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)

Five vervet monkeys were administered increasing doses (4--12 mg/kg/day) of d-amphetamine over a period of 35 days. Three phases od behavioural change were discerned: phase 1 during which animals exhibited repetitive stereotyped action sequences with rapid head movements, occasional abnormal grooming, picking at the cage, hand-staring and snatching; phase 2 in which behaviour became progressively more restricted and animals became markedly unresponsive to auditory, visual and tactile stimuli; phase 3 was characterised by the abrupt development of gross over-responsiveness to environmental stimuli, ataxia and tremor. At post-mortem, by comparison with controls, amphetamine-treated monkeys showed marked depletions of the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in corpus striatum and cerebral cortex and reductions in the activities of tyrosine hydroxylase and dopa decarboxylase in striatum. Turnover of these monoamines, assessed by high-performance liquid chromatography determinations of their respective metabolites, was also reduced. These findings are interpreted as evidence of monoamine neurone destruction, most severely in the case of DA neurones. Though there was a non-significant reduction in 3H-spiperone binding (reaching almost 50% in nucleus accumbens), numbers of receptors for the monoamines nA and 5-HT were not significantly changed, and the activities of the enzymes choline acetyltransferase and glutamine decarboxylase were similar in experimental and control animals. The contrast of these findings with those seen in post-mortem brains in schizophrenia is discussed.
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PMID:Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey. 613 May 56

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

Latent inhibition (LI) of a conditioned emotional response (CER) has been proposed as a quantitative measure of selective attention. We have assessed the parallels of the pharmacology of LI in rats with the clinical pharmacology of schizophrenia. Drug and vehicle treated rats were divided into groups and preexposed 20 times to cage illumination as a CS, or not preexposed. All groups were conditioned with 2 CS-footshock pairings. The following day CER, as measured by interruption of drinking in response to CS presentation, was recorded. LI was observed as a decreased CER in preexposed relative to non-preexposed animals. LI was enhanced by haloperidol 0.3 mg/kg after 7 or 14 daily treatments, but not after a single acute dose. Haloperidol doses of 0.3 and 0.03 mg/kg enhanced LI, while doses of 0.003 and 3.0 mg/kg had no effect. Haloperidol enhancement of LI was unaffected by the coadministration of the anticholinergic agent trihexyphenidyl. Enhancement of LI is exhibited by the antipsychotic drugs fluphenazine, chlorpromazine, thiothixene, thioridazine, mesoridazine, and metoclopramide but not clozapine. The non-antipsychotic drugs pentobarbital, imipramine, chlordiazepoxide, trihexyphenidyl, and promethazine failed to enhance LI. LI exhibits striking parallels to the clinical pharmacology of schizophrenia.
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PMID:Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioral model of clinical drug action. 789 30

Chronic nicotine (NIC) pretreatment has been shown to enhance NIC-induced locomotor stimulation, an effect that seems critically dependent on activation of brain dopamine (DA) systems. In the present study the effects of chronic, intermittent NIC treatment were examined in the rat to establish whether such behavioral sensitization is associated with specific, regional changes in brain dopaminergic activity. Male rats received daily injections in their home cage with either saline (SAL) or NIC (0.5 mg/kg, s.c.) for 12 days. Twenty-four hours later, the locomotor activity of the animals subjected to NIC challenge as well as the functional responsiveness of the mesolimbocortical dopaminergic system were assessed. To this end, microdialysis experiments were performed in awake animals, measuring extracellular concentrations of DA and its metabolites in the prefrontal cortex (PFC) and the nucleus accumbens (NAC). Extracellular single cell recordings from DA neurons in the ventral tegmental area (VTA) were also performed in anesthetized animals. NIC (0.5 mg/kg, s.c.) increased all measured parameters of locomotor activity, with the exception of rearing, in SAL-pretreated animals; these effects were substantially enhanced after pretreatment with NIC. Nicotine (0.5 mg/kg, s.c.) increased DA release in both the PFC and the NAC in SAL-treated animals. Nicotine pretreatment significantly enhanced this effect in the PFC, whereas it did not affect the response in the NAC. Low doses of intravenously administered NIC dose-dependently increased burst activity, starting at 12 micrograms/kg in the SAL pretreated animals and at 6 micrograms/kg in the NIC-pretreated animals, and also dose-dependently increased firing rate in SAL as well as NIC-pretreated animals, although starting at a higher dose level, i.e., 25 micrograms/kg. These results demonstrate that behavioral sensitization after chronic NIC treatment is accompanied by an enhanced dopamine release specifically within the PFC. This phenomenon may be highly significant for the dependence-producing effects of NIC, particularly in association with major psychiatric disorder, such as schizophrenia.
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PMID:Condition-independent sensitization of locomotor stimulation and mesocortical dopamine release following chronic nicotine treatment in the rat. 886 31

