a mixed 5-HT1A-5-HT1B agonist, which was previously shown to increase DA release in the n. acc, left LI unchanged. Moreover, bilateral microinjections of S-CM-GTNH2 into the rat DS tended to potentiate LI, in spite of the increase in DA in n. acc demonstrated here. It is concluded that not all increases in DA release in the n. acc are functionally equivalent. Sensitization of receptors or impulse-dependent increase in DA release might be necessary to disrupt LI. The possible role of altered serotonergic transmission, through h5-HT1B receptors (human homologue of the rat 5-HT1B receptors) located in the DS, in acute schizophrenia needs to be further investigated.
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PMID:Dopamine release in the nucleus accumbens and latent inhibition in the rat following microinjections of a 5-HT1B agonist into the dorsal subiculum: implications for schizophrenia. 1095 52

Rearing rats in social isolation has been suggested as an animal model of schizophrenia, based mainly on the similarity between the attenuation of prepulse inhibition (PPI) in isolated rats and in schizophrenic patients. The medial prefrontal cortex (mPFC) plays a major role in the pathophysiology of schizophrenia. Thus, a postmortem micropunch analysis measuring dopamine (DA), DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) in the dorsal and ventral subregion of the mPFC, the caudate putamen (CPu) and nucleus accumbens (NAc) was carried out on socially isolated or group-housed male Sprague-Dawley (SD) rats. Additionally, in vivo microdialysis with D-amphetamine (1 mg/kg ip) stimulation was performed in isolated animals and their controls, examining the ventral mPFC for acetylcholine (ACh), DOPAC and HVA levels. Simultaneously, recording of motor activity was performed. In the neurochemical postmortem tissue analysis we found no difference in any of the brain regions tested between isolated and group-reared animals. Amphetamine increased ACh levels in the mPFC, induced a decrease in DOPAC and HVA levels, and increased motor activity. A close to significant Drug x Housing interaction reflected the fact that the amphetamine-induced decrease of DOPAC was confined to the group-housed animals. In conclusion, social isolation leads only to moderate changes in the dopaminergic system in the mPFC, whereas the cholinergic system remains unaffected.
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PMID:Long-term social isolation and medial prefrontal cortex: dopaminergic and cholinergic neurotransmission. 1475 67

The neonatal ventral Hippocampus (nVH) lesion in rats has been used as a model to test the hypothesis that early neurodevelopmental abnormalities lead to behavioral changes putatively linked to schizophrenia. The schizophrenic patients tend to social isolation. In addition, considerable evidence from behavioral and neurochemistry studies strongly implicate the dopamine (DA) system and the medial part of the prefrontal cortex (mPFC) in the pathophysiology of the social isolation syndrome. In order to assess effects of the postweaning social isolation (pwSI) on the DA system of the nVH lesions, we investigated the DA content and its metabolite, DOPAC in different limbic subregions in rats postpubertally at postnatal day (P) 78 following nVH lesions at P7 with and without pwSI for 8 weeks. The DA and DOPAC were measured by HPLC with electrochemical detection. The nVH lesion induces increase in the DA content in the hippocampus with no effect in the mPFC, nucleus accumbens and caudate-putamen, while the pwSI induces major increase in the DA content in limbic subregions such as the mPFC, nucleus accumbens and hipocampus with opposite effect in the caudate-putamen. These results suggest that while pwSI has an effect in the postpubertal content of DA in both sham and nVH lesions in rats, the nVH-lesioned rats appear to be affected to a greater extent than the sham animals underscoring the influence of pwSI differences in the development of behaviors in the nVH-lesioned animals.
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PMID:Neonatal ventral hippocampus lesion alters the dopamine content in the limbic regions in postpubertal rats. 1503 85


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