Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.
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PMID:The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice. 1022 32

M-100907 is a highly selective 5-HT2A antagonist that is being developed by Aventis Pharmaceuticals, formerly Hoechst Marion Roussel (HMR), for the potential treatment of schizophrenia. M-100907 is in phase III trials for chronic schizophrenia [307936], [307942], [307940]. In August 1999, development was discontinued for acute schizophrenia (schizoaffective disorder) on the basis of poor results [335083]. M-100907 is a potent antagonist in every putative animal behavioral model of schizophrenia that involves activation of 5-HT2A receptors [181713]. Interestingly, M-100907 is also active in animal models involving blockade of NMDA glutamatergic channel receptors, an effect known to resemble some behavioral symptoms of schizophrenia in man [390328]. M-100907 belongs to a series of piperidine derivatives, which were originally disclosed in the associated patent, EP-00208235. M-100907 is specifically claimed in a later patent, EP-00531410. This patent describes superior in vivo potency for M-100907 and its claims include the use of M-100907 for the treatment of thromboembolic disorders. The use of M-100907 for the treatment of various developmental neurological disorders such as autism and attention deficit hyperactivity disorder is disclosed in WO-09956750. In 1996, this product was designated one of HMR's nine top priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118]. In January 1999, BT Alex Brown predicted sales of US $30 million in 2000 rising to US $220 million in 2002 [318220]. In April 1999, ABN Amro predicted annual sales of DM 50 million in 2000, rising to DM 150 million in 2002 [328676].
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PMID:M-100907 (Aventis). 1152 4

In a hypoglutamatergic rodent model, we have observed certain behaviours that might have relevance for the cognitive impairments seen in autism and schizophrenia. Thus, hypoglutamatergic mice show defective habituation, impaired attention, a meagre behavioural repertoire and a general behavioural primitivization. The aim of the present study was to characterise and quantify changes in movement pattern in mice rendered hypoglutamatergic by means of MK-801 treatment, using an automated video tracking system. Further, the effects of four different antipsychotic drugs, the classical neuroleptic haloperidol, the atypical antipsychotic clozapine, the DA D2/5-HT2A antagonist risperidone and the selective 5-HT2A-receptor antagonist M100907, were compared with respect to effects on NMDA antagonist-induced movement pattern alterations. We found that each receptor antagonist had a unique effect on the MK-801-induced behavioural primitivization. Haloperidol was unable to affect the monotonous behaviour induced by MK-801, while risperidone, clozapine and M100907 produced movement patterns of high intricacy.
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PMID:A behavioural pattern analysis of hypoglutamatergic mice--effects of four different antipsychotic agents. 1172 21

Neuropathological studies in autistic brains have shown small neuronal size and increased cell packing density in a variety of limbic system structures including the hippocampus, a change consistent with curtailment of normal development. Based on these observations in the hippocampus, a series of quantitative receptor autoradiographic studies were undertaken to determine the density and distribution of eight types of neurotransmitter receptors from four neurotransmitter systems (GABAergic, serotoninergic [5-HT], cholinergic, and glutamatergic). Data from these single concentration ligand binding studies indicate that the GABAergic receptor system (3[H]-flunitrazepam labeled benzodiazepine binding sites and 3[H]-muscimol labeled GABA(A) receptors) is significantly reduced in high binding regions, marking for the first time an abnormality in the GABA system in autism. In contrast, the density and distribution of the other six receptors studied (3[H]-80H-DPAT labeled 5-HT1A receptors, 3[H]-ketanserin labeled 5-HT2 receptors, 3[H]-pirenzepine labled M1 receptors, 3[H]-hemicholinium labeled high affinity choline uptake sites, 3[H]-MK801 labeled NMDA receptors, and 3[H]-kainate labeled kainate receptors) in the hippocampus did not demonstrate any statistically significant differences in binding.
J Autism Dev Disord 2001 Dec
PMID:Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. 1181 63

