ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Sensorimotor gating of the startle reflex can be studied in humans and laboratory animals using measures of prepulse inhibition (PPI) of the startle reflex. PPI is reduced in patients with specific neuropsychiatric disorders and in rats after manipulation of the limbic cortex, striatum, pallidum or pontine tegmentum. Studies are rapidly identifying the neurochemical and neuroanatomical substrates regulating PPI in laboratory animals; this detailed circuit information has been used as a ‘blueprint’ to identify possible candidate substrates responsible for PPI deficits in psychiatrically disordered humans. In parallel, studies have also begun to assess the homology of pharmacological effects on PPI across species, as an initial step towards translating detailed neural circuit information from rats to humans. Despite this rapid progress, there is an increasing danger of overlooking important methodological and interpretative issues that could impact either positively or negatively on the ultimate utility of models based on measures of PPI. Some of these issues — ranging from the cross‐species methods for quantifying specific variables to the relevance of genetic drift to animal and human studies of PPI — and their implications for future studies are the focus of this review.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Behavioural sensitization to psychostimulants may develop context‐dependently in certain circumstances. Animals given a stimulant repeatedly in a test cage but not in other environments may show enhanced drug‐induced behaviour in the test cage. Conditioning mechanisms have been claimed to be responsible for these phenomena. However, several recent findings are not properly accounted for by conditioning. In addition, growing evidence supports the hypothesis that behavioural sensitization reflects neural changes induced by repeated exposure to psychostimulants (the pharmacological hypothesis). However, the pharmacological hypothesis itself fails to account for environmental influences. In this paper, we propose a hypothesis on the role of environment that is complementary to the pharmacological hypothesis. According to our hypothesis, environment does not have a causal role in the development of sensitization, but it modifies the mode of expression of the sensitized behaviour. Sensitization primarily reflects a neuroadaptive change induced by repeated exposure of the neural system to psychostimulants. However, psychostimulants are known to induce different behaviours in different environments. Therefore, repeated administration of a psychostimulant in different environments would result in augmentation of different behaviours. Our hypothesis potentially accommodates various previous observations. We briefly review the literature and present our hypothesis.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Negative or defect symptoms refer to a reduction in normal functioning. In schizophrenia, negative symptoms encompass, among others, anhedonia, flat affect, avolition and social withdrawal. These symptoms have been found to be particularly prominent in the more chronic phase of the illness and seem to be virtually insensitive to current antipsychotic treatment. This review focuses on the possibilities and limitations of animal models for the negative symptoms of schizophrenia. Following a review of the negative symptoms in schizophrenia, attention is focused on the two symptoms most often modelled in animals — anhedonia and social withdrawal. We then look at the important question of how to model schizophrenic pathology in animals. Since the exact pathology is still far from clear, most efforts have in the past concentrated on using psychotomimetic drugs such as amphetamine or phencyclidine. The recently accumulated knowledge that schizophrenia probably results from disturbances in the normal development of the brain has led to a surge of new animal models in which the long‐term consequences of early manipulations are investigated. However, so far these models have predominantly concentrated on the positive rather than the negative symptoms of schizophrenia. The last part of this review is dedicated to the question of validation of animal models for anhedonia and social withdrawal. The general conclusion is that very few models have so far been adequately tested. The lack of currently effective treatment further hampers the study of such validation.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Neurotrophic factors, such as nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety‐like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic‐like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The recent enthusiasm among clinicians for the so‐called "atypical antipsychotics" has both improved treatment for schizophrenic patients and provided a welcome stimulus for basic research on antipsychotic mechanisms. Even the newer drugs have shortcomings, and research is underway aimed at identifying novel agents with greater efficacy and safety. Much of this effort is directed towards compounds which, in addition to blocking dopamine receptors, also act on other neurotransmitter receptors such as 5‐HT2, 5‐HT1Aand α2‐adrenergic receptors. However, there is also a large amount of scientific activity seeking to discover and develop selective dopamine receptor subtype antagonists (including compounds which specifically block D3or D4receptors) or drugs that specifically target the dopamine autoreceptor. Finally, a number of drug development programmes are searching for non‐dopaminergic antipsychotics. Drugs that do not have affinity for dopamine receptors but act through neurotensin, sigma or cannabinoid CB1receptors or glutamatergic mechanisms are currently being evaluated. If any of these agents prove to have clinical efficacy this may lead to a third generation of antipsychotics. It is likely, however, that the mechanisms of action of such drugs will nevertheless imply the intimate involvement of dopaminergic pathways.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Neonatal ventral hippocampal lesions in the rat result in post‐pubertal onset of behavioural abnormalities, modelling some aspects of schizophrenia. We further assessed the behavioural effects of neonatal lesions in rats in a variety of cognitive tasks and in the prepulse inhibition (PPI) of startle response paradigm. Prepubescent, lesioned rats exhibited startle responses and PPI similar to controls whereas, at adulthood, they showed a deficit in PPI. Lesioned rats acquired both passive and active avoidance responses. However, compared to controls, they showed a deficit in passive avoidance retention and in acquisition of active avoidance responses. In a cued Morris water‐maze task, lesioned rats demonstrated adequate sensorimotor functions and appropriate motivation to escape from water. However, they were impaired in place learning and in remembering the location of a submerged platform. In conclusion, neonatal ventral hippocampal lesions result in the post‐pubertal emergence of long‐lasting deficits in sensorimotor gating and in the capacity to acquire and retain information in tests of spatial and avoidance learning. Therefore, this neurodevelopmental model of schizophrenia seems to exhibit an interesting degree of validity in possibly simulating some cognitive impairments and sensorimotor gating deficits frequently observed in psychotic patients.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Neonatal lesions of the ventral hippocampus in rats produce changes in spontaneous and pharmacologically induced dopamine‐dependent behaviors that emerge in early adulthood. Neural mechanisms underlying these changes may have implications for understanding the neurobiology of schizophrenia, putatively a neurodevelopmental disorder. In this study, we evaluated the effects of MK‐801 (dizocilpine), on automated measures of distance traveled and stereotypies in adult rats with neonatal (postnatal day 7) lesions, and tested the effects of haloperidol, clozapine and an AMPA antagonist LY293558 on the MK‐801‐induced behaviors. The lesioned rats showed significantly greater increases in motor activity after 0.05 and 0.1 mg/kg of MK‐801 than did controls. Both haloperidol (0.1 and 0.4 mg/kg) and clozapine (4 and 10 mg/kg) reduced hyperlocomotion elicited by 0.2 mg/kg MK‐801 in the ventral hippocampus (VH)‐lesioned and sham rats. Haloperidol was more potent than clozapine in decreasing MK‐801‐induced stereotypy, especially in the lesioned rats. Moreover, an AMPA antagonist normalized exaggerated MK‐801‐induced hyperolocomotion in the lesioned rats at doses that had no effect in controls. These results demonstrate that the lesioned rats are more sensitive to MK‐801 during adulthood than control rats, and that antidopaminergic drugs as well as AMPA antagonists antagonize the MK‐801‐induced behaviors. The neonatal lesion rat model may be useful to further our understanding of the interactions between dopamine and glutamate and their role in the pathophysiology of schizophrenia.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID