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 risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.
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PMID:Alterations in hippocampal excitability, synaptic transmission and synaptic plasticity in a neurodevelopmental model of schizophrenia. 2185 89

Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia [methyl-azoxymethanol acetate (20 mg/kg, i.p.) injected into G17 pregnant female rats, with offspring tested as adults], the extant hyperdopaminergic state combines with the excitatory actions of a first- (haloperidol; 0.6 mg/kg, i.p.) and a second- (sertindole; 2.5 mg/kg, i.p.) generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1, 3, 7, 15, and 21 d continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia.
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PMID:Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia. 2186 75

Administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In this study, we investigated the molecular phenotype of adult MAM rats by focusing on the frontal cortex and hippocampal areas, as these are known to be affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM treatment on E17 resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.
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PMID:The methylazoxymethanol acetate (MAM-E17) rat model: molecular and functional effects in the hippocampus. 2215 47

Ziprasidone, commercially available as Geodon capsules, is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder. It is a BCS Class II drug that shows up to a 2-fold increase in absorption in the presence of food. Because compliance is a major issue in this patient population, we developed and characterized solubilized formulations of ziprasidone in an effort to improve absorption in the fasted state, thereby resulting in a reduced food effect. Three formulations utilizing solubilization technologies were studied: (1) an amorphous inclusion complex of ziprasidone mesylate and a cyclodextrin, (2) a nanosuspension of crystalline ziprasidone free base, and (3) jet-milled ziprasidone HCl coated crystals made by spray drying (CCSD) the drug with hypromellose acetate succinate. The formulations were characterized by in vitro methods appropriate to each particular solubilization technology. These studies confirmed that ziprasidone mesylate - cyclodextrin was an amorphous inclusion complex with enhanced dissolution rates. The ziprasidone free base crystalline nanosuspension showed a mean particle size of 274 nm and a monomodal particle size distribution. In a membrane permeation test, the CCSD showed a 1.5-fold higher initial flux compared to crystalline ziprasidone HCl. The three formulations were administered to fasted beagle dogs and their pharmacokinetics compared to Geodon capsules administered in the fed state. The amorphous complex and the nanosuspension showed increased absorption in the fasted state, indicating that solubilized formulations of ziprasidone have the potential to reduce the food effect in humans.
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PMID:In vitro and in vivo characterization of amorphous, nanocrystalline, and crystalline ziprasidone formulations. 2234 51

This special theme issue of Schizophrenia Bulletin presents a series of related articles focusing on auditory hallucinations, prepared by members of the International Consortium on Hallucination Research [InCoHR] working groups. The InCoHR is a large collaborative framework that serves as a platform for researchers to meet and collaborate on multidisciplinary projects relating to auditory hallucinations [AH] and discuss methodological issues facing transdiagnostic research. Laroi et al. observe the similarities in characteristic features of AHs in different clinical and nonclinical groups, but they also note that differences exist, reflecting the contribution of disease-related process. Waters et al. use findings of shared cognitive impairments across different diagnostic groups with AHs to propose a novel theoretical cognitive framework. Allen et al. describe that the neurobiological substrates of AHs include neural systems involved in language processing, as well as sensory and nonsensory brain regions and that studies are increasingly using fine-grain analysis of patients' characteristics in analyzing neuroimaging data. Ford et al. discuss different neurophysiological approaches and describes hallucination-related alterations in activity in temporal and frontal regions of the brain and particularly in auditory cortical areas. Finally, Sommer et al. review different treatment options for AHs in schizophrenia and other disorders, including pharmacological treatment, cognitive-behavioral therapy [CBT] and acceptance and commitment therapy [ACT], transcranial magnetic stimulation [TMS], and electroconvulsive therapy [ECT]. These related publications describe the current substance and direction of research on AHs across different diagnostic groups.
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PMID:Multidisciplinary approaches to understanding auditory hallucinations in schizophrenia and nonschizophrenia populations: the International Consortium on Hallucination Research. 2283 51

Calcyon, once known for interacting directly with the dopamine D(1) receptor (D(1)DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Although its direct interaction with D(1)DR has been shown to be misinterpreted, it still plays important roles in D(1)DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D(1)DR through PSD-95. Calcyon is phosphorylated on Ser-169 by the PKC activator phorbol 12-myristate 13-acetate or by the D(1)DR agonist SKF-81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D(1)DR at the cell surface was enhanced by phorbol 12-myristate 13-acetate and SKF-81297 in the presence of calcyon, but not in the presence of its S169A phospho-deficient mutant, suggesting that the phosphorylation of calcyon and the internalization of the surface D(1)DR are tightly correlated. Our results suggest that calcyon regulates D(1)DR trafficking by forming a ternary complex with D(1)DR through PSD-95 and thus possibly linking glutamatergic and dopamine receptor signalings. This also raises the possibility that a novel ternary complex could represent a potential therapeutic target for the modulation of related neuropsychiatric disorders.
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PMID:Calcyon forms a novel ternary complex with dopamine D1 receptor through PSD-95 protein and plays a role in dopamine receptor internalization. 2284 80

Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAM-treated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcription-polymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.
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PMID:Aberrant dopamine D2-like receptor function in a rodent model of schizophrenia. 2285 62

Cognitive deficits associated with schizophrenia (CDS) are implicated as a core symptom cluster of the disease and are associated with poor daily life functioning. Unfortunately, current antipsychotic agents provide little alleviation of CDS, representing a critical unmet therapeutic need. Here we investigated the effects of ABT-239 and A-431404, non-imidazole histamine H(3) receptor (H(3)R) antagonists, in animal models with relevance to CDS. As N-methyl-d-aspartate receptor hypofunction is considered an important factor in the pathogenesis of schizophrenia, acute administration of ketamine or MK-801 was used to induce cognitive impairments. The assays employed in the current studies were spontaneous alternation in cross-maze, used as an indication of working memory, and inhibitory avoidance (IA), used to assess long-term memory retention. Risperidone and olanzapine were also tested to directly compare the effects of H(3)R antagonists to two widely used antipsychotics. ABT-239 and A-431404, but not risperidone and olanzapine, attenuated ketamine-induced deficits on spontaneous alternation in cross-maze, while none of these compounds affected alternation performance on their own. ABT-239 and A-431404 also attenuated MK-801-induced impairments in IA; no effects were observed when given alone. Risperidone and olanzapine, however, failed to attenuate MK-801-induced deficits in IA and produced dose-dependent impairments when given alone. ABT-239 was also investigated in methylazoxymethanol acetate (MAM) treated rats, a neurodevelopmental model for schizophrenia. Chronic, but not acute, treatment with ABT-239 significantly improved spontaneous alternation impairments in MAM rats tested in cross-maze. In summary, these results suggest H(3)R antagonists may have the potential to ameliorate CDS.
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PMID:Preclinical evaluation of non-imidazole histamine H3 receptor antagonists in comparison to atypical antipsychotics for the treatment of cognitive deficits associated with schizophrenia. 2290 30

The N-methyl-D-aspartate (NMDA) receptor has long been associated with learning and memory processes as well as diseased states, particularly in schizophrenia (SZ). Additionally, SZ is increasingly recognized as a neurodevelopmental disorder with cognitive impairments often preceding the onset of psychosis. However, the cause of these cognitive deficits and what initiates the pathological process is unknown. Growing evidence has implicated the glutamate system and, in particular, N-methyl-D-aspartate receptor (NMDAR) dysfunction in the pathophysiology of SZ. Yet, the vast majority of SZ-related research has focused on NMDAR function in adults leaving the role of NMDARs during development uncharacterized. We used the prenatal methylazoxymethanol acetate (MAM, E17) exposure model to determine the alterations of NMDAR protein levels and function, as well as associated cognitive deficits during development. We found that MAM-exposed animals have significantly altered NMDAR protein levels and function in the juvenile and adolescent hippocampus. Furthermore, these changes are associated with learning and memory deficits in the Morris Water Maze. Thus, in the prenatal MAM-exposure SZ model, NMDAR expression and function is altered during the critical period of hippocampal development. These changes may be involved in disease initiation and cognitive impairment in the early stage of SZ.
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PMID:Gestational methylazoxymethanol exposure leads to NMDAR dysfunction in hippocampus during early development and lasting deficits in learning. 2296 15

The nucleus accumbens (NAc) receives converging inputs from the medial prefrontal cortex (mPFC) and the hippocampus which have competitive interactions in the NAc to influence motivational drive. We have previously shown altered synaptic plasticity in the hippocampal-NAc pathway in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in rodents that is dependent on cortical inputs. Thus, because mPFC-hippocampal balance is known to be partially altered in this model, we investigated potential pathological changes in the hippocampal influence over cortex-driven NAc spike activity. Here we show that the reciprocal interaction between the hippocampus and mPFC is absent in MAM animals but is able to be reinstated with administration of the antipsychotic drug, sulpiride. The lack of interaction between these structures in this model could explain the attentional deficits in schizophrenia patients and shed light onto their inability to focus on a single task.
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PMID:Disruption of prefrontal cortical-hippocampal balance in a developmental model of schizophrenia: reversal by sulpiride. 2306 77


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