Prior studies have suggested a common etiology involved in Tourette's syndrome and several comorbid conditions and symptomatology. Reportedly, current medications used in Tourette's syndrome have intolerable side-effects or are ineffective for many patients. After thoroughly researching the literature, I hypothesize that magnesium deficiency may be the central precipitating event and common pathway for the subsequent biochemical effects on substance P, kynurenine, NMDA receptors, and vitamin B6 that may result in the symptomatology of Tourette's syndrome and several reported comorbid conditions. These comorbid conditions and symptomatology include allergy, asthma, autism, attention deficit hyperactivity disorder, obsessive compulsive disorder, coprolalia, copropraxia, anxiety, depression, restless leg syndrome, migraine, self-injurious behavior, autoimmunity, rage, bruxism, seizure, heart arrhythmia, heightened sensitivity to sensory stimuli, and an exaggerated startle response. Common possible environmental and genetic factors are discussed, as well as biochemical mechanisms. Clinical studies to determine the medical efficacy for a comprehensive magnesium treatment option for Tourette's syndrome need to be conducted to make this relatively safe, low side-effect treatment option available to doctors and their patients.
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PMID:The central role of magnesium deficiency in Tourette's syndrome: causal relationships between magnesium deficiency, altered biochemical pathways and symptoms relating to Tourette's syndrome and several reported comorbid conditions. 1186 98

The isoprenoid pathway and its metabolites--digoxin, dolichol, and ubiquinone--were assessed in autism. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to determine the role of cerebral dominance in the genesis of autism. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity in autism. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in autism. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead to autism. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarizing tryptophan catabolites--serotonin, quinolinic acid (NMDA agonist), strychnine (blocks glycinergic inhibitory transmission), and nicotine (promotes dopamine release) and decreased levels of hyperpolarizing tyrosine catabolites--dopamine, noradrenaline, and morphine--contributing to membrane Na+-K+ ATPase inhibition. Increased nicotine levels can produce increased dopaminergic transmission in the presence of low dopamine levels. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+-K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistence important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging and defective apoptosis leading to abnormal synaptogenesis. Autism can thus be considered a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway. The biochemical patterns including hyperdigoxinemia observed in autism correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for autism.
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PMID:A hypothalamic digoxin-mediated model for autism. 1458 53

Valproic acid (VPA) is a powerful teratogen causing birth defects in humans, including autism spectrum disorder (ASD), if exposure occurs during the first trimester of embryogenesis. Learning and memory alterations are common symptoms of ASD, but underlying molecular and synaptic alterations remain unknown. We therefore studied plasticity-related mechanisms in the neocortex of 2-week-old rats prenatally exposed to VPA and tested for changes in glutamate-mediated transmission and plasticity in the neocortex. We found a selective overexpression of NR2A and NR2B subunits of NMDA receptors, as well as the commonly linked kinase calcium/calmodulin-dependent protein kinase II. Synaptic plasticity experiments between pairs of pyramidal neurons revealed an augmented postsynaptic form of long-term potentiation. These results indicate that VPA significantly enhances NMDA receptor-mediated transmission and causes increased plasticity in the neocortex. Enhanced plasticity introduces a surprising perspective to the potential molecular and synaptic mechanisms involved in children prenatally exposed to VPA.
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PMID:Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. 1767 8

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.
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PMID:Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. 1802 40

Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism- and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist d-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.
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PMID:Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. 2014 39

Synapse malformation underlies numerous neurodevelopmental illnesses, including autism spectrum disorders. Here we identify the lipid raft protein flotillin-1 as a promoter of glutamatergic synapse formation. We cultured neurons from the hippocampus, a brain region important for learning and memory, and examined them at two weeks in vitro, a time period rich with synapse formation. Double-label immunocytochemistry of native flot-1 with glutamatergic and GABAergic synapse markers showed that flot-1 was preferentially colocalized with the glutamatergic presynaptic marker vesicular glutamate transporter 1 (VGLUT1), compared to the GABAergic presynaptic marker glutamic acid decarboxylase-65 (GAD-65). Triple-label immunocytochemistry of native flot-1, VGLUT1, and NR1, the obligatory subunit of NMDA receptors, indicates that Flot-1 was preferentially localized to synaptic rather than extrasynaptic NR1. Furthermore, electrophysiological results using whole-cell patch clamp showed that Flot-1 increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) but not miniature inhibitory postsynaptic currents (mIPSCs), whereas amplitude and decay kinetics of either type of synaptic current was not affected. Corresponding immunocytochemical data confirmed that the number of glutamatergic synapses increased with flot-1 overexpression. Overall, our anatomical and physiological results show that flot-1 enhances the formation of glutamatergic synapses but not GABAergic synapses, suggesting that the role of flot-1 in neurodevelopmental disorders should be explored.
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PMID:Flotillin-1 promotes formation of glutamatergic synapses in hippocampal neurons. 2066 24


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