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 behavioral and biological responses to d-amphetamine have been studied extensively in patients with schizophrenia and depression, and to a lesser degree in bipolar affective disorders. Because of theories linking borderline personality disorder to those illnesses, amphetamine, 30 mg, p.o., was administered to eight borderline patients in a double-blind, placebo-controlled study and the results were compared to the responses of normal subjects under identical conditions. Amphetamine led to symptoms of psychosis in four out of eight (50%) borderline patients. No normal subject became psychotic during the procedure. Global ratings of well-being were significantly elevated in the borderline group compared to the normal group. In addition the global response was highly inversely correlated with the patient's score on the Diagnostic Interview for Borderlines. Borderline patients had a nonsignificantly decreased growth hormone response following amphetamine compared to normals. Thus, borderline patients appear to be pharmacodynamically separable from normals.
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PMID:Amphetamine response in borderline patients. 386 51

Rats with bilaterally implanted lateral hypothalamic electrodes were tested daily for self-stimulation to each side of the brain; rotation (circling behavior) was recorded concomitantly. All rats rotated in a perferred direction regardless of the side of the brain stimulated and all rats had asymmetries in self-stimulation sensitivity (threshold and rate-intensity functions) related to the direction of rotation. Amphetamine both enhanced rotation and potentiated the asymmetry in self-stimulation sensitivity. Subsequently rats were tested in a choice procedure providing concurrent access to rewarding stimulation of either side of the brain; currents were titrated such that, under baseline conditions, rats continually alternated between self-stimulating one side of the brain or the other. Amphetamine induced a robust preference for stimulation to the more sensitive side of the brain (the side having a lower threshold). The results are discussed in relation to mechanisms of drug reinforcement and to biological etiologies of schizophrenia. It is proposed that schizophrenia results from a lateralized overactivity of dopaminergic neuronal systems mediating reward and that amphetamine mimics schizophrenic symptomatology by enhancing lateralization of the same systems.
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PMID:Amphetamine enhancement of reward asymmetry. 678 52

Neonatal, bilateral lesion of the ventral hippocampus (VH) in rats recently has been proposed as a model of schizophrenia because these animals show postpubertal hypersensitivity to stress and to dopamine (DA) agonists that can be reversed by neuroleptic treatment. In search of the mechanisms of postpubertal emergence of hyperdopaminergic behavior in this model, we investigated developmental expressions of DA D1, D2, and D3 receptors in various striatal and limbic subregions of rats that had received bilateral ibotenic acid lesion of the VH at postnatal day 7 (PD7). D-Amphetamine-, apomorphine-, and stress-induced changes in locomotor activity were measured and, in accordance with previous reports, we observed an increased locomotor activity at PD56 in the hippocampal-lesioned group. The expression of DA D1, D2, and D3 receptors was then estimated in these rats by ligand autoradiography at PD41 and PD62. We observed that the levels of DA D3 receptors, as measured by tritiated 7-hydroxy-N,N-di-n-propyl-2-amino-tetralin ([3H]7-OH-DPAT) binding, are markedly reduced at PD62 in the limbic areas of lesioned rats compared with sham controls particularly in the nucleus accumbens, olfactory tubercles, and islands of Calleja. A small but significant increase in D1 receptors was also seen in the caudate-putamen of the lesioned animals at PD62, whereas no significant change in the overall expression of D2 receptors ([3H]spiperone binding) was noted. In view of the inhibitory role of D3 receptors on locomotion and, presumably, other DA-mediated behaviors, it is suggested that behavioral changes in the neonatally hippocampal-lesioned rats may be mediated by altered D3 receptor levels.
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PMID:Decreased binding of dopamine D3 receptors in limbic subregions after neonatal bilateral lesion of rat hippocampus. 860 46

The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamine-induced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [123I] (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide ([123I]IBZM). The amphetamine-induced decrease in [123I]IBZM binding potential was significantly greater in the schizophrenic group (-19.5 +/- 4.1%) compared with the control group (-7.6 +/- 2.1%). In the schizophrenic group, elevated amphetamine effect on [123I]IBZM binding potential was associated with emergence or worsening of positive psychotic symptoms. This result suggests that psychotic symptoms elicited in this experimental setting in schizophrenic patients are associated with exaggerated stimulation of dopaminergic transmission. Such an observation would be compatible with an abnormal responsiveness of dopaminergic neurons in schizophrenia.
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PMID:Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. 879 84

