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)

Since the discovery of the antipsychotic effects of chlorpromazine by the french psychiatrists Delay and Deniker in 1952, preclinical pharmacologists have proposed several laboratory tests, that have been used to demonstrate the potential activity of drugs in the treatment of mental disorders including schizophrenia, depressive illness and anxiety. Tests are divided into behavioural tests and neurochemical tests. Electrophysiology tests are not considered in this paper. Concerning schizophrenia, in spite that there is no valid model, behavioural tests presently used are: antagonism against various responses induced by dopamine receptor agonists, inhibition of conditioned behaviours, latent inhibition, startle reaction, models related to the neurodevelopmental hypothesis. For antidepressant activity, models are based on antagonism of various effects of reserpine. More anthropomorphic models involve helplessness behaviours, social isolation, changes induced by limbic system lesions. Biochemical investigations mainly involve in vitro and in vivo tests: study of changes in the metabolism of neurotransmitters using microdialysis and other procedures, interaction with receptor subtypes. As a result of advances in molecular biology, other tools are now emerging, but classical tests remain useful.
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PMID:[Behavioral and neurochemical methods in research on new psychotropic drugs]. 945 31

Since the discovery of the antipsychotic effects of chlorpromazine by the French psychiatrists DELAY and DENIKER in 1952, preclinical pharmacologists have proposed several laboratory tests, that have been used to demonstrate the potential activity of drugs in the treatment of mental disorders including schizophrenia, depressive illness and anxiety. Tests are divided into behavioural tests and neurochemical tests. Electrophysiology tests are not considered in this paper. Concerning schizophrenia, although there is no valid model, behavioural tests presently used are: antagonism against various responses induced by dopamine receptor agonists, inhibition of conditioned behaviours, latent inhibition, startle reaction, models related to the neurodevelopmental hypothesis. For antidepressant activity, models are based on antagonism of various effects of reserpine. More anthropomorphic models involve helplessness behaviours, social isolation, changes induced by limbic system lesions. Biochemical investigations mainly involve in vitro and in vivo tests: study of changes in the metabolism of neurotransmitters using microdialysis and other procedures, interaction with receptor subtypes. As a result of advances in molecular biology, other tools are now emerging, but classical tests remain useful.
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PMID:[Behavioral and neurochemical methods in research on new psychotropics]. 977 24

Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25microg/0.5microl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague-Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394-8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113-121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field. From our results, we suggest that N-methyl-D-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.
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PMID:Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity. 1111 8

Prepulse inhibition (PPI) refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. PPI has been extensively employed as an assay for sensorimotor gating, and its disruption has been characterized in specific disease conditions, including schizophrenia. In animals, dopamine agonists disrupt PPI, and this disruption can be antagonized by antipsychotic drug treatment. The present study extended these fundamental findings to C57BL6 mice, and further evaluated the subjects' reaction to the prepulse stimulus alone in relation to the expression of PPI. Not only did apomorphine (2.0 mg/kg, intraperitoneal (i.p.)) attenuate PPI but it also enhanced reactivity to the prepulse stimulus. The dual effects of apomorphine appear paradoxical in view of the positive correlation, detectable in both the control and apomorphine groups, between prepulse reactivity and PPI magnitude. The present findings contradict the hypothesis that apomorphine disrupts PPI via reduced detectability or perception of the prepulse, and we further propose that enhanced distractibility may provide a parsimonious account for the dual effects of apomorphine. Moreover, haloperidol pretreatment (0.4 mg/kg, i.p.) fully antagonized the effects of apomorphine upon prepulse reactivity as well as on PPI. The present results add to our understanding of the relevance and applicability of the PPI paradigm in modeling schizophrenia-like symptoms in animals.
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PMID:Apomorphine-induced prepulse inhibition disruption is associated with a paradoxical enhancement of prepulse stimulus reactivity. 1466 20

