Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of evidence suggest that the nicotinic acetylcholine receptor alpha7 (nAChR alpha7) is involved in central nervous system disorders like schizophrenia and Alzheimer's disease as well as in inflammatory disorders like sepsis and pancreatitis. The present article describes the in vivo effects of JN403, a compound recently characterized to be a potent and selective partial nAChR alpha7 agonist. JN403 rapidly penetrates into the brain after i.v. and after p.o. administration in mice and rats. In the social recognition test in mice JN403 facilitates learning/memory performance over a broad dose range. JN403 shows anxiolytic-like properties in the social exploration model in rats and the effects are retained after a 6h pre-treatment period and after subchronic administration. The effect on sensory inhibition was investigated in DBA/2 mice, a strain with reduced sensory inhibition under standard experimental conditions. Systemic administration of JN403 restores sensory gating in DBA/2 mice, both in anaesthetized and awake animals. Furthermore, JN403 shows anticonvulsant potential in the audiogenic seizure paradigm in DBA/2 mice. In the two models of permanent pain tested, JN403 produces a significant reversal of mechanical hyperalgesia. The onset was fast and the duration lasted for about 6h. Altogether, the present set of data suggests that nAChR alpha7 agonists, like JN403 may be beneficial for improving learning/memory performance, restoring sensory gating deficits, and alleviating pain, epileptic seizures and conditions of anxiety.
 ...
PMID:The selective nicotinic acetylcholine receptor alpha7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain. 1879 55

We have performed a comparative study of the content of glutamate (Glu), aspartate (Asp), taurine (Tau), glycine (Gly) and gamma-amino-butyric acid (GABA) in the cortex, hippocampus, and striatum of the DBA/2J, Balb/c and C57BL/6 mice brain. The levels of Glu, Tau and GABA in DBA/2J hippocampus was lower than those in other experimental strains. These findings are consistent with published data on the specific neurophysiological properties of DBA/2J (neuroleptic sensitive prepulse inhibition, deficit), thus allowing this strain to be used in modeling schizophrenia. Taking into account these facts, in the next step we investigated the effects of dilept, the new neurotensine-derived dipeptide with antipsychotic activity (GZR-123, methyl ester of N-caproyl-L-prolyltyrosine), on the content of neurotransmitter acids in DBA/2J mice brain structures. In a dose of 0.8 mg/kg (i.p.) dilept induced a statistically significant increase in the levels of Glu, Tau and GABA in striatum of DBA/2J, as well as insignificant increase in the levels of these amino acids in the cortex. These effects are quite similar to those described for the parent peptide neurotensine, in case of its intracerebral administration. The results of our study prove the necessity of the further development of dilept as a potential antipsychotic drug.
 ...
PMID:[Interstrain differences in the content of excitatory and inhibitory amino acids in the brain of DBA/2J, Balb/c and C57BL/6 mice: characteristics of the effect of a dipeptide antipsychotic drug dilept]. 1881 33

Dysbindin-1 (dystrobrevin binding protein-1) has been reported as a candidate gene associated with schizophrenia. Dysbindin-1 mRNA and protein levels are significantly reduced in the prefrontal cortex and hippocampus of schizophrenia subjects. To understand the in-vivo functions of dysbindin-1, we studied schizophrenia relevant behaviors in adult male Sandy homozygous (sdy/sdy) and heterozygous (sdy/+) mice that have a natural mutation in dysbindin-1 gene (on a DBA/2J background) resulting in loss of protein expression. Spontaneous locomotor activity of sdy/sdy and sdy/+ mice in novel environment was not significantly different from DBA/2J controls. However, on repeated testing in the same environment for 7 days, sdy/sdy mice, in contrast to DBA/2J controls showed a lack of locomotor habituation. Locomotor activating effect of a low dose of d-amphetamine (2.5 mg/kg i.p.), a behavioral measure of mesolimbic dopamine activity, was significantly reduced in the mutant mice. Interestingly, sdy/sdy mice showed enhanced locomotor sensitization to repeated five daily injection of amphetamine. Possible cognitive impairment in Sandy mutants was revealed in novel object recognition test as sdy/sdy and sdy/+ mice spent significantly less time exploring novel objects compared to DBA/2J. Sdy/sdy mice also showed deficits in emotionally motivated learning and memory showing greater freezing response to auditory conditioned stimulus (CS) in fear conditioning paradigm. In thermal nociceptive test, the latency of paw withdrawal in sdy/sdy and sdy/+ animals was significantly higher compared to DBA/2J indicating hypoalgesia in the mutants. Taken together, these data suggest that dysbindin-1 gene deficiency leads to significant changes in cognition and altered responses to psychostimulants.
 ...
PMID:Behavioral characterization of dysbindin-1 deficient sandy mice. 1898 10

Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5-HT transporter (5-HTT) mRNA level, 5-HT(1A) receptor mRNA level, and 5-HT(1A) receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5-HTT mRNA level in the midbrain and a reduced density of 5-HT(1A) receptors in the frontal cortex without significant changes in 5-HT(1A) receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light-dark box and elevated plus-maze tests, were found. The results suggested the involvement of decreased 5-HTT gene expression and 5-HT(1A) receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive-like behaviors.
 ...
PMID:Serotonin transporter, 5-HT1A receptor, and behavior in DBA/2J mice in comparison with four inbred mouse strains. 1953 37

GABA cell dysfunction in both schizophrenia (SZ) and bipolar disorder (BD) involves decreased GAD(67) expression, although this change involves fundamentally different networks of genes in the 2 disorders. One gene that is common to these 2 networks is cyclin D2, a key component of cell cycle regulation that shows increased expression in SZ, but decreased expression in BD. Because of the importance of cell cycle regulation in maintaining functional differentiation and DNA repair, the current study has examined the genes involved in the G(1) and G(2) checkpoints to generate new hypotheses regarding the regulation of the GABA cell phenotype in the hippocampus of SZ and BD. The results have demonstrated significant changes in cell cycle regulation in both SZ and BD and these changes include the transcriptional complex (TC) that controls the expression of E2F/DP-1 target genes critical for progression to G(2)/M. The methyl-CpG binding domain protein (MBD4) that is pivotal for DNA repair, is significantly up-regulated in the stratum oriens (SO) of CA3/2 and CA1 in SZs and BDs. However, other genes associated with the TC, and the G(1) and G(2) checkpoints, show complex changes in expression in the SO of CA3/2 and CA1 of both SZs and BDS. Overall, the patterns of expression observed have suggested that the regulation of functional differentiation and/or genomic integrity of hippocampal GABA cells varies according to diagnosis and their location within the trisynaptic pathway.
 ...
PMID:Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars. 1956 23

The 5-HT(3) receptor antagonist, ondansetron, has been shown to correct the auditory gating deficit in medicated schizophrenia patients. Inhibition of 5-HT(3) receptors releases acetylcholine, the endogenous ligand for nicotinic acetylcholine receptors. The schizophrenia-related auditory gating deficit is modulated, in part, by nicotinic acetylcholine receptors, as is the mouse (DBA/2) model of the deficit. The present study assessed the effects of both acute and chronically administered ondansetron on auditory gating in DBA/2 mice. Auditory gating is defined as a decrease in amplitude of response to the second of a paired identical auditory stimulus presented 0.5 s following an initial auditory stimulus. Acute ondansetron administration at the lowest dose (0.1 mg/kg, IP) tested had no effect, while other doses (0.33 and 1 mg/kg, IP) produced improvements in auditory gating. The improvements were produced through both an increase in response to the first auditory stimulus and a decrease in the response to the second auditory stimulus. Co-administration of an alpha7 nicotinic acetylcholine receptor antagonist, alpha-bungarotoxin, or the alpha4beta2 nicotinic acetylcholine receptor antagonist dihydro-beta-erythroidine, with the 0.33 mg/kg dose of ondansetron blocked the improvement in auditory gating produced by ondansetron alone. There was no difference in response between the chronically injected mice and naive mice. Both showed improved auditory gating, thus, demonstrating no "carry over" effect of daily injections. These data demonstrate that indirect stimulation of nicotinic acetylcholine receptors by ondansetron can improve auditory gating parameters in DBA/2 mice.
 ...
PMID:Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism. 1972 91

