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)

Longitudinal assessments (every six weeks for one year) were made of plasma norepinephrine, dopamine, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG) in 40 adolescents with schizophrenia, 20 on clozapine therapy and 20 on conventional medication. In addition to the plasma catecholamine determinations, serum levels of 5-HT were determined as a measure of serotoninergic status. All analyses were performed by HPLC-ECD (high-performance liquid chromatography with electrochemical detection). Clinical ratings of symptomatology were obtained with the Brief Psychiatric Rating Scale (BPRS) and the Andreasen scales for negative and positive symptoms (SANS and SAPS). Compared with the typical neuroleptic medication, clozapine administration was accompanied by a significant increase in plasma norepinephrine and MPHG and serum serotonin levels. The fluctuations in the biogenic amines were closely associated with the observed symptomatology. Plasma MHPG was linked to depressive symptoms (BPRS), and negative symptoms (SANS) were related to changes in the serum serotonin levels. The pathophysiological implications and clinical consequences of these findings are discussed.
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PMID:[Effect of clozapine on biogenic amines within the scope of drug treatment of schizophrenic psychoses in adolescence]. 785 24

The pharmacology of 5-HT and the classification of 5-HT receptors have become increasingly complex. However, recent advances have produced a new nomenclature system for 5-HT receptors. 5-HT3 receptors are neuronal receptors coupled directly to cation channels. Recently, many selective 5-HT3-receptor antagonists including tropisetron, zacopride, ondansetron, granisetron, zatosetron, nazasetron, YM060 and YM114 (KAE-393) have been developed. Many actions attributable to the 5-HT3-receptor have been described in both the peripheral and central nervous systems, and clinical trials are already showing the potential use of these 5-HT3 receptor antagonists in a number of disorders of the gastrointestinal tract and central nervous system, such as nausea and vomiting induced by cancer chemotherapy, anxiety, depression, schizophrenia and migraine. In addition, endogenous 5-HT is suggested to be one of the substances that mediate stress-induced responses in gastrointestinal function, i.e., increase in fecal pellet output and diarrhea. Moreover, YM060, YM114 (KAE-393) and granisetron have been reported to inhibit restraint stress- and 5-HT-induced increases in fecal pellet output and diarrhea in rats and mice, indicating that endogenous 5-HT may mediate stress-induced changes in bowel function through the 5-HT3 receptor. Therefore, 5-HT3-receptor antagonists are new therapeutic drugs for stress-induced gastrointestinal dysfunctions like irritable bowel syndrome (IBS).
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PMID:[Serotonin (5-HT)3 receptors: antagonists and their pharmacological profiles]. 795 7

Thirty-three years ago, Gaddum and Picarelli classified the serotonin (5-HT) receptors in the guinea-pig ileum into D and M types based on the activity of dibenzyline (D) and morphine (M) to block contractions of intestinal smooth muscles caused by 5-HT. The subsequent location of specific ligand binding sites for 5-HT in the brain has led to the identification of 10 5-HT receptor subtypes in rat brain. While there is some controversy over the functional importance of many of these receptor subtypes, there is evidence that they fall into two major groups according to the nature of their coupling to secondary messengers or ion channels. Thus the 5-HT1 and 5-HT2 receptors appear to occupy the G protein receptor subfamily which may be coupled either to adenylate cyclase (most 5-HT1 subtypes) or phosphatidyl inositol (5-HT2 subtypes). The central "M" receptors (now termed 5-HT3) appear to occupy a ligand-gated ion channel superfamily. The cloning of these receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. A problem now arises with regard to the linking of the changes in the cellular activity of the various receptor subtypes with the plethora of behavioural changes that arise as a consequence of the actions of 5-HT in the brain. The present review summarizes the evidence implicating the role of specific 5-HT receptor subtypes in thermoregulation, modulation of cardiovascular function, eating disorders, sleep, sexual activity, anxiety states, aggression, schizophrenia and depression. A summary of the relationship between these receptor subtypes and their possible involvement in the aetiology of these diseases is also given.
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PMID:Serotonin receptors--where are they going? 802 39