Prepulse inhibition (PPI) of the acoustic startle reflex has been extensively employed as a test of sensorimotor gating or early attentional control in neuropsychiatric research, because a number of psychiatric conditions, including schizophrenia, exhibit PPI deficiencies. In both human and animal studies, PPI is commonly demonstrated by an attenuation of the acoustic startle reflex when the startle-inducing pulse stimulus is shortly preceded by a weak non-startling prepulse stimulus. This weakening of the startle reaction is attributed to, and therefore also provides an indirect measure of, the inhibition triggered by the perception of the prepulse stimulus. The relative ease in measuring the overt pulse-elicited startle reaction, in comparison with the relatively weak prepulse-elicited reaction (PPER) has led to a near complete neglect of the latter in recent literature. However, the assumption that the prepulse used in PPI is non-startling, does not imply that it is associated with no measurable responses. In fact the feasibility and reliability of obtaining such measures has been confirmed in both rodents and humans, and here we review the key findings derived from the direct evaluation of prepulse-elicited reaction in PPI, including under conditions that lead to PPI deficits. The theoretical implications and potential interpretative values of PPER are discussed. It is concluded that PPER should no longer be ignored; its emphasis may shed light on the kind of inhibition or gating dysfunction relevant to PPI disruption seen in pathological conditions including schizophrenia.
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PMID:Distinct forms of prepulse inhibition disruption distinguishable by the associated changes in prepulse-elicited reaction. 1911 60

The present study investigates the impact of dexamethasone (DEX) given in tapering doses in the postnatal period on MK-801-induced locomotor activity and MK-801-evoked deficits of sensorimotor gating of adult rats (60 days old). It has been found that DEX given on postnatal day 1 (0.5 microg/g), day 2 (0.3 microg/g) and day 3 (0.1 microg/g) has no effects on spontaneous locomotor activity and does not influence locomotion observed after MK-801 given in a dose of 0.2 and 0.4 mg/kg. Postnatal DEX treatment did not alter the efficacy of sensorimotor gating and its deficits evoked by MK-801 at a dose of 0.2 and 0.4 mg/kg. However, a slight increase in the amplitude of startle reaction has been noted in DEX-treated animals. In conclusion, the results of the present study indicate that DEX given postnatally in tapering doses, although pharmacologically effective (decrease in a gain of body and brain weight), has no potential pro-psychotic effects and does not influence pharmacologically induced psychoses by MK-801. The above data indicate that apart from other side effects, the therapeutic application of DEX in the postnatal period is possibly safe in terms of the risk for developing schizophrenia.
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PMID:Impact of postnatal dexamethasone on psychotomimetic effects of MK-801 measured on adult rats. 2008 Dec 38

Prepulse modification of acoustic startle reaction (ASR) was studied in patients with schizophrenia and healthy controls according to the protocol recommended by the Consortium on the genetics of schizophrenia. Patients displayed the reduced ASR magnitude of prepulse inhibition (PPI) and increased startle latency prepulse facilitation (PPF) at 60 ms lead interval. The ASR amplitude PPF at 2500 ms lead interval was also impaired in patients. Effects of the recent head trauma and psychoactive drug experience on the ASR prepulse modification were different in patients and controls. The high baseline amplitude and short ASR latency in patients were correlated with the excitation level measured with the PANSS (item P4) whereas the PPF reduction was correlated with the high total score on the PANSS positive subscale. These results suggest the possibility of using ASR prepulse modification in clinical neurophysiology.
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PMID:[Prepulse modification of acoustic startle reaction in patients with schizophrenia and healthy controls]. 2135 Apr 28