Our previous work demonstrated that neonatal (on postnatal day 7, PD7) excitotoxic damage of the ventral hippocampus (VH) results in delayed emergence of behaviors related to dopaminergic (DA) transmission. In this study, the developmental effects of VH lesions induced at two other ages were investigated in the rat. Ibotenic acid or artificial cerebrospinal fluid was infused into the VH of 3- (PD3) or 14- (PD14)-day-old rat pups. Amphetamine-induced (1.5 mg/kg, i.p.) locomotor activity was assessed in the sham and lesioned rats prior to (PD35) and after puberty (PD56 and PD86). Apomorphine-induced (0.75 mg/kg s.c.) stereotypic behaviors were measured on PD56. Similar VH lesions resulted in different profiles of behavioral abnormalities depending upon the age at which they were induced. The PD3 lesioned rats displayed hyperlocomotion to amphetamine only after puberty, while the PD14 lesioned rats manifest hyperlocomotion as early as 3 weeks after surgery (at PD35). Moreover, the PD3 lesioned rats tended to show more stereotypic behaviors in response to apomorphine than the sham-operated controls, while the PD14 rats had a profoundly diminished stereotypic response. The behavioral changes in the PD3 lesioned rats are reminiscent of those previously described in animals lesioned at PD7. In contrast, the deficits in the PD14 lesioned animals resemble those seen before in rats lesioned in adulthood. These results indicate that the pattern of impairments associated with the excitotoxic VH lesion varies with age at lesion, i.e. a similar pattern seems to be associated with lesions up to PD7, but not by PD14. To the extent that the neonatal VH lesion in the rat models certain phenomenological aspects of schizophrenia, including the temporal pattern of symptom onset, these results provide evidence that the model requires an early defect in limbic cortical development.
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PMID:Behavioral changes in rats with early ventral hippocampal damage vary with age at damage. 926 76

Aromatic L-amino acid decarboxylase (AADC) is rate limiting in the production of 2-phenylethylamine (2PE). AADC activity and 2PE serum concentrations have been found to be increased in schizophrenic patients. Both antipsychotic and psychotogenic drugs, including amphetamine, affect the activity and encoding mRNA levels of AADC. Amphetamine is an analogue of 2PE and has a similar physiological effect. We have looked at the effects of chronic (32 day) treatment of rats with LSD (0.12 microg/kg/day) and phencyclidine (PCP; 10 mg/kg/day) on AADC mRNA levels. Both drugs up-regulated AADC mRNA levels in striatum, nucleus accumbens, hippocampus and cerebellum by between 50% and 150%. A splicing variant of AADC, present in human brain, which lacks the 3rd exon does not appear to be present in rat brain. These results are consistent with the hypothesis that over activity of AADC leading to increased production of 2PE is involved in endogenous psychosis such as schizophrenia.
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PMID:Does phenylethylamine have a role in schizophrenia?: LSD and PCP up-regulate aromatic L-amino acid decarboxylase mRNA levels. 938 86

We have previously reported that an apparently uncomplicated Caesarean section birth produces long-term alterations in steady-state levels of dopamine in the central nervous system of the rat. In addition, adult rats that had been born by Caesarean section, either with or without acute global anoxia, showed markedly greater dopamine release from the nucleus accumbens in response to repeated stress, in comparison to vaginally born controls. The aim of the present study was to test whether these birth complications also result in long-term changes in behavior mediated by dopamine systems. For this, we investigated effects of a low dose (0.5 mg/kg) of amphetamine on activity levels in three-month-old rats that had been born vaginally (control), by rapid Caesarean section, or by Caesarean section with 15 min of global anoxia. Amphetamine induced a significantly greater increase in locomotor activity in animals born by Caesarean section or by Caesarean section+ 15 min anoxia, in comparison to the drug's effects in vaginally born controls. Behavioral responses were further analysed from video recordings of the animals' behavior. In confirmation of automated activity counts, both animals born by Caesarean section and by Caesarean section + 15 min anoxia showed a significant increase in the duration and frequency of moving and a decrease in the duration and frequency of standing, in comparison to vaginally born controls. Animals delivered by Caesarean section showed a significant increase in the duration of sniffing and a decrease in the duration and frequency of grooming when compared to vaginally born controls. Animals delivered by Caesarean section + 15 min anoxia showed a significant increase in the duration and frequency of rearing, in comparison to controls. The pattern of behavioral changes observed indicates that, as adults, animals born by Caesarean section and by Caesarean section with added global anoxia both show heightened behavioral responses to amphetamine, in comparison to vaginally born animals. These findings highlight the sensitivity of dopamine pathways to variations in birth procedure and add experimental support to epidemiological evidence implicating birth complications in the pathophysiology of disorders involving central dopaminergic neurons, such as schizophrenia.
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PMID:Birth insult increases amphetamine-induced behavioral responses in the adult rat. 975 77