Studies have reported that d-amphetamine can induce a schizophreniform psychosis in humans and can induce abnormal behaviour patterns in monkeys that resemble the psychotic symptoms observed in man. The purpose of the present study was to identify a drug administration regime that in squirrel monkeys reliably could induce such behaviours in order to use this as a model of schizophrenia. The behavioural effects of acute, subchronic and continuous administration of d-amphetamine were determined in male and female squirrel monkeys during short term separation from the colony and in the home cage. It was found that abnormal behaviours developed in both male and female subjects and that they were most evident in the home cage. The number of subjects responding was highest during continuous infusion followed by subchronic treatment. The study indicated that prolonged administration of high doses of d-amphetamine is necessary for the development of abnormal behaviours. These findings suggest that animal models of schizophrenia based on d-amphetamine should be based on chronic administration or continuous infusion of d-amphetamine instead of acute injections.
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PMID:Effects of administration regime on the psychotomimetic properties of d-amphetamine in the squirrel monkey (Saimiri sciureus). 907 85

Intracerebroventricular (i.c.v.) administration of kainic acid (KA) to rats produces neuronal loss in the hippocampus and other areas of the limbic system. The present study demonstrates that i.c.v. KA enhances the locomotor response to novelty and saline injection, as well as to amphetamine and MK-801. Sixteen to 18 days after i.c.v. administration of KA or vehicle, lesioned and control rats were placed in a novel cage, and locomotor activity and grooming were recorded for 30 min prior to and 60 min following a subcutaneous injection of saline, D-amphetamine, or MK-801. In response to the novel cage and after each injection, KA rats exhibited increased locomotor activity relative to controls. Grooming behavior was found to be elevated in the KA rats when compared to controls, but only in response to the novel cage and saline injection. The possibility that damage to the limbic system disrupts dopaminergic regulation of locomotor behavior is discussed, as well as implications for neuropathology in schizophrenia.
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PMID:Kainic acid lesions enhance locomotor responses to novelty, saline, amphetamine, and MK-801. 907 71

Isolation rearing of rat pups from weaning produces neurochemical and behavioural changes that may have relevance to the neurodevelopmental basis of neuropsychiatric disorders such as schizophrenia. Although limited, studies have begun to probe for neuroanatomical changes produced by isolation rearing. In the present study, rat pups were reared in isolation, i.e., housed one per cage, from weaning. After 8 weeks of isolation, 'isolates' were compared to their socially reared controls (housed three per cage) in two behavioural paradigms: locomotor activity in a novel open field and prepulse inhibition (PPI) of the acoustic startle response. Subsequently, all rats were sacrificed and their brains removed. The hippocampus was sectioned and analysed immunohistochemically using an antibody to the synapse-specific protein synaptophysin, to gain an estimate of the synaptic content of selected hippocampal subfields. Isolates demonstrated locomotor hyperactivity and deficits in PPI relative to socially reared controls. Analysis of synaptophysin immunoreactivity suggested that isolates had significantly reduced synaptic content in the hippocampal dentate gyrus molecular layer, with smaller, non-significant reductions in the CA1 and CA3 regions. This pattern of change may be consistent with reduced neuronal input to the dentate gyrus via the entorhinal cortex, suggesting developmental changes in hippocampal-cortical circuitry. These preliminary studies extend the characterisation of isolation rearing as a model for the investigation of neurodevelopmental diseases such as schizophrenia.
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PMID:Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats. 1019 49