Animals confronting threatening stimuli respond with a coordinated set of autonomic, neuroendocrine, neurochemical, and behavioral responses that constitute the stress response. The role of the NMDA receptor and its glycine modulatory site was investigated in a rat conditioned stress model. Behavioral, neuroendocrine, and neurochemical analyses were conducted. Regional dopamine (DA) and serotonin (5-HT) utilization was assessed by postmortem tissue measurements of metabolite-to-parent neurotransmitter ratios. Rats were conditioned to fear a tone previously paired with footshock. The following day, rats were systemically administered saline or the NMDA glycine site antagonist (+)-HA-966 before exposure to thirty minutes of conditioned stress. Conditioned stress resulted in a selective increase in medial prefrontal cortical DA and 5-HT utilization, elevation in serum corticosterone, and freezing behavior in control animals. The conditioned stress-induced increase in DA utilization in control animals was also detected in the lateral prefrontal cortex and nucleus accumbens, whereas DA utilization was not affected in the perirhinal or cingulate cortices, lateral-basolateral amygdaloid complex, anterior ventromedial caudatoputamen, or posterior dorsolateral caudatoputamen. Pretreatment with (+)-HA-966 at 15 mg/kg completely abolished the conditioned stress-induced increase in DA utilization in the medial and lateral prefrontal cortices. This effect was regionally specific since (+)-HA-966 pretreatment did not block increased DA utilization in the nucleus accumbens. This effect was also neurochemically specific since the stress-induced increase in 5-HT utilization in the medial prefrontal cortex was not affected by (+)-HA-966 pretreatment. Pretreatment with (+)-HA-966 did not affect stress-induced serum corticosterone elevation but did attenuate the freezing response. Control experiments demonstrated that (+)-HA-966 pretreatment did not (1) induce sedation, (2) interfere with habituation to a novel environment, (3) alter basal DA, 5-HT, or serum corticosterone levels, or (4) block acquisition of aversive memories. These data suggest that the NMDA receptor complex and associated glycine modulatory site may play an important role in the afferent control of the mesoprefrontal cortical DA system during conditioned stress. The relevance of these findings to schizophrenia and human anxiety disorders such as post-traumatic stress disorder are discussed.
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PMID:The NMDA glycine site antagonist (+)-HA-966 selectively regulates conditioned stress-induced metabolic activation of the mesoprefrontal cortical dopamine but not serotonin systems: a behavioral, neuroendocrine, and neurochemical study in the rat. 804 62

Aggressive behavior is a common feature of schizophrenia and is associated with the presence of 'soft' neurological signs. Since early age of onset of schizophrenia has been found to be associated with the negative syndrome, which according to Crow (1982) is related to structural brain abnormalities, I predicted that early age of onset may be a biological risk factor for aggressive behavior in the disease. To test this hypothesis, I investigated in 52 chronic institutionalized schizophrenic patients (mean age = 32.8 years; SD = 8.0), the association between age of onset of the disease and the severity of belligerent behavior. The age of onset was judged from the patient's histories as the age at which florid symptoms first emerged. Patients with early onset schizophrenia had a significantly higher belligerent score compared to those with later-onset schizophrenia (p < .05). These findings support the hypothesis of an association between early age of onset of schizophrenia and the risk of aggressive behavior and suggest, furthermore, that schizophrenic symptoms which emerge early may predict a higher risk of aggressive behavior. Furthermore, this study suggest that the neurochemical mechanisms which underlie the early emergence of symptoms may also predispose to aggressive behavior in schizophrenia. Specifically, since aggressive behavior has been linked to impairment of serotonergic (5-HT) functions, I propose that the timing of onset of schizophrenia may be partly associated with dysregulation of the 5-HT system. In a second study, I investigated whether schizophrenic patients with aggressive (suicide) behavior are characterized by more extensive brain damage and hence greater degree of cerebral atrophy on CT scan. The study, which involved 26 schizophrenic patients (mean age: 31.3 years; SD = 6.8), revealed that patients with aggressive behavior had a significantly greater degree of parieto-occipital atrophy on CT scan (p < .05). In contrast, ventricular size and prefrontal cortical atrophy did not distinguish aggressive from nonaggressive patients. These findings suggest that cortical atrophy may be a neuroradiological marker of aggressive behavior in schizophrenia.
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PMID:Aggressive behavior in schizophrenia: relationship to age of onset and cortical atrophy. 806 5

A new HincII polymorphism for the human serotonin 1D receptor variant (5-HT1D beta) is reported. In light of evidence indicating possible dysfunction of the 5-HT neurotransmitter system in schizophrenia, this new 5-HT receptor polymorphism was tested for linkage to schizophrenia in 5 Canadian pedigrees. Although 1 of the 5 pedigrees tested had a slightly positive lod score, there was no evidence overall for linkage to schizophrenia under dominant, recessive, or two locus models.
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PMID:New polymorphism for the human serotonin 1D receptor variant (5-HT1D beta) not linked to schizophrenia in five Canadian pedigrees. 810 76

Alterations in density of some serotonin receptor sites (5-HT1A receptors, 5-HT2 receptors and 5-HT uptake sites) have been reported in postmortem studies of brain obtained from subjects with schizophrenia, suggesting a disturbance in serotonergic transmission in schizophrenia. The purpose of the present study is to investigate [3H]-LY278584 binding to serotonin 5-HT3 receptors in postmortem samples of amygdala from schizophrenic and matched control subjects. As all of the schizophrenic patients but none of the controls had been treated with neuroleptics, we first investigated in rodents the effects of short-term and long-term haloperidol administration on limbic 5-HT3 receptors, and we found no effects. No differences in the maximum number of 5-HT3 binding sites (Bmax) or equilibrium dissociation constant (Kd) between schizophrenics and controls were found in amygdala. This study does not support the presence of an alteration of 5-HT3 receptors in amygdala in schizophrenic patients.
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PMID:Serotonin 5-HT3 receptors in schizophrenia: a postmortem study of the amygdala. 835 29

