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)

Schizophrenic patients are known to suffer from a number of information processing disturbances, including deficits in both prepulse inhibition of startle and latent inhibition. Since these behavioral phenomena can also be observed in animals, they represent an ideal starting point for developing animal models having construct validity for specific deficits observed in schizophrenia. The principal question is how to induce a condition in animals most similar to the schizophrenic deficit. In the present study, we have selected rats on the basis of their response to an open filed or to the dopaminergic agonist apomorphine, and evaluated their prepulse inhibition and latent inhibition. We used three different selection procedures (open field selection for novelty response, gnawing cage selection for apomorphine response, and pharmacogenetic selection for apomorphine response). The results show that, irrespective of the selection procedure used, rats with a high response to novelty or apomorphine susceptible (collectively called APO-SUS rats) show diminished prepulse inhibition of the acoustic startle response as compared to rats with a low response to novelty or apomorphine unsusceptible (collectively called APO-UNSUS rats). This difference was apparent only at low prepulse intensities. Moreover, these APO-SUS rats show diminished latent inhibition in a conditioned taste aversion paradigm as compared to APO-UNSUS rats. Given the fact that the pharmacogenetically bred APO-SUS rats show several central nervous, endocrinological, and immunological similarities to schizophrenic patients, they are hypothesised to represent an interesting nonpharmacological animal model for schizophrenia-prone patients.
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PMID:The behavior of APO-SUS rats in animal models with construct validity for schizophrenia. 747 11

Neonatal excitotoxic hippocampal damage in the rat results in postpubertal onset of a variety of abnormal behaviors related to excessive dopaminergic transmission in the mesolimbic/nigrostriatal system, and thus may be considered an animal model of some aspects of schizophrenia. Because sensorimotor gating is impaired in adult patients with schizophrenia and in rats with experimentally induced mesolimbic dopamine hyperactivity, the present experiments investigated the effects of neonatal (postnatal day 7, PD7) ibotenic acid (3 micrograms) lesions of the ventral hippocampus (VH) on the amplitude and prepulse inhibition (PPI) of acoustic startle in prepubertal (PD35) and postpubertal (PD56) rats. Startle was elicited using 105 and 118-dB pulses alone or preceded by 4, 8, or 16 dB above-background prepulses in rats treated with vehicle or apomorphine (APO; 0.025 or 0.1 mg/kg SC). At PD35, PPI in VH-lesioned rats did not differ significantly from these measures in sham operated rats. Apomorphine significantly increased startle amplitude and reduced PPI in both sham operated and VH-lesioned rats at PD35. At PD56, startle amplitude in VH-lesioned rats was not significantly different from controls, but PPI was reduced significantly compared to controls. Ventral hippocampus lesioned rats also exhibited an exaggerated reduction in PPI after treatment with APO. These findings provide further evidence of postpubertal impairments that may be related to increased mesolimbic dopamine transmission and receptor sensitivity in rats with neonatal hippocampal damage, and provide further support for the fidelity of this animal model of schizophrenia.
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PMID:Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. 871 Oct 62

Impaired ability to 'gate out' sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) and latent inhibition (LI). The present study investigated in rats the effects of increasing or decreasing dopamine (DA) receptor activation within the medial prefrontal cortex (mPFC) by local administration of the indirect DA receptor agonist amphetamine (AMPH; 10.0 microg/side) or the DA antagonist cis-flupenthixol (FLU; 12.0 microg/side) on PPI and LI as well as on systemic AMPH-induced activity. The effects of intra-mPFC apomorphine (APO; 10.0 microg/side) on PPI were also tested. AMPH infusions decreased systemic AMPH-induced increase in locomotor activity in the open field, whereas FLU infusion was ineffective. Both infusions had no effect on LI and PPI. However, APO infusions induced a disruption of PPI. These results provide additional evidence that the mPFC is a component of the neural circuitry mediating PPI but plays no role in LI. In addition, they show that the behavioral outcomes produced by DA receptor activation/blockade in the mPFC of the rat cannot be explained by postulating a simple reciprocal relationship between the cortical and subcortical DA systems.
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PMID:Effects of local infusions of dopaminergic drugs into the medial prefrontal cortex of rats on latent inhibition, prepulse inhibition and amphetamine induced activity. 1062 35

1. It has been hypothesized that psychotic symptoms in depression may be due to increased dopamine activity secondary to hypothalamic-pituitary-adrenal (HPA) axis overactivity. 2. To test this hypothesis, the authors examined the cortisol response to dexamethasone suppression test (DST, 1 mg orally) and multihormonal responses to apomorphine (APO, 0.75 mg s.c.)--a dopamine agonist--in 150 drug-free hospitalized patients with DSM-IV major depressive episode with psychotic features (MDEP, n=35), major depressive episode without psychotic features (MDE, n=74), or schizophrenia paranoid type (SCZ, n=41), and 27 hospitalized healthy controls (HCs). 3. MDEPs showed increased activity of the HPA system (i.e. higher post-DST cortisol levels) than HCs, SCZs and MDEs. However, there were no differences in adrenocorticotropic hormone (ACTH), cortisol, prolactin and growth hormone (GH) responses to APO between MDEPs and MDEs and HCs. On the other hand, SCZs showed lower APO-induced ACTH stimulation and a higher rate of blunted GH than HCs, MDEs and MDEPs, suggesting a functional alteration of the hypothalamic dopamine receptors in SCZs. 4. In the total sample and in each diagnostic group, DST suppressors and non-suppressors showed no differences in hormonal responses to APO. 5. These results suggest a lack of causal link between HPA axis hyperactivity and dopamine dysregulation. In contrast to schizophrenia, psychotic symptoms in depression seem not to be related to dopamine function dysregulation.
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PMID:Dopaminergic function and the cortisol response to dexamethasone in psychotic depression. 1080 Jul 44

