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)

Glucocorticoid hormones are important in the maintenance of many brain functions. Although their receptors are distributed abundantly throughout the brain, including the prefrontal cortex (PFC), it is not clear how glucocorticoid functions, particularly with regard to cognitive processing in the PFC. There is evidence of PFC cognitive deficits such as working memory impairment in several stress-related neuropsychiatric disorders, including depression, schizophrenia, and Parkinson's disease. Disruption of the hypothalamo-pituitary-adrenal (HPA) system, which is characterized by attenuated glucocorticoid negative feedback, is also observed. In rats, chronic stress induces working memory impairment as a result of decreased dopaminergic transmission in the PFC. These chronically stressed rats also show HPA disruption; this is caused in part by a reduced glucocorticoid response in the PFC. These findings implicate reduced glucocorticoid actions in working memory impairment. In the present study, we examined the effects of the suppression of endogenous glucocorticoids by adrenalectomy (ADX) on working memory in rats and explored the involvement of PFC dopaminergic activities in memory. The ADX impaired working memory, decreased dopamine release, and upregulated D1 receptors in the PFC. These dysfunctions were prevented by corticosterone replacement that reproduced normal physiological plasma levels, indicating that suppression of glucocorticoids causes these dysfunctions. Moreover, the ADX-induced working memory impairment was ameliorated by intra-PFC infusions of a D1 receptor agonist, SKF 81297. Thus, suppression of glucocorticoids impaired working memory through a D1 receptor-mediated hypodopaminergic mechanism in the PFC. This finding indicates that endogenous glucocorticoids are essential for maintaining PFC cognitive function and suggests that HPA disruption contributes to PFC cognitive deficits.
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PMID:Endogenous glucocorticoids are essential for maintaining prefrontal cortical cognitive function. 1520 21

Recent research shows that categorizing patients with schizophrenia based on frontal-striatal and frontal-temporal memory profiles may yield neurobiologically meaningful disease subtypes. We hypothesize that parents of patients exhibit similar memory profiles. Both parents of 36 patients with schizophrenia (N = 72) and 26 healthy married control couples (N = 52) participated in this study. All subjects were physically healthy and had no history of neurological illness or alcohol/drug abuse. The presence of a psychiatric and/or personality disorder was assessed with the Comprehensive Assessment of Symptoms and History (CASH) interview, the Schedule for Affective Disorders and Schizophrenia-lifetime (SADS-L) interview and the Structured Interview for DSM-IV Personality Disorders (SIDP-IV), respectively. Cluster analysis of selected measures from the Dutch version of the California Verbal Learning Test (CVLT) delineated parents into two subgroups with distinct memory deficits and a third subgroup without impairments. Specific frontal-striatal and frontal-temporal subgroups, however, were not found. In addition, our results indicated that mothers seem to be more protected against the negative effects of genetic liability to schizophrenia than fathers. Furthermore, relatives with a higher level of intelligence may have more cognitive reserve to compensate for the negative impact of implied brain dysfunction on verbal memory than relatives with a low level of intelligence. Although the parents of patients with schizophrenia could be delineated into subgroups with primary memory deficits, frontal-striatal and frontal-temporal subgroups could not be unambiguously identified. The association that emerged between level of intelligence, gender and severity of memory impairment deserves further exploration.
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PMID:Memory profiles in parents of patients with schizophrenia. 1545 Sep 12

The maintenance of a mental image in memory over a time scale of seconds is mediated by the persistent discharges of neurons in a distributed brain network. The representation of the spatial location of a remembered visual stimulus has been studied most extensively and provides the best-understood model of how mnemonic information is encoded in the brain. Neural correlates of spatial working memory are manifested in multiple brain areas, including the prefrontal and parietal association cortices. Spatial working memory ability is severely compromised in schizophrenia, a condition that has been linked to prefrontal cortical malfunction. Recent computational modeling work, in interplay with physiological studies of behaving monkeys, has begun to identify microcircuit properties and neural dynamics that are sufficient to generate memory-related persistent activity in a recurrent network of excitatory and inhibitory neurons during spatial working memory. This review summarizes recent results and discusses issues of current debate. It is argued that understanding collective neural dynamics in a recurrent microcircuit provides a key step in bridging the gap between network memory function and its underlying cellular mechanisms. Progress in this direction will shed fundamental insights into the neural basis of spatial working memory impairment associated with mental disorders.
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PMID:A neural circuit basis for spatial working memory. 1553 40

