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)

The effects of the antipsychotic/antidepressant drug CI-686 on apomorphine- and amphetamine-induced stereotypies, dopamine metabolism, neuroleptic binding, and serum prolactin levels were determined. CI-686 displayed profiles of activity in each of these systems that differs markedly from those of other antipsychotics. CI-686's unique preclinical profile suggests a mechanism of action other than dopamine antagonism which could have implications regarding current thinking on the pathophysiology of schizophrenia.
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PMID:Atypical antidopaminergic properties of CI-686: a potential antipsychotic agent. 4 73

Amphetamine-induced stereotyped behavior in animals is proposed as a model for schizophrenia. Chronic amphetamine administration produces stereotyped behavior and a paranoid schizophreniform syndrome in man, whereas in animals a behavioral sensitization to stereotypy is evoked. We now show that phenylethylamine (PEA), an amphetamine-like stimulant concentrated in the limbic system of human brain, produces stereotypy in rats with a behavioral sensitization when chronically administered. In comparing amphetamine-induced stereotypy with PEA-induced stereotypy, we found that the alpha-adrenergic blocking agents phentolamine and phenoxybenzamine selectively antagonize PEA stereotypy, whereas the beta-adrenergic blocking agent propranolol fails to alter significantly stereotypies evoked by PEA or amphetamine administration. Catecholamine depletion by alpha-methyl-p-tyrosine administration blocks stereotypies induced by both PEA amphetamine, whereas selective norepinephrine depletion antagonizes only PEA stereotypy; the amino acid precursors of both norepinephrine and dopamine potentiate stereotypies. Therefore, PEA-elicited stereotypy, but not amphetamine-elicited stereotypy, is dependent upon norepinephrine; the significance of this for the PEA animal model of schizophrenia is discussed.
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PMID:A new animal model for schizophrenia: interactions with adrenergic mechanisms. 20 65

We found in a representative sample of 392 first hospital admissions for schizophrenia a higher mean age at onset in females by 3.2 to 3.9 years, whereas the lifetime risk was equal for both sexes. In males the rates of onset show a steep increase reaching the maximum value in the age group 15-24 years, followed then by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease a second smaller peak is observed consistently in females within the age group 45-49 years and over. After having excluded alternative explanations for this gender differences (for example, diagnosis artefacts, sociocultural factors), we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold for schizophrenia, which is lowered again during the menopause. Alternatively we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of schizophrenia in males. We tested these hypotheses in animal models by investigating the effects of the gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. Testosterone showed no clear influence on the tested dopamine-mediated behaviour. Oestradiol caused a significant reduction on both dopamine-agonist and dopamine-antagonist induced behaviour. These effects were stronger in neonatal animals. Since oestradiol caused a 2.8-fold reduction of dopamine receptor affinity for sulpiride, we assumed that the behavioural changes caused by oestradiol were accounted for by a down-regulation of the dopaminergic system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Estradiol inhibits dopamine mediated behavior in rats--an animal model of sex-specific differences in schizophrenia]. 131 53

In a representative sample of 392 first hospital admissions for schizophrenia from a population of 1.5 million we assessed the "true" age of onset by a semi-standardized interview "IRAOS". We demonstrated that the mean age at onset of the disease is 3-4 years higher in females than in males, with the lifetime risk being exactly equal. In males, the rates of onset show a steep increase - starting from school age and reaching their maximum value in the age group 15-24 years - followed by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease, a second smaller peak is observed consistently in females within the age group 45-49 years and over. After having excluded competing explanations, we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold, which is lowered again during the menopause. Alternatively, we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of the disease in males. We tested the hypotheses in three animal models by examining the effect of gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. No clear influence by testosterone was shown. Oestradiol caused a significant reduction of both dopamine-agonist and dopamine-antagonist induced behaviour. The effects were stronger in neonatal rats. Since oestradiol caused the dopamine (DA) receptor affinity for sulpiride to be reduced by a factor of 2.8, we assumed that the behavioural changes due to oestradiol were accounted for by a down-regulation of DA receptor sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission. Evidence from an epidemiological study and from animal experiments. 165 19

Blockade of glutamatergic transmission in the striatum (using the NMDA-antagonist DL-2-amino-5-phosphonovaleric acid AP-5) was recently shown to induce stereotyped sniffing in rats. Comparable stereotyped behaviour is well known to be elicited by stimulation of dopamine activity, which since long was the basis for experimental models to check for possible antipsychotic activity of new compounds. However, whereas dopamine-induced stereotypies are antagonized only by classical neuroleptics, stereotypies induced by blockade of glutamatergic transmission are antagonized by classical as well as by atypical antipsychotics. Umespirone, a novel psychotropic which has been reported to exhibit behavioural effects predictive for antipsychotic as well as anxiolytic potential was evaluated for antagonistic effects against AP-5-induced behaviour. The profile of umespirone was compared with the profile of a non-benzodiazepine anxiolytic buspirone as well as with previously published data of neuroleptics. Umespirone like clozapine specifically antagonized AP-5-induced sniffing, i.e. did not impair spontaneous sniffing but reversed AP-5-induced excessive sniffing. In contrast, buspirone impaired spontaneous and AP-5-induced sniffing to about the same extend. These results are in accordance with the glutamate hypothesis of schizophrenia and again give evidence that umespirone should have antipsychotic potential and a very low liability to exhibit unspecific sedative action.
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PMID:Antagonism of AP-5-induced sniffing stereotypy links umespirone to atypical antipsychotics. 167 23