Outgrowth of solid tumors requires blood supply to the tumor. Tumor angiogenesis is dependent on the interplay between tumor-derived angiogenic factors and stromal cells. Recently, it has been shown that the neurotransmitter dopamine is a potent inhibitor of VEGF-induced angiogenesis. Moreover, there is evidence that patients with schizophrenia have a hyperreactive dopaminergic system and are relatively protected from cancer. We hypothesized that hyperreactivity of the dopaminergic system is related to reduced angiogenesis and tumor development. Therefore, we investigated tumor growth and angiogenesis in two lines of Wistar rats with high (APO-SUS) or low (APO-UNSUS) dopaminergic reactivity. Subcutaneous implants of mammary adenocarcinoma cells (MADB106) in matrigel remained 35% smaller in APO-SUS rats than in APO-UNSUS rats (P<0.01). Moreover, APO-SUS rats developed less lung metastases after i.v. administration of MADB106 tumor cells. Furthermore, hemoglobin content (APO-SUS: 40.6+/-7.6; APO-UNSUS: 76.9+/-13 mg/dl, P<0.05) and expression of the endothelial determinant PECAM-1 in tumors from APO-SUS rats were reduced (APO-SUS: 37+/-18; APO-UNSUS 69+/-25 units, P<0.01), indicating that reduced angiogenesis is responsible for reduced tumor development in APO-SUS rats. These results suggest a novel link between dopaminergic reactivity, angiogenesis, and tumor development and may explain part of the individual differences in cancer progression.
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PMID:Reduced tumor growth, experimental metastasis formation, and angiogenesis in rats with a hyperreactive dopaminergic system. 1220 50

Many years ago we found a bimodal distribution of a number of different behaviors in our regular outbred Wistar stock. This was observed in the response to novelty, the response in a resident-intruder test as well as in the stereotypy response to the dopamine agonist apomorphine. On the basis of that, we decided to selectively breed these animals, which resulted in the the APO-SUS and APO-UNSUS lines. The APO-SUS rats show a strong, stereotyped gnawing response, whereas APO-UNSUS show only a weak gnawing response. Follow-up studies have shown that the phenotypical expression of these rats depend on genetic and early and late environmental factors. Because these rats were not selected on the basis of a specific behavioral trait, but rather on the basis of a difference in susceptibility for a specific neurotransmitter, it is not surprising that these animals show major differences in the neurochemical state of the central nervous system. In fact, in many respects they represent mirror images of each other. Moreover, these animals show clear differences in their endocrine and immunological systems. APO-SUS rats can be characterized as having a hyper-reactive hypothalamus-pituitary-adrenal axis, and a dominance of the T(H2) system. Apart from discussing the main differences between APO-SUS and APO-UNSUS rats, the review specifically focuses on the former as a potential model for schizophrenia. We have been able to show that APO-SUS rats indeed share a large number of behavioral, neurochemical, endocrinological, and immunological similarities with patients suffering from schizophrenia. Because schizophrenia is also likely to result from an interaction between genetic and early stressful life events, the APO-SUS rat might represent a promising animal model for studying this severe mental disorder.
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PMID:Apomorphine susceptibility and animal models for psychopathology: genes and environment. 1240 16

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in Harlan Sprague-Dawley (SDH) vs Wistar (WH) rats. In the present study, we assessed the inheritance pattern of this phenotypic difference. Sensitivity to the PPI-disruptive effects of apomorphine was compared across parental SDH and WH strains, offspring (F1) of an SDH x WH cross, and subsequent offspring (N2) of an SDH x F1 cross. Apomorphine sensitivity followed a gradient of SDH>N2>F1>WH. Parental SDH and WH strains exhibited comparable sensitivity to the PPI-disruptive effects of phencyclidine. The nature of this gradient of APO sensitivity suggests relatively simple additive effects of multiple genes on the phenotype of PPI sensitivity.
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PMID:Sensitivity to sensorimotor gating-disruptive effects of apomorphine in two outbred parental rat strains and their F1 and N2 progeny. 1258 75