Clozapine is an effective antipsychotic drug, but its effects on cognitive function are unclear. Previously, we found that clozapine caused a working memory deficit, which was reversed by nicotine. Hippocampal systems are important in determining clozapine effect on memory. In the current study, the memory effects of clozapine and nicotine administration were determined in rats with lesions of the fimbria-fornix, a fiber bundle which carries cholinergic and other projections between the septum and the hippocampus. Female Sprague-Dawley rats were trained on a win-shift procedure in the radial-arm maze, in which each arm entry was rewarded once per session. Then, 13 rats received bilateral knife-cut lesions of the fimbria-fornix, while 14 rats underwent sham surgery. The rats were tested after subcutaneous injections with combinations of clozapine (0 and 1.25 mg/kg) and nicotine (0, 0.2, and 0.4 mg/kg). In sham-operated rats, clozapine caused a significant (P<0.005) working memory impairment. Fimbria-fornix lesions also caused a significant (P<0.05) memory impairment. Interestingly, clozapine had the opposite effect on working memory in the lesioned vs sham-operated rats. In contrast to its effects in controls, clozapine (1.25 mg/kg) significantly (P<0.05) attenuated the working memory deficit caused by fimbria-fornix lesions. Nicotine (0.2 mg/kg) did not quite significantly improve memory in lesioned rats. The effects of clozapine and nicotine were not additive in the lesioned rats. This study demonstrates the efficacy of clozapine in improving working memory in fimbria-fornix-lesioned rats, whereas it causes impairments in intact rats. Therapeutic treatment with clozapine in people with malfunctions of the hippocampus such as seen in schizophrenia may improve cognitive performance, whereas the same doses of clozapine may impair memory in individuals without hippocampal malfunction.
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PMID:Reversal of clozapine effects on working memory in rats with fimbria-fornix lesions. 1568 87

Patients with severe mental illness are at increased risk to commit acts of aggression in the inpatient hospital setting. Aggressive behaviors have severe negative consequences for the patient, victims, clinical staff, and the therapeutic community as a whole. While risk factors of community and inpatient aggression overlap, many predictive factors diverge between the two settings. For example, while medication noncompliance has been a robust predictor of community aggression, this factor has little predictive value for inpatient settings where patients' pharmacotherapy is closely monitored. Relatively fewer investigators have examined a wide range of predictive factors associated with aggressive acts committed on the psychiatry inpatient service, often with conflicting results. The present study examined demographic, clinical, and neurocognitive performance predictors of self, other, object, and verbal aggressiveness in 118 acute inpatients. Results revealed that the arrival status at the hospital (voluntary vs involuntary), female gender, and substance abuse diagnosis were predictors of verbal aggression and aggression against others. Impaired memory functioning also predicted object aggression. Fewer symptoms, combined with higher cognition functioning, however, were significant predictors of self-aggressive acts committed on the inpatient service. The need for relating predictors of specific types of aggressiveness in schizophrenia is discussed.
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PMID:Predictors of aggression on the psychiatric inpatient service. 1572 29

Studies of localized brain dysfunctions have revealed connections between patterns of cognitive dysfunction and specific profiles of memory impairment. The amnesic type of memory impairment is defined by deficits in both free recall and recognition memory, whereas the dysexecutive memory impairment is characterized by retrieval deficits, i.e. a disproportional impairment in free recall relative to recognition memory. The present study tests whether classifications of psychiatric patients into recall impaired only (= RO group) and Recall and Recognition impaired (= RR group) correspond to the executive type and amnesic type of memory impairment. The alternative hypothesis is that the two groups merely differ in degree of neuropsychological and psychiatric disturbance. Forty-four subjects impaired on California Verbal Learning Test (CVLT) were selected from a larger database of 103 impaired and non-impaired subjects with schizophrenia or recurrent major depression. Subjects were classified into RO and RR groups and compared on measures of memory strategy (recency effect and interference on CVLT), overall neuropsychological function (Stroop Test and WAIS-R similarity) and psychiatric symptom load (positive and negative symptoms). Repeated measures ANOVA showed no effects of group, i.e. the RR group did not perform consistently below the RO group with regard to memory strategy, neuropsychological function or psychiatric symptom load. Two out of three analyses showed group x test interaction, supporting the dissociation of distinct executive and amnesic profiles among psychiatric patients. The RO group was more susceptible to interference but had better recency score than the RR group. The RO had higher negative symptoms while the RR group had higher positive symptoms.
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PMID:Validation of distinct amnesic and executive type memory deficit in a psychiatric sample based on retrieval performance. 1576 47

