Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Neurodevelopmental risk factors in schizophrenia

The authors review environmental and neurodevelopmental risk factors for schizophrenic disorders, with emphasis on minor physical anomalies, particularly craniofacial anomalies and dermatoglyphic variations. The high prevalence of these anomalies among schizophrenic subjects supports the neurodevelopmental theory of the etiology of schizophrenia, since they suggest either genetically or epigenetically controlled faulty embryonic development of structures of ectodermal origin like brain and skin. This may disturb neurodevelopment that in turn may cause these subjects to be at increased risk for the development of schizophrenia and related disorders. The precise confirmation of this theory, at least in some cases, will provide further understanding of these illnesses, allowing easy and inexpensive identification of subjects at risk and providing guidelines for the development of new pharmacological interventions for early treatment and even for primary prevention of the illness

Memory functions in geriatric chronic schizophrenic patients: a neuropsychological study

This study characterized memory functions in geriatric schizophrenic inpatients with a battery of memory tests sensitive to neuropsychological impairments in either temporal or frontal brain regions. In patients clinically rated as cognitively impaired (n = 24), nearly all of these measures showed deficits relative to less impaired patients (n = 25). Factor analysis found consistent correlations between the tests and their putative cortical localization. Discriminant analysis suggested the pattern of impairments was not consistent with a generalized deficit. These results introduce the possibility, to be directly tested with neuropathological study, that the severe cognitive deficits in elderly schizophrenic patients are due to dysfunctions in either the temporal or frontal regions of the cerebral cortex, with the specific type of dysfunction varying across cases

Social-Adaptive Functioning Evaluation (SAFE): A Rating Scale for Geriatric Psychiatric Patients

Geriatric chronic psychiatric inpatients often remain in a chronic psychiatric hospital because of serious deficits in adaptive life functions. Because the addi-tional complications and adaptive changes associated with aging have not been considered in previous scales, the Social-Adaptive Functioning Evaluation (SAFE) was developed. The items in the scale measure social-interpersonal, instrumental, and life skills functioning and are designed to be rated by observation, caregiver contact, and interaction with the subject if possible. Interrater and test-retest reliability were examined (ft = 60) and convergent and discriminant validity were rated against other relevant measures ( « = 50) in separate studies, with all being found adequate. Th

Verbal fluency deficits in geriatric and nongeriatric chronic schizophrenic patients

This study examined age-related differences and correlates of deficits on phonological and category fluency tasks performed by schizophrenic patients. Equal numbers (n = 41) of geriatric (age > 64) and nongeriatric chronically hospitalized schizophrenic patients were examined with tests of phonological and category fluency, verbal learning and delayed recall, confrontation naming, and reading, as well as overall estimates of cognitive impairment. Both types of fluency tests were performed very poorly by both groups. Age-related differences were found to be statistically significant. In both groups, category fluency impairments were correlated with deficits in naming, while phonological fluency deficits were best predicted by memory impairments. These data suggest that category fluency impairments are part of a general profile of impaired semantic functioning, whereas phonological fluency deficits may be induced by alterations in information processing capacity

Validity and utility of the ADAS-L for measurement of cognitive and functional impairment in geriatric schizophrenic inpatients

This study examined the usefulness of the Alzheimer's Disease Assessment Scale-Late Version (ADAS-L) for assessing cognitive and behavioral impairment in geriatric schizophrenic patients. Subjects were 339 geriatric schizophrenic inpatients. Discriminant function analyses compared the Mini-Mental State Examination (MMSE) with the ADAS-L as independent variables predicting the level of impairment on the criterion measure, the Clinical Dementia Rating. The ADAS-L surpassed the MMSE at correctly distinguishing severe to profound impairment; the MMSE was superior for identifying absent or questionable impairment. Findings provide evidence for the concurrent validity of the ADAS-L as an instrument for measuring impairment in geriatric schizophrenic inpatients

Postmortem Studies in Schizophrenia

The past decade has seen renewed interest in the neuropathology of schizophrenia. The advent of new postmortem techniques and functional imaging, along with a greater understanding of the neuropsychology of schizophrenia, have provided many new clues to the nature of the underlying brain dysfunction in this disorder. There has also been a greater understanding of the presence of severe cognitive dysfunction among many elderly persons with schizophrenia. In this article, a series of investigations are described that seek to answer basic questions about the neuropathology of schizophrenia, in particular as it pertains to cognitive impairment. The first study describes neuropathological findings in 100 consecutively autopsied persons with schizophrenia, the majority of whom had had detailed antemortem assessments. Results from this first study prompted the conclusion that schizophrenia is not characterized by classical, histologically identifiable neuropathology. Moreover, most cases of dementia in schizophrenia are probably not the result of neuropathologically identifiable dementing illnesses. The next four studies examined chemical markers that are altered in Alzheimer's disease and some other dementing conditions and have also been suggested to be abnormal in schizophrenia: choline acetyltransferase, catecholamines and indolamines, neuropeptides, and synaptic proteins. Schizophrenia cases as a group did not show a cholinergic deficit; nor did they differ from elderly comparison cases with respect to cortical catecholamines and indolamines. Among the schizophrenia cases, however, cognitive impairment was negatively correlated with choline acetyltransferase activity. Those with cognitive impairment showed evidence of cortical noradrenergic and serotonergic deficits. Neuropeptide deficits were also present in schizophrenia, but their pattern differed from that seen in Alzheimer's disease. Increased synaptic protein activity was found in the cingulate cortex of persons with schizophrenia, and this activity was correlated with schizophrenia symptoms. From this second series of studies, it was concluded that some biological measures in schizophrenia may be related to cognitive impairment (e.g., cortical amines), whereas others may be related to diagnosis (e.g., neuropeptide deficits). In addition, synaptic organization may correlate with schizophrenia symptoms