Rigorous experimental design can minimize the high risk of false positives and false negatives in the behavioral phenotyping of a new transgenic or knockout mouse. Use of well established, quantitative, reproducible behavioral tasks, appropriate Ns, correct statistical methods, consideration of background genes contributed by the parental strains, and attention to litter and gender issues, will maximize meaningful comparisons of -/-, +/-, and +/+ genotypes. Strategies developed and used by our laboratory are described in this review. Preliminary observations evaluate general health and neurological reflexes. Sensory abilities and motor functions are extensively quantitated. Specific tests include observations of home cage behaviors, body weight, body temperature, appearance of the fur and whiskers, righting reflex, acoustic startle, eye blink, pupil constriction, vibrissae reflex, pinna reflex, Digiscan open field locomotion, rotarod motor coordination, hanging wire, footprint pathway, visual cliff, auditory threshold, pain threshold, and olfactory acuity. Hypothesis testing then focuses on at least three well-validated tasks within each relevant behavioral domain. Specific tests for mice are described herein for the domains of learning and memory, feeding, nociception, and behaviors relevant to discrete symptoms of human anxiety, depression, schizophrenia, and drug addiction. An example of our approach is illustrated in the behavioral phenotyping of C/EBPdelta knockout mice, which appear to be normal on general health, neurological reflexes, sensory and motor tasks, and the Morris water task, but show remarkably enhanced performance on contextual fear conditioning.
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PMID:Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. 1044 92

Presentation of a weak stimulus immediately before a startling stimulus decreases the magnitude of the resultant startle response. This phenomenon, termed prepulse inhibition (PPI), provides an operational measure of sensorimotor gating, and is deficient in schizophrenia patients. Clinically observed PPI deficits can be modeled in rodents by housing rats individually from weaning until adulthood. The developmental time course of isolation rearing-induced PPI deficits, however, is unknown. The present studies characterized the ontogeny of isolation-induced PPI deficits and hyperactivity. Separate groups of Sprague-Dawley and Lister hooded rats were either singly housed (ISO) or socially housed (SOC, groups of two to three per cage) upon weaning and then maintained in these housing conditions for different periods of time until assessment of PPI and locomotor activity; animals were tested at time points that roughly corresponded to before puberty (2 weeks postweaning), during puberty (4 weeks postweaning), or after puberty (6-7 weeks post weaning). PPI deficits were seen in Sprague-Dawley ISO rats at either the 4- or 6-, but not the 2-week time points. In contrast, hyperactivity was noted in these animals starting at the 2-week time point. Lister rats showed the same general pattern of ISO-induced effects, with ISO-induced hyperactivity (observed 4 weeks postweaning) preceding ISO-induced PPI deficits (observed 7 weeks postweaning). Therefore, ISO produces dissociable effects on PPI and locomotor activity, with PPI deficits emerging only during or after puberty. ISO might thus provide a useful noninvasive tool with which to study the neural substrates of delayed-onset sensorimotor gating abnormalities.
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PMID:Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats. 1049 57

Previous data demonstrate that a single injection of phencyclidine enhances amphetamine-induced behaviors 24 h later, suggesting that the delayed effects of a single dose of phencyclidine may produce a schizophrenia-like state in animals. These behavioral changes were accompanied by altered patterns of c-Fos induction, suggesting possible neurochemical correlates to the observed behaviors. Because investigations into PCP's ability to model schizophrenia have found that the effects of repeated, or subchronic, PCP administration differ according to the dose and administration paradigm, this study sought to determine whether single and subchronic PCP exposure produce different effects on amphetamine-induced behaviors and c-Fos induction. No differences were observed between these administration paradigms; both single and subchronic PCP exposure enhanced amphetamine-induced c-Fos in the striatum, decreased c-Fos in the prefrontal cortex, and decreased the number of cage-crossings. However, the observation that PCP pretreatment affected c-Fos induction in the same manner observed previously while having an opposite effect on amphetamine-induced behavior suggests that these behavioral and neurochemical effects are dissociated.
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PMID:The effects of phencyclidine pretreatment on amphetamine-induced behavior and c-Fos expression in the rat. 1115 Apr 88


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