Epidemiological studies have reported that the risk of developing schizophrenia increases with the number of genes one shares with patients suffering from schizophrenia [Gottesman Schizophrenia Genesis, New York: Freeman; 1991]. In addition, stressful life events are known to increase the risk of developing schizophrenia [Schizophr Res 30 (1998) 251] resulting in the stress hypothesis of schizophrenia. Remarkably, stress increases the release of dopamine and noradrenaline in the nucleus accumbens [Brain Res 554 (1991) 217], which links the stress hypothesis with the known dopamine hypothesis of schizophrenia. Additionally an increased dopamine transmission in the nucleus accumbens (Nacc) is known to disturb prepulse inhibition (ppi) [Pharmacol Biochem Behav 49 (1994) 155], a phenomenon observed in, among others, schizophrenics [Arch Gen Psychiatry 47 (1990) 181]. Some years ago we have genetically selected two rat-lines which are marked by a high (APO-SUS) and by a low (APO-UNSUS) apomorphine susceptibility. Similar to schizophrenics the APO-SUS rat-line shows a reduced ppi [J Neurosci 15 (1995) 7604]. However, these data were obtained after a period of mild stress, namely a 24-h period of social isolation. Mild stress changes the line specific differences of APO-SUS and APO-UNSUS rats. The stress pushes the APO-SUS rat in the direction of an APO-UNSUS and vice versa, especially as far as it concerns the dopamine and noradrenaline activity in the nucleus accumbens [Cools AR, van-den Bos R, Ellenbroek BA, Gaiting function of noradrenaline in the ventral striatum: its role in behavioural responses to environmental and pharmacological challenges. In: Willner P, Scheel-Kruger J, editors. The mesolimbic dopamine system: from motivation to action. New York: Wiley; 1991 [Chapter 6]; Cools AR, Rots NY, De-Kloet ER, Apomorphine-susceptible and apomorphine-unsusceptible Wistar rats: a new tool in the search for the function of striatum in switching behavioural strategies. In: Pea G (Ed.), The basal ganglia IV, New York: Plenum Press; 1994; Brain Res Bull 24 (1990) 49; Behav Neurosci 108 (1994) 1107]. Therefore, in the present paper we investigated the ppi response in non-stressed, i.e. non-isolated APO-SUS and APO-UNSUS rats. In agreement with this hypothesis, we found that removal of the stress led to an increase of ppi in the APO-SUS, but a decrease in the APO-UNSUS. These data clearly shows that the ppi is stress-dependent in APO-SUS and APO-UNSUS rats. It is suggested that the differential stress-induced change in the dopaminergic and the noradrenergic system influences the reaction of APO-SUS and APO-UNSUS rats on ppi.
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PMID:Removal of short-term isolation stress differentially influences prepulse inhibition in APO-SUS and APO-UNSUS rats. 1274 53

Prior exposure to the psychotomimetic drug phencyclidine (PCP) produces a number of schizophrenia-like behaviors in animals. The goal of the present study was to determine whether prior exposure to PCP produces decreased reward function, thereby modeling one aspect of negative schizophrenic symptomatology. To this aim, the consequences of prior exposure to PCP were assessed on two types of appetitive consumptive behavior. In the first set of experiments, the effects of PCP (15 mg/kg, 20 h before testing) on sucrose consumption were tested for three consecutive days under conditions of deprivation and nondeprivation. In the deprivation condition, animals were water deprived for 4 h prior to injection of PCP or saline (SAL). Twenty hours following the injection (24 h after the onset of water deprivation), animals were allowed access to either 5% sucrose or water for 30 min. In the nondeprivation condition, 5% sucrose consumption was measured for 30 min, 20 h after PCP or SAL injection and water consumption was measured during the 23.5 h preceding sucrose consumption. PCP decreased both sucrose and water consumption under deprivation conditions on the second and third day of testing but selectively decreased sucrose consumption under nondeprivation conditions on all three testing days. LiCl (50 mg/kg, 20 h before testing) did not significantly reduce sucrose consumption in the nondeprivation paradigm, indicating that the effect of PCP was not due to conditioned taste aversion. In the second experiment, PCP (15 mg/kg, 20 h before testing) decreased operant performance when animals were switched from a continuous reinforcement schedule of food delivery to a fixed ratio (FR4) schedule. Apomorphine (APO, 30 microg/kg, 30 min before testing), a positive control, induced a similar performance deficit. However, the PCP-induced deficit was not apparent until the third day of FR4 testing while the APO deficit was apparent on the first day. The effects of PCP on sucrose consumption demonstrate PCP-induced decreases in reward function. However, the delayed appearance of the PCP-induced decrease in operant performance suggests that these results may be better explained by a PCP-induced attentional deficit, also characteristic of schizophrenic psychopathology.
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PMID:Prior exposure to phencyclidine decreases voluntary sucrose consumption and operant performance for food reward. 1464 37

A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a reduced expression of Aph-1b, a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. The reduced expression is due to a duplicon-based genomic rearrangement event resulting in an Aph-1b dosage imbalance. The expression levels of the other gamma-secretase components were not affected. However, gamma-secretase cleavage activity was significantly changed, and the APO-SUS/-UNSUS Aph-1b genotypes segregated with a number of behavioral phenotypes. Thus, a subtle imbalance in the expression of a single, developmentally important protein may be sufficient to cause a complex phenotype.
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PMID:Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders. 1572 Dec 36


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