The startle reaction (also known as the startle response, the startle reflex, or the alarm reaction) is the psychological and physiological response to a sudden unexpected stimulus, such as a flash of light, a loud noise (acoustic startle reflex), or a quick movement near the face. Abnormalities of startle response have been observed in many stress-related mental disorders, such as schizophrenia and post-traumatic stress disorder (PTSD). However, the molecular mechanisms of startle in stress-associated conditions--for example, whether the startle reaction is associated with any gene variance--is still unknown. In this paper, we will carry out a systematic review by retrieving, assessing, and combining, when applicable, individual studies investigating association of the molecular variation of candidate gene with the startle response. The systematic review is based on the search for numerous publications using the keywords "startle gene" on September 15, 2010 using PubMed, which comprises more than 20 million citations for biomedical literature from MEDLINE and life science journals. A total of 486 publications regarding genes associated with startle have been obtained and reviewed here. There are fewer than 20 publications associating genes with the startle response between 1979, when the first valuable paper was published, and 1999. However, publications have dramatically increase from 2001 and reaches over 70 in 2009. We have characterized them into three categories: startle-associated gene studies in humans, in animals, as well as in both human and animals. This review of research strategy may provide the information for identifying a biomarker for startle response, with the objective of translating research into clinical utility: diagnosis and treatment of stress-induced mental disorders.
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PMID:Startle response related genes. 2185 31

Gene-environment interactions have an important role in the development of psychiatric disorders. To generate and validate a new substrain of rats with signs related to schizophrenia, we used selective breeding after postweaning social isolation and chronic ketamine treatment through several generations of animals and compared the subsequent strain to naive rats that were not genetically manipulated. We further investigated whether social isolation and ketamine treatment augmented the appearance of schizophrenic-like signs in these rats. Four experimental groups were studied (n=6-15 rats/group): naive rats without any treatment (NaNo); naive rats with postweaning social isolation and ketamine treatment (NaTr); 15th generation of selectively bred animals without any treatment (SelNo) or selectively bred rats with both isolation and ketamine treatment (SelTr). The startle reaction, tail-flick and novel object recognition tests were used to classify the animals into low- or high-risk for schizophrenia. Reduced pain sensitivity, higher degree of the startle reaction, disturbed prepulse inhibition, altered motor activity and decreased differentiation index in the memory test were observed in the 15th generation of the substrain, along with enhanced grooming behavior. Five functional indices (TF latency, startle reaction, prepulse inhibition, differentiation index, and grooming activity) were rated from 0 to 2, and the analysis of the summarized score revealed that the NaNo group had the lowest overall indication of schizophrenic-like signs, while the SelTr animals scored the highest, suggesting that both heritable and environmental factors were important in the generation of the behavioral alterations. We assume that further breeding after this complex treatment may lead to a valid and reliable animal model of schizophrenia.
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PMID:Characterization of gene-environment interactions by behavioral profiling of selectively bred rats: the effect of NMDA receptor inhibition and social isolation. 2319 16

Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia-related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (complex treatment). Our aim was to determine the sex-specific effects of these interventions on several processes. Sensory gating to acoustic stimulation, pain sensitivity, motor behavior, spatial learning and memory deficits on the hole-board test were assessed in the 17th generation of selectively bred Wistar rats compared to their naive counterparts with or without complex treatment. We found differences between the sexes: selectively bred males with complex treatment showed the lowest pain sensitivity; however, the results of the prepulse inhibition test indicated that female rats showed enhanced impairment of sensory gating and increased acoustic startle reaction. The cognitive performance, working and reference memory ratios were significantly decreased by selective breeding and showed sex-specific alterations, with the smallest value in male rats of the new substrain. Based on these results, the animals of the new substrain could be classified into the high-risk for schizophreniform phenotype with the highest sensitivity of males with complex treatment. Decreased cognitive performance highlighted spatial learning deficits in the selectively bred and treated rats that escalate the validity of our new and complex rat model of schizophrenia. The results indicate the same sex selectivity as observed in humans, with increased incidence of risk ratios for men to develop schizophrenia relative to women.
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PMID:Sex-specific alterations in behavioral and cognitive functions in a "three hit" animal model of schizophrenia. 2569 94


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