Tomas Petrasek

Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study.

Schizophrenia is a chronic and devastating illness. Exact causes of the disease remain elusive; however, neurodevelopmental changes in the brain glutamate system are recognized to play an important role. Several animal models of the disease are induced by a systemic blockade of N-methyl-d-aspartate (NMDA) receptors. This study examined the animal model of schizophrenia-like behaviours induced by acute treatment with MK-801, a non-competitive NMDA-receptor antagonist. Behavioural flexibility is an ability to adapt to the changes in environment, and schizophrenia is often accompanied by its decrease. The study tested the effect of MK-801 on behavioural flexibility in an active place avoidance task and the Morris water maze (MWM). Flexibility was tested under reversal conditions, i.e., after changing the location of the target. Each spatial task addressed different functions; continuous coordinate-frame segregation was present in the active place avoidance and precise place representation in the MWM. Results showed that reversal was altered in both tasks by MK-801 at doses of 0.10-0.15 mgkg(-1). Some impairment was observed in the active place avoidance task at 0.08 mgkg(-1). Swimming towards a visible platform was impaired only by the highest dose (0.15 mgkg(-1)). The results demonstrate that a significant impairment of behavioural flexibility accompanies this acute animal model of schizophrenia-like behaviours, and that active place avoidance had higher sensitivity for such deficits than the MWM. This suggests the usefulness of the reversal paradigm in both tasks for examining novel drugs with antipsychotic and procognitive actions.

Dopamine D2 receptors and alpha1-adrenoceptors synergistically modulate locomotion and behavior of rats in a place avoidance task

The processing of spatial information is the focus of interest for many cognitive neuroscientists. Approximately 10 years ago, a novel behavioral paradigm called active allothetic place avoidance (AAPA) was designed allowing the simultaneous assessment of locomotor and spatial behavior. The present study describes the effect of the combined treatment of Long-Evans rats with alpha1-adrenergic and D2 antagonists prazosin (1mg/kg and 2 mg/kg) and sulpiride (10 mg/kg and 30 mg/kg) on locomotion and avoidance behavior in the AAPA task. Results show that co-application of both drugs leads to disturbances in locomotion and avoidance in rats at the doses, which caused no impairments when administered independently. This finding suggests that both types of receptors act synergistically to regulate locomotion and possibly spatial behavior.

Nogo-A downregulation impairs place avoidance in the Carousel maze but not spatial memory in the Morris water maze

Nogo-A protein is an important inhibitor of axonal growth, which also regulates neuronal plasticity in the CNS. Mutations in the gene encoding Nogo-A or abnormalities in Nogo-A expression are linked to neuropsychiatric disorders such as schizophrenia. The present study assesses the impact of constitutively reduced expression of Nogo-A on place navigation in a novel transgenic rat model. Two spatial paradigms were used: (1) A battery of tests in the Carousel maze requiring continuous processing of spatial information with increasing demands for the segregation of reference frames and behavioral flexibility and (2) a delayed-matching-to-place version of the Morris water maze (MWM), which requires place navigation and is sensitive to deficits in one-trial-encoded place representation. The Carousel maze testing revealed a subtle but significant impairment in management of reference frames. Matching-to-place learning in the Morris water maze was unaffected, suggesting an intact representation of an unmarked goal. Our results show that Nogo-A deficiency leads to cognitive deficit in processing of the reference frames. Such a deficit may be the result of neuro-developmental alterations resulting from Nogo-A deficiency.

