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)

Prepulse inhibition is the phenomenon in which a weak prepulse stimulus suppresses the response to a startling stimulus. Patients with schizophrenia have impaired prepulse inhibition which is thought to reflect dysfunctional sensorimotor gating mechanisms. To investigate the potential genetic basis for differences in sensorimotor gating, the responses of 13 inbred strains of mice were evaluated using the prepulse inhibition paradigm. Ten male mice from A/J, AKR/J, BALB/cByJ, BUB/BnJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, FVB/NJ, ST/bJ, 129/J, 129/SvJ, 129/SvEvTac inbred strains were tested for acoustic prepulse inhibition of acoustic and tactile startle responses. There was a wide range of responses among the inbred strains of mice. Exact strain distributions were determined for each combination of prepulse sound level and startle stimulus. In general, mice from the 129/SvEvTac, AKR/J, 129/J, and 129/SvJ strains displayed high levels of prepulse inhibition of both the acoustic and tactile startle responses. C57BL/6J, C57BL/10J and BUB/BnJ mice showed low levels of prepulse inhibition. There was also a wide range in the amplitude of the acoustic and tactile startle responses. C57BL/10J and FVB/NJ mice displayed the greatest startle responses and DBA/2J, 129/J and 129/SvJ had the poorest startle responses. There was no correlation between the level of prepulse inhibition and the amplitude of the startle response. These findings indicate that inbred strains of mice may be a useful tool to study the genetic basis of sensorimotor gating.
 ...
PMID:Inbred strain differences in prepulse inhibition of the mouse startle response. 926 14

Abnormal sensory inhibition is a measurable indicator of a sensory processing deficit which is observed in schizophrenia, and other disorders, and which may be heritable. This deficit has also been observed in certain inbred mouse strains where the intensity of the deficit has been correlated with reduction in the number of hippocampal alpha-bungarotoxin-sensitive nicotinic receptors. Nicotine and certain nicotinic agonists produce brief periods of normal sensory inhibition in these mice. Similarly, nicotine also transiently normalizes sensory inhibition in schizophrenics. The present study assessed the effects of a novel nicotinic partial agonist (GTS-21), selective for the alpha-bungarotoxin site, on sensory inhibition in DBA mice, a strain with no sensory inhibition under routine experimental conditions. GTS-21 produced a dose-dependent normalization of sensory inhibition which was blocked by alpha-bungarotoxin but not mecamylamine. In contrast to other nicotinic agonists, normalization of sensory inhibition by GTS-21 and two related anabaseine compounds, DMAB-anabaseine and DMAC-anabaseine, was observed when administered a second time to the animal, after a 40-min delay. Our results indicated that the anabaseine compounds increase sensory inhibition through alpha7 nicotinic receptors, and that their ability to act repeatedly on these receptors may be less affected by desensitization.
 ...
PMID:Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. 960 May 76

People with schizophrenia exhibit impaired ability to modify electroencephalographic event-related potential (ERP) responses to novel stimuli. These deficits serve as a window into the abnormalities of neuronal organization and function and are thought to reflect a component of genetic vulnerability for schizophrenia. We describe differences among inbred mouse strains for ERPs following a novelty detection paradigm, as a model for genetic contributions to disease vulnerability. Auditory-evoked potentials were recorded during an auditory oddball task in nonanesthetized C57BL/6J, C3H/HeJ, and DBA/2J mice prior to and following ketamine (10 mg/kg). Stimuli consisted of 80 sets of 24 standard tones followed by one novel tone. Principal component analysis yielded four temporal components that contribute to the auditory ERP responses to standard and novel stimuli. Two principal components that varied between standard and novel stimuli also differed among inbred mouse strains. Post hoc analyses indicate that strain effects on novelty detection are due to a significant difference between the response to novel and standard tones in C3H/HeJ mice that is absent in the other two strains. Inbred strains of mice vary in their ability to perform neuronal detection of change in the auditory environment. The ability to model novelty detection deficits in mice will aid in identifying genetic contributions to abnormal neuronal organization in people with schizophrenia.
 ...
PMID:Effects of strain, novelty, and NMDA blockade on auditory-evoked potentials in mice. 1265 12

Previous data have shown differences among inbred mouse strains in sensory gating of auditory evoked potentials, prepulse inhibition (PPI) of startle, and startle amplitude. These measures of sensory and sensorimotor gating have both been proposed as models for genetic determinants of sensory processing abnormalities in patients with schizophrenia and their first-degree relatives. Data from our laboratory suggest that auditory evoked potentials of DBA/2J mice differ from those previously described for DBA/2Hsd. Therefore, we compared evoked potentials and PPI in these two closely related substrains based on the hypothesis that any observed endophenotypic differences are more likely to distinguish relevant from incidental genetic heterogeneity than similar approaches using inbred strains that vary across the entire genome. We found that DBA/2Hsd substrain exhibited reduced inhibition of evoked potentials and reduced startle relative to the DBA/2J substrain without alterations in auditory sensitivity, amplitude of evoked potentials or PPI of startle. These results suggest that gating of auditory evoked potentials and PPI of startle measure different aspects of neuronal function. The differences between the substrains might reflect genetic drift. Alternatively, differences could arise from different rearing environments or other non-genetic factors. Future studies will attempt to determine the cause of these differences in sensory and sensorimotor processing between these two closely related inbred mouse strains.
 ...
PMID:Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse substrains. 1460 76