Schizophrenic women have been consistently found to have a later age of onset and a less severe clinical course of illness as compared with schizophrenic men. Because these differences are not explained by diagnostic artifacts or sociocultural factors, we tested the hypothesis that they are determined by the influence of the gonadal hormones testosterone and estradiol on dopaminergic (DA) neurotransmission. We used animal models in which the effects of the hormones on behavioral changes induced by the DA antagonist haloperidol (catalepsy) and by the DA agonist apomorphine (oral stereotypies, grooming and sitting behavior) were investigated in neonatal and in adult treated rats. No consistent effects of testosterone were observed. Estradiol significantly reduced the behavioral changes induced by both haloperidol and apomorphine, and this effect was more pronounced in neonatally treated animals. These results suggest a downward regulation of DA neurotransmission by estradiol, which is supported by the results of 3H-sulpiride binding determinations in brain homogenates from the same animals: estradiol caused a 2.8-fold reduction of DA receptor affinity to sulpiride. Our findings suggest that estradiol might act as a protective modulator in schizophrenia by enhancing the vulnerability threshold for psychosis through the downward regulation of DA neurotransmission. Such mechanism could explain, at least in part, the later onset and the more favorable course of schizophrenia in female patients.
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PMID:An animal model for the effects of estradiol on dopamine-mediated behavior: implications for sex differences in schizophrenia. 175 27

MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclohepten-5,10-imi ne hydrogen maleate], which blocks glutamatergic transmission at the NMDA-receptor-gated ion channel, induced stereotypies which are similar to those found after intrastriatal injections of AP-5, e.g. sniffing and locomotion. Tests in familiar or unfamiliar environment (non-stressful or stressful situation) did not qualitatively change MK-801-induced effects. Haloperidol (0.1 mg/kg, IP) delayed the onset and shortened the duration of MK-801 (0.16; 0.33 mg/kg, IP)-induced stereotypy whereas clozapine (5 mg/kg, SC) potently antagonized it. However, exact quantification of sniffing, measured in an experimental chamber designed for this purpose, revealed an antagonism by both drugs, haloperidol as well as clozapine. Stereotypy is considered to represent an animal model of schizophrenia, and the antagonism of stereotypy with classical (haloperidol) as well as with atypical (clozapine) antipsychotic drugs is in accordance with the glutamate hypothesis of schizophrenia.
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PMID:MK-801-induced stereotypy and its antagonism by neuroleptic drugs. 197 47

Based on psychopathological and clinicocatamnestic studies made in 96 patients suffering from schizophrenia associated with obsessions running mainly an attack-like course the psychopathological characteristics of obsessions were specified and their relation to other psychopathological disorders was determined. In part of cases, obsession underwent qualitative changes acquiring the character of disturbances similar to value judgements, delirium and catatonic stereotypies. The typology of obsessions associated with schizophrenia was elaborated; two types of obsessions were distinguished: obsessions with goal-oriented protection measures and obsessions with the development of disturbances superficially similar to catatonic stereotypies. Obsessions and their course were found to be related to the degree of personality changes.
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PMID:[Psychopathology and the clinical course of schizophrenia associated with obsessive disorders]. 215 31

Partial dopamine agonists showing high affinity but low efficacy at D2 receptors can act as dopaminergic "buffers," reducing dopaminergic activity when it is excessive, and promoting it when reduced. This makes them of interest as potential therapeutic agents for the treatment of both positive and negative symptoms in schizophrenia, where they should also result in fewer or less severe motor disturbances than classical neuroleptics. SDZ 208-911 and SDZ 208-912 are amino-ergolines exhibiting partial agonistic properties in the rat, where they inhibit apomorphine-induced stereotypies, are only weakly cataleptogenic, induce varying degrees of circling behavior after unilateral lesioning of the nigrostriatal pathway, and strongly suppress prolactin secretion. The least agonistically acting agent, SDZ 208-912, should be effective against positive symptoms, whereas SDZ 208-911 could be suitable for the treatment of negative symptoms. In addition to possible therapeutic effects, the clinical testing of this class of agent should help to elucidate the status of central dopaminergic function in schizophrenic psychosis.
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PMID:Partial brain dopamine D2 receptor agonists in the treatment of schizophrenia. 257 20

The relationship between amphetamine-induced stereotyped behavior and a neuroendocrine index of arousal, plasma corticosterone (CCS), was investigated. 6-Hydroxydopamine lesions of the caudate-putamen, which produced dopamine depletions of 60%, blocked stereotypy and prolonged the elevation in corticosterone associated with d-amphetamine treatment (5 mg/kg). Similar dopamine depleting lesions of the nucleus accumbens, which attenuated the locomotor, but not the stereotypic, response to AMPH did not have this effect on CCS. This pattern of results supports the hypothesis that stereotypy has a coping function which may serve to alter arousal and further suggests important differences between the nigrostriatal and mesolimbic dopamine projections in modulating the responsiveness of the neuroendocrine system. These results have implications for understanding the function of behavioral stereotypies common to a number of psychopathological conditions, including schizophrenia and childhood autism.
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PMID:Attenuation of amphetamine-stereotypy by mesostriatal dopamine depletion enhances plasma corticosterone: implications for stereotypy as a coping response. 270 84


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