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.
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PMID:Combined alpha2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat. 1585 71

Studies in schizophrenia suggest that verbal learning and memory may distinguish three subgroups of patients: an unimpaired memory profile group and two groups that have memory profiles similar to those seen in cortical and subcortical dementias. Using the Hopkins Verbal Learning Test, Revised edition (HVLT-R), this study attempted to differentiate patients into three memory profile groups and to examine the validity of these groups with respect to vocational outcomes and neuropsychological functioning. Results from this study replicated previous findings and extended them by demonstrating a link to vocational outcome. In addition, the proportion of patients in each group closely resembled that obtained in previous studies. Specifically, the relatively unimpaired memory group (42%) showed overall better memory and neuropsychological performance than the two impaired groups, the subcortical group (38%) showed impaired recall but intact recognition and deficits in visuospatial functioning, and the cortical group (20%) showed deficits in recall, recognition, and sustained attention/executive functioning. There were no clinical differences between the three groups, but both the unimpaired and subcortical groups increased the number of hours worked following a vocational rehabilitation program. Given these differences, more research is warranted to explore the effect of memory impairment subtypes on vocational outcome measures.
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PMID:The implications of memory profiles in schizophrenia on vocational and neuropsychological functioning. 1588 8

Retrieving category associates (e.g., FRUIT-ORANGE) may induce forgetting other category members (e.g., FRUIT-BANANA), a phenomenon known as retrieval-induced forgetting (RIF). We designed 2 experiments to examine the role of RIF in the associative memory impairment of schizophrenia (SZ). Subjects studied 36 category-exemplar pairs, generated from 6 categories composed of 6 members each. For half of the studied category-exemplar pairs, subjects practiced retrieval by completing word stems, followed by a delayed category-cued recall on all of the practiced and unpracticed items. Experiment 1 used unrelated category exemplars-pairs (e.g., FRUIT-ORANGE, METALS-IRON), whereas experiment 2 included related category exemplar pairs (e.g., COTTON-SHIRT, LEATHER-SKIRT). SZ showed reduced associative memory but normal RIF for unrelated categories used in experiment 1. For experiment 2, SZ showed a significant decline in associative memory for related but not unrelated category-exemplars in comparison to controls. Results suggested faulty specificity/distinctiveness for encoding and retrieval, but not abnormal RIF in the associative memory disturbance of SZ.
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PMID:Retrieval-induced forgetting in schizophrenia. 1588 11

It is hypothesized that olanzapine, an atypical antipsychotic drug, has beneficial effects on cognitive impairment and neuropathological changes in treating neurodegenerative diseases. In the present study, we investigated the effects of chronic administration of olanzapine on the spatial memory impairment and hippocampal cell death induced by the direct injection of okadaic acid (OA), a potent neurotoxin, into the rat hippocampus. After being pretreated with olanzapine (0.5 or 2 mg/kg/day, i.p.) for 2 weeks, the rats were unilaterally microinjected with OA (100 ng) into the hippocampus, and then were continuously administrated with olanzapine for an additional week The rats were trained on a spatial memory task in an eight-arm radial maze before OA administration, and tested on the same task 18 h after the last olanzapine injection. After the behavioral test, the rats were killed for Nissl staining and terminal deoxynucleutidyl transferase-mediated biotinylated UTP nick end labeling staining. OA significantly induced spatial memory impairment, and caused pyramidal cell loss in the CAI and apoptotic cell death in the hippocampus. Olanzapine significantly attenuated OA-induced spatial memory impairment and the OA-induced neuropathological changes in the hippocampus. These findings suggest that olanzapine may have therapeutic effects in treatment of cognitive impairment and neuropathological changes of schizophrenia and other neurodegenerative diseases.
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PMID:Olanzapine attenuates the okadaic acid-induced spatial memory impairment and hippocampal cell death in rats. 1588 20


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