Nogo-A-deficient Transgenic Rats Show Deficits in Higher Cognitive Functions, Decreased Anxiety, and Altered Circadian Activity Patterns

Decreased levels of Nogo-A-dependent signaling have been shown to affect behavior and cognitive functions. In Nogo-A knockout and knockdown laboratory rodents, behavioral alterations were observed, possibly corresponding with human neuropsychiatric diseases of neurodevelopmental origin, particularly schizophrenia. This study offers further insight into behavioral manifestations of Nogo-A knockdown in laboratory rats, focusing on spatial and non-spatial cognition, anxiety levels, circadian rhythmicity, and activity patterns. Demonstrated is an impairment of cognitive functions and behavioral flexibility in a spatial active avoidance task, while non-spatial memory in a step-through avoidance task was spared. No signs of anhedonia, typical for schizophrenic patients, were observed in the animals. Some measures indicated lower anxiety levels in the Nogo-A-deficient group. Circadian rhythmicity in locomotor activity was preserved in the Nogo-A knockout rats and their circadian period (tau) did not differ from controls. However, daily activity patterns were slightly altered in the knockdown animals. We conclude that a reduction of Nogo-A levels induces changes in CNS development, manifested as subtle alterations in cognitive functions, emotionality, and activity patterns.

A dose–response study of the effects of pre-test administration of beta-adrenergic receptor antagonist propranolol on the learning of active place avoidance, a spatial cognition task, in rats

The involvement of various neurotransmitter receptors in the brain in the regulation of spatial behavior is a focus of interest for many cognitive neuroscientists. Active allothetic place avoidance (AAPA) task have been demonstrated to require spatial mapping and cognitive coordination and is highly dependent upon hippocampus. The present study was designed to evaluate the role of beta-adrenergic receptors in the modulation of locomotor and spatial behavior in this task. Four doses of centrally active beta-adrenergic antagonist propranolol (5, 20, 25 and 30 mg/kg) were administered intraperitoneally 30 min prior to testing in the place avoidance task. Four daily sessions were pursued, each lasting 20 min. A dose of 25 mg/kg was found to induce a deficit in spatial behavior (measured by number of entrances into the shock sector) without altering locomotion; lower doses were without effect. The highest dose (30 mg/kg) impaired both locomotion and avoidance behavior. The results suggest that beta-adrenoceptors are involved in the regulation of behavior in the place avoidance task and that it is possible to dissociate the effect of propranolol on the spatial performance and locomotion in the AAPA using dose-selection.

Synergistic effects of dopamine D2-like receptor antagonist sulpiride and beta-blocker propranolol on learning in the Carousel maze, a dry-land spatial navigation task☆

Spatial navigation attracts the attention of neuroscientists as an animal analogue of human declarative memory. The Carousel maze is a dry-land navigational paradigm, which proved to be useful in studying neurobiological substrates of learning. The task involves avoidance of a stable sector on a rotating arena and is highly dependent upon the hippocampus. The present study aims at testing hypothesis that sulpiride (a centrally-active dopamine D2-like receptor antagonist) and propranolol (a beta-blocker) impair spatial learning in the Carousel maze after combined systemic administration. These doses were previously shown to be subthreshold in this task. Results showed that both substances affected behavior and significantly potentiated their negative effects on spatial learning. This suggests central interaction of both types of receptors in influencing acquisition of this dynamic-environment task.

Behavioral Tests for Evaluation of Information Processing and Cognitive Deficits in Rodent Animal Models of Neuropsychiatric Disorders

Neuropsychiatric disorders represent a serious medical and human issue. In general, these diseases are detrimental to the quality of life and sociability of afflicted patients. Moreover, they are an immense socio-economic burden. Brain disorders are sometimes denoted as graveyards of pharmaceutical enterprises , referring to relatively a large proportion of drugs for these diseases failing to prove efficient or safe in later phases of clinical trials. Our understanding of what really happens in the central nervous system (CNS) is very limited, especially in relation to normal and pathological behaviors. This limitation also effects the research of neuropsychiatric disorders. We do not know the exact pathogenic mechanisms of numerous diseases, such as Alzheimers disease or schizophrenia, which prevents the causal treatment of many of them. The symptomatic-like treatment often yields an insufficient therapeutic outcome and in many cases, is accompanied by serious side-effects (as is the case for classical antipsychotics in refractory schizophrenic patients). In some areas of neuro-science research, we are often just beginning to understand brain-behavior relationships in health and disease.