Dysbindin-1 reductions appear to be common in dysfunctional brain areas of schizophrenia cases. In the absence of a dysbindin-1 knockout, sandy (sdy) mice provide our only means of studying the potential contribution of this protein to clinical features of schizophrenia in live animals. Our knowledge of sandy mice is reviewed here. These mice have a deletion mutation that arose spontaneously in DBA/2J mice in the gene encoding dysbindin-1 (Dtnbp1). This null protein mutation (Dtnbp1(sdy)) leads to an absence of dysbindin-1 in homozygotes, as well as reductions in several direct and indirect binding partners of dysbindin-1 that contribute to the protein assembly known as BLOC-1. Studies of sdy mice on the original DBA/2J background and on a C57BL/6J background indicate that the Dtnbp1(sdy) mutation does not affect viability, basic sensory or motor functions, or measures of anxiety and motivation. Such studies do indicate, however, that the mutation affects several biological functions, including adrenal neurosecretion and pre- and postsynaptic aspects of dopaminergic, glutamatergic, and GABAergic transmission. These effects and those on prepulse inhibition, social interaction, and diverse aspects of spatial memory suggest that homozygous sdy mice may model various features of schizophrenia.
 ...
PMID:The sandy (sdy) mouse: a dysbindin-1 mutant relevant to schizophrenia research. 2030 21

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animals using acoustic prepulse inhibition of the startle. Both classical and atypical antipsychotics have been shown to improve prepulse inhibition in DBA/2J mice, a non-pharmacological model for impaired sensorimotor gating. The purpose of the present study was to clarify whether metabotropic glutamate receptors participate in control of sensorimotor gating. We evaluated various metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice. This basal level of prepulse inhibition in DBA/2J mice was increased by only the mGlu(1) receptor antagonists [2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one] (CFMTI), 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (YM-298198), and (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685). There was no effect after treatments with the mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), the mGlu(2/3) receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), the mGlu(2/3) receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), the mGlu(7) receptor agonist N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the mGlu(7) receptor antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP), or the mGlu(8) receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG). These findings indicate that inhibition of mGlu(1) receptor selectively increases prepulse inhibition in DBA/2J mice and suggest that mGlu(1) receptor antagonists could be a novel treatment for some aspects of schizophrenia.
 ...
PMID:Pharmacological effects of metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice. 2037 Dec 35

Selective attention was assessed in mice using a classical fear conditioning procedure. Mice were trained by three regimens involving contextual and/or cued conditioning (classical fear conditioning). Most notably, C57BL/6J mice exhibited salient contextual blocking, whereas DBA/2J and ICR mice did not. This study provides a new method to assess the selective attention of mice and describes an animal model for certain human mental disorders, such as schizophrenia.
 ...
PMID:Strain differences of selective attention in mice: effect of Kamin blocking on classical fear conditioning. 2043 88

Genetic variability in the proportion of the two alternative dopamine D2 receptor (D2R) mRNA splice variants, D2R-long (D2L) and D2R-short (D2S), influence corticostriatal functioning and could be implicated in liability to psychopathology. This study compared mesostriatal D2L/D2S ratios and associated neural and behavioral phenotypes in mice of the DBA/2J and C57BL/6J-inbred strains, which differ for schizophrenia- and addiction-like phenotypes. Results showed that DBA/2J mice lack the striatal predominance of D2L that has been reported in the rat and in C57BL/6J mice and confirmed in the latter strain by this study. Only C57BL/6J mice showed enhanced striatal c-Fos expression under D1R and D2/3R co-stimulation, indicating synergistic interaction between the subtypes of DA receptors. Instead, DBA/2J mice were characterized by opposing effects of D2/3R and D1R stimulation on striatal c-Fos expression, in line with a more pronounced influence of D2S isoform, and did not express stereotyped climbing under D1R and D2/3R co-stimulation, as reported for D2L-/- mice. Finally, strain-specific modulation of c-Fos expression by D1R and D2/3R co-stimulation was selectively observed in striatal compartments receiving inputs from the prefrontal cortex and involved in the control of motivated behaviors. These results show differences in tissue-specific D2R splicing in mice with intact genotypes and support a role for this phenotype in individual variability of corticostriatal functioning and in liability to psychopathology.
 ...
PMID:Strain-specific proportion of the two isoforms of the dopamine D2 receptor in the mouse striatum: associated neural and behavioral phenotypes. 2054 14


<< Previous 1 2 3 4 5 6 Next >>