Several studies suggest that disturbances of serotonin (5-HT) functions may be involved in the pathophysiology of hallucinations in schizophrenia. It is now well established that the choroid plexus (CP) is innervated by serotonin (5-HT) neurons, which may regulate its activity, and it is possible that decreased 5-HT functions may facilitate the process of its calcification. It is thus conceivable that calcification of the CP may be associated with hallucinations in schizophrenia. I studied in 18 chronic schizophrenic patients the association of CP calcification (CPC) size as ascertained from CT scan, to severity of hallucinations and, for comparison, to four other positive symptoms as well as global psychopathology score. Analysis of variance indicated that CPC size was specifically associated with hallucinations (p < .001) and none of the other psychopathology measures. These findings reveal a relationship between CPC and hallucinations in schizophrenia and suggest that the former may be a neuroradiological marker of hallucinations in the disease.
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PMID:Choroid plexus calcification as a possible marker of hallucinations in schizophrenia. 840 58

Serotonin (5-HT) uptake sites were mapped by autoradiographic means with [3H]cyano-imipramine ([3H]CN-IMI), the 5-HT1A receptor with [3H]8-hydroxy-2-[di-n-propyl-amino]tetralin ([3H]8-OH-DPAT), and the 5-HT2 receptor with both [3H]ketanserin and [125I]lysergic acid diethylamide ([125I]LSD) in eight nonneurologic controls and 10 cases with a diagnosis of schizophrenia. In the striatum, there was a marked heterogeneous patterning of 5-HT uptake sites that corresponded to the striosomal/matrix compartmentalization of the striatum. This organization was not matched with an equally heterogeneous pattern of either 5-HT2 or 5-HT1A receptors. For the isocortex, a general organizational scheme was observed with the 5-HT1A receptor expression high in the external laminae and deep laminae, but 5-HT2 receptor expression was higher in the internal laminae. There was a laminar distribution of 5-HT uptake sites that approximated the combined distributions of the 5-HT1A receptor and the 5-HT2 receptor. In the parahippocampal gyrus and hippocampus, the distribution of 5-HT uptake sites was complementary to the distribution of 5-HT1A and 5-HT2 receptors. In schizophrenic cases, there was a large increase in the number and altered striosomal/matrix organization of 5-HT uptake sites in the striatum. There was also an increase in the numbers of 5-HT2 receptors in the nucleus accumbens and ventral putamen of the schizophrenics. The number of 5-HT1A receptors was not modified. There was a marked reduction in 5-HT uptake sites in the external and middle laminae of the anterior cingulate, frontal cortex, and posterior cingulate, and no changes were observed in the motor cortex, temporal cortex, or hippocampus. Increased numbers of 5-HT1A receptors were found in the posterior cingulate, motor cortex, and hippocampus. Serotonin2 receptors were substantially elevated in the posterior cingulate, temporal cortex, and hippocampus, but not in the frontal, anterior cingulate, or motor cortices. Examination of the temporal lobe and hippocampus of a group of nonschizophrenic suicides (n = 8) indicated the alterations in 5-HT system in the limbic regions of the striatum, the limbic cortex, and hippocampus of the schizophrenic cases may be disease specific.
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PMID:Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. 774 66

Interactions between serotonin (5-HT) and dopamine (DA) neuronal systems in the prefrontal cortex (PFC) may be important in the pathophysiology of cognitive disorders such as schizophrenia. We have examined the effect of 5-HT, applied locally through a microdialysis probe, on extracellular DA in the PFC, and compared the response to that observed in the striatum. 5-HT in concentrations of 1 to 10 microM increased extracellular DA dose-dependently to a greater extent in the PFC than in the striatum. The PFC response was pharmacologically characterized to determine the 5-HT receptor subtype mediating the increase in DA levels. The coperfusion of selective 5-HT2A and 5-HT3 antagonists MDL 100,907 ((R-(+)-(2,3-dimethoxyphenyl)-1-[2(4-flourophenylethyl)]-4- piperidine-methanol) and MDL 72222 (3-tropanyl-3,5-dichlorobenzoate), respectively, with 5-HT failed to significantly attenuate the 5-HT induced increase of extracellular DA. Furthermore, the local application of the 5-HT2A/2C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl aminopropane did not yield an increase in extracellular DA. On the other hand, coperfusion of the selective 5-HT1B/1D antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide)) with 5-HT completely blocked the effect of 5-HT alone. Infusion of the selective 5-HT1B agonists CP 93,129 (3-(1,2,5,6-tetrahydro-4-pyridyl)pyrrolo[3,2-b]pyrid-5-one) and CP 94,253 (3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrolo[3,2-b]pyridine) resulted in a significant increase in extracellular DA and the effect of CP 93,129 was attenuated by coperfusion of GR 127935. The results obtained demonstrate a functional interaction between DA and 5-HT pathways in the PFC, with evidence of potential mediation by the 5-HT1B receptor subtype.
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PMID:Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization. 861 47


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