Schizophrenia patients may exhibit high tobacco smoking rates in part to self-medicate sensory gating deficits with nicotine contained in tobacco. To test this hypothesis, we induced sensori-motor gating deficits in four mouse strains with phencyclidine, a noncompetitive antagonist of glutamatergic N -methyl-d-aspartate receptors. Nicotine attenuated the disruption in prepulse inhibition induced by phencyclidine in DBA/2J and C3H/HeJ but not in C57BL/6J or 129T2/SvEmsJ mice. These results highlight genetic variations in the regulation by nicotinic cholinergic systems of the dysfunction in glutamatergic transmission contributing to gating deficits in schizophrenia. Further, these findings support the hypothesis of self-medication of gating deficits in schizophrenia through tobacco smoking, and suggest that treatments targeting genetic dysfunctions in nicotinic-glutamatergic interactions that would treat cognitive deficits will assist schizophrenia patients in minimizing tobacco smoking.
 ...
PMID:Strain-specificity in nicotine attenuation of phencyclidine-induced disruption of prepulse inhibition in mice: relevance to smoking in schizophrenia patients. 1499 Aug 73

Histamine H3 receptor antagonists/inverse agonists have been proposed as potential therapeutic agents for the treatment of a number of neurological disorders ranging from attention deficit hyperactivity disorder and Alzheimer's disease to narcolepsy and schizophrenia. With respect to the latter, schizophrenic patients typically exhibit impaired prepulse inhibition (PPI) of startle, a reflex that can be modeled in many animal species. Certain strains of mice naturally display poor PPI and it was recently suggested that these mice might offer a new way to screen for novel antipsychotic compounds. To examine whether H3 receptor antagonists might enhance PPI in mice with naturally occurring deficits, DBA/2 and C57BL/6 were tested in a startle paradigm with three prepulse intensities: 5, 10 and 15 dB above background. Both thioperamide and ciproxifan enhanced PPI in the DBA/2 strain; thioperamide also showed a trend towards enhancing PPI in C57BL/6. Risperidone, an atypical antipsychotic, enhanced PPI in both the DBA/2 and the C57BL/6 strain. These data confirm previous reports describing a natural deficit in PPI in some mouse strains that is amenable to enhancement with known antipsychotics. Further, these data suggest that H3 receptor antagonists/inverse agonists have anti-psychotic potential for disorders such as schizophrenia.
 ...
PMID:Enhancement of prepulse inhibition of startle in mice by the H3 receptor antagonists thioperamide and ciproxifan. 1521 8

According to the dopamine (DA) hypothesis of schizophrenia and the strong evidence for decreased cerebral lateralization in schizophrenic patients, we postulated that hyperactivity of the dopaminergic system could be associated with a reduced behavioral lateralization in mice. Mice lacking the dopamine transporter (DAT) gene were used as a genetic model of persistent hyperdopaminergia. The DAT null mutation was transferred on C57BL/6JOrl (B6) and DBA/2JOrl (D2) inbred backgrounds for more than 10 generations of backcrossing to derive three DAT strains, B6, D2, and B6xD2(F1). Adult mutant mice of the three DAT strains and their littermates were tested for paw preference using Collins' protocol. Our results demonstrated that, whatever the genetic background, persistent hyperdopaminergia directly impairs the degree of lateralization without affecting the direction. Our results support the degree of lateralization as a good candidate phenotype to further improve genetic analysis of cerebral lateralization in normal and pathological conditions.
 ...
PMID:Constitutive hyperdopaminergia is functionally associated with reduced behavioral lateralization. 1535 85

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pK(i) = 8.9) and human (pK(i) = 9.5) H3Rs. Acute functional blockade of central H3Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0-3.0 mg/kg) and N40 (1.0-10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.
 ...
PMID:Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist. 1560 77

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
 ...
PMID:Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. 1595 94

Interleukin-1 (IL-1) is implicated in the pathogenesis of various psychiatric diseases. Peripheral administration of IL-1alpha to neonatal rats induces cognitive and behavioral abnormalities and, therefore, the IL-1alpha-treated animals might serve as a schizophrenia model. The present study assessed genetic influences on IL-1alpha-triggered behavioral impairments, using four different strains of neonatal mice, C3H/He, DBA/2, C57BL/6, and ddY. Neonatal treatments with IL-1alpha differentially altered adult behavioral/cognitive traits in a strain-dependent manner. IL-1alpha treatment decreased prepulse inhibition in DBA/2 and C57BL/6 mice but not in C3H/He and ddY. The treatment increased locomotor activity and startle responses in DBA/2 mice and, conversely, decreased startle responses in C3H/He mice. Behavioral alterations were most remarkable in DBA/2 mice but undetectable in ddY mice. The magnitudes of IL-1alpha actions differed between the brain and periphery and were influenced by mouse genetic background. The IL-1-triggered acute signaling, Ikappa-B degradation, was significant in the frontal cortex of DBA/2 mice and in the hypothalamus of C3H/He mice. An increase in brain p38 MAP kinase phosphorylation was also most marked in the DBA/2 strain. In contrast, subchronic influences of IL-1alpha injections failed to illustrate the strain-dependent behavioral alterations. The peripheral effects of IL-1alpha did not match the strain-dependency of the behavioral alterations, either. Acceleration of tooth eruption and eyelid opening as well as attenuation of weight gain was most marked in C3H/He mice and the induction of serum amyloid protein was the largest in ddY mice. Thus, the peripheral effects of IL-1alpha in DBA/2 mice were relatively inferior to those in the other strains. The present animal study suggests that, in early postnatal development, circulating IL-1alpha trigger brain cytokine signaling and produce distinct influences on later neurobehavioral traits, both depending on genetic background.
 ...
PMID:Strain-dependent behavioral alterations induced by peripheral interleukin-1 challenge in neonatal mice. 1613 77


1 2 3 4 5 6 Next >>