N-Methyl-d-Aspartate Receptor – Nitric Oxide Synthase Pathway in the Cortex of Nogo-A-Deficient Rats in Relation to Brain Laterality and Schizophrenia

It has been suggested that Nogo-A, a myelin-associated protein, could play a role in the pathogenesis of schizophrenia and that Nogo-A-deficient rodents could serve as an animal model for schizophrenic symptoms. Since changes in brain laterality are typical of schizophrenia, we investigated whether Nogo-A-deficient rats showed any signs of disturbed asymmetry in cortical N-methyl-d-aspartate (NMDA) receptor–nitric oxide synthase (NOS) pathway, which is reported as dysfunctional in schizophrenia. In particular, we measured separately in the right and left hemisphere of young and old Nogo-A-deficient male rats the expression of NMDA receptor subunits (NR1, NR2A, and NR2B in the frontal cortex) and activities of NOS isoforms [neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) in the parietal cortex]. In young controls, we observed right/left asymmetry of iNOS activity and three positive correlations (between NR1 in the left and NR2B laterality, between NR2B in the right and left sides, and between NR1 in the right side and nNOS laterality). In old controls, we found bilateral decreases in NR1, an increase in NR2B in the right side, and two changes in correlations in the NR1–nNOS pathway. In young Nogo-A-deficient rats, we observed an increase in iNOS activity in the left hemisphere and two changes in correlations in NR1–nNOS and NR2A–eNOS, compared to young controls. Finally, we revealed in old Nogo-A-deficient animals, bilateral decreases in NR1 and one change in correlation between eNOS–iNOS, compared to old controls. Although some findings from schizophrenic brains did not manifest in Nogo-A-deficient rats (e.g., no alterations in NR2B), others did (e.g., alterations demonstrating accelerated aging in young but not old animals, those occurring exclusively in the right hemisphere in young and old animals and those suggesting abnormal frontoparietal cortical interactions in young animals).

Combined administration of alpha1-adrenoceptor antagonist prazosin and beta-blocker propranolol impairs spatial avoidance learning on a dry arena.

Spatial learning is a widely studied type of animal behavior often considered as a model of higher human cognitive functions. Noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. The present study aimed at studying the effects of separate or combined systemic administration of the alpha1-adrenergic antagonist prazosin (1 and 2 mg/kg) and beta-blocker propranolol (5 and 20 mg/kg) on the hippocampus-dependent learning in the active allothetic place avoidance (AAPA) task. Both centrally active drugs impaired spatial learning when administered together, exerting no effect in separate applications. Locomotion was impaired only in a combined application of higher doses of both drugs (2 mg/kg prazosin and 20 mg/kg propranolol). These results suggest an in vivo interaction between these two types of receptors in spatial navigation regulation.

A Rat Model of Alzheimer’s Disease Based on Abeta42 and Pro-oxidative Substances Exhibits Cognitive Deficit and Alterations in Glutamatergic and Cholinergic Neurotransmitter Systems

Alzheimer’s disease (AD) is one of the most serious human, medical, and socioeconomic burdens. Here we tested the hypothesis that a rat model of AD (Samaritan; Taconic Pharmaceuticals, USA) based on the application of amyloid beta42 (Abeta42) and the pro-oxidative substances ferrous sulfate heptahydrate and L-buthionine-(S, R)-sulfoximine, will exhibit cognitive deficits and disruption of the glutamatergic and cholinergic systems in the brain. Behavioral methods included the Morris water maze (MWM; long-term memory version) and the active allothetic place avoidance (AAPA) task (acquisition and reversal), testing spatial memory and different aspects of hippocampal function. Neurochemical methods included testing of the NR1/NR2A/NR2B subunits of NMDA receptors in the frontal cortex and CHT1 transporters in the hippocampus, in both cases in the right and left hemisphere separately. Our results show that Samaritan rats™ exhibit marked impairment in both the MWM and active place avoidance tasks, suggesting a deficit of spatial learning and memory. Moreover, Samaritan rats exhibited significant changes in NR2A expression and CHT1 activity compared to controls rats, mimicking the situation in patients with early stage AD. Taken together, our results corroborate the hypothesis that Samaritan rats are a promising model of AD in its early stages.