Amphetamine-induced psychosis is frequently associated with a chronic, high-dose, daily pattern of amphetamine exposure. In the present study we investigate the effects of prenatal exposure to amphetamine during the development of the central noradrenergic (NA) system in adult rats. Pregnant Wistar rats were given 4 mg/kg/day of d-amphetamine (AMPH), subcutaneously, from gestational day 8 to 21. No additional drug treatment was given to the animals until the beginning of the experiments, in adult, control and prenatally amphetamine treated rats. Since we study the electrophysiology and neurochemistry of the central NA system, we investigated the electric activity of locus coeruleus (LC) norepinephrine (NE) neurons and the levels of NE on prefrontal cortex. What we found, was a decreased number of spontaneously active cells in the LC nucleus with a lower pattern of discharge whereas, the basal levels of NE in the prefrontal cortex, was greatly increased. The increased cortical NE levels, observed in the present study may account for the proposed hyperactive NA system being responsible for some psychotic symptoms observed in paranoid schizophrenia. Besides, our results concerning the permanent alteration observed in the central NA system, in rats prenatally exposed to amphetamine, raise the possibility that this animal model may be useful to further study the neurobiologic alterations underlying certain clinical features involved in some psychosis such as schizophrenia.
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PMID:Permanent alteration of central noradrenergic system by prenatally administered amphetamine. 987 28

Our objective was to determine if amphetamine improves visuospatial working memory, which is impaired in the schizophrenia spectrum and may be modulated by dopamine in prefrontal cortex. To this end, oral amphetamine (30 mg) was administered to 12 patients with schizophrenia spectrum personality disorders and 13 patients with other, nonschizophrenia-related personality disorders. Visuospatial working memory was assessed using the Dot test; a test in which subjects are asked to memorize and reproduce the position of a dot on a sheet of paper. Patients with schizophrenia spectrum personality disorders performed significantly worse than the comparison group in the placebo condition and showed significantly greater improvement after amphetamine, as compared to a nonschizophrenia-related personality disorder comparison group. Patients with greatest impairment at baseline improved most. Amphetamine tended to improve negative symptoms; whereas, positive symptoms remained unchanged. Amphetamine may improve visuospatial working memory in schizophrenia spectrum patients.
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PMID:Effects of amphetamine on visuospatial working memory performance in schizophrenia spectrum personality disorder. 1063 86

Hypofunction of prefrontal cortical regions, such as dorsolateral and orbital regions, has been suggested to contribute to the symptomatology of schizophrenia. In the rat, the medial and the lateral prefrontal cortices are considered as homologs of the primate dorsolateral and orbital prefrontal cortices, respectively. The present study investigated in rats the effects of lesions of the medial and lateral prefrontal cortices on latent inhibition, prepulse inhibition and amphetamine-induced activity. These paradigms are known to be modulated by the mesolimbic dopaminergic system, a system that has been suggested to be involved in the symptomatology of schizophrenia. Latent inhibition and prepulse inhibition are disrupted in schizophrenic patients as well as in rats treated with amphetamine. Amphetamine-induced activity was tested under dim light (low stress) and bright light (high stress) because stressful situations selectively increase mesocortical dopamine activity. Lateral prefrontal cortex lesioned animals did not differ in their behavior from control animals in any of the paradigms used in this study. Medial prefrontal cortex lesions did not affect latent inhibition but increased prepulse inhibition. In the amphetamine-induced activity experiment, prior to drug administration, open field locomotion was reduced under bright illumination for all lesion groups. After amphetamine administration, medial prefrontal cortex lesions attenuated the hyperlocomotor effect of the drug under the dim light condition and potentiated it under the bright light condition. The results indicate that medial and lateral prefrontal cortex can be functionally differentiated by their involvement in the modulation of behavior requiring mesocorticolimbic dopamine activation. The results in amphetamine induced activity suggest that the behavioral outcomes associated with medial prefrontal cortex depend on the background (stress) against which the evaluation is made. The results also support the notion that prepulse inhibition may be a better model than latent inhibition of the symptoms of schizophrenia associated with dysfunctional prefrontal activity.
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PMID:The effects of ibotenic acid lesions of the medial and lateral prefrontal cortex on latent inhibition, prepulse inhibition and amphetamine-induced hyperlocomotion. 1082 29


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