A combination of genetic factors and early life events is thought to determine the vulnerability ... more A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997
Variability in susceptibility to diseases is a well known phenomenon that has been attributed to ... more Variability in susceptibility to diseases is a well known phenomenon that has been attributed to genetic and environmental factors. At the level of the immune system, the reactivity of two types of T helper cells (Th1 and Th2 cells) plays an important role in determining disease susceptibility. Inflammatory (autoimmune) diseases are stimulated by cytokines produced by Th1 cells. Th2 cytokines stimulate antibody production (e.g., IgE) and eosinophilia as observed in allergic reactions or during parasitic infections. We describe here that the reactivity in a Th1 or a Th2 disease model significantly differs between individual rats that show group-specific differences in reactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as well as in their behavioral responses to stress. We used two outbred lines of Wistar rats, apomorphine-susceptible rats that have a relatively hyperreactive HPA axis (APO-SUS) and apomorphine-unsusceptible rats that have a relatively hyporeactive HPA axis (...
Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depre... more Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. As individual differences exist in central serotonin neurotransmission, the impact of ATD may vary accordingly. In this experiment, we investigated the hypothesis that male serotonin transporter knockout (SERT(-/-)), rats marked by a lower SERT function, are more vulnerable to the effects of ATD in an object recognition task than male wildtype (SERT(+/+)) and heterozygous (SERT(+/-)) rats. Twelve male SERT(+/+), SERT(+/-), and SERT(-/-) rats were treated with standard dose and low-dose ATD using a gelatine-based protein-carbohydrate mixture lacking tryptophan. In the control treatment, L: -tryptophan was added to the mixture. Four hours after treatment, the rats were subjected to the object recognition task. In addition, the effects of ATD on plasma amino acid concentrations ...
The rat is one of the most important model organisms for biomedical and pharmacological research.... more The rat is one of the most important model organisms for biomedical and pharmacological research. However, the generation of novel models for studying specific aspects of human diseases largely depends on selection for specific traits using existing rat strains, thereby solely depending on naturally occurring variation. This study aims to provide the tools to manipulate the rat genome in a more directed way. We developed robust, automated, and scaleable reverse genetic methodology based on ENU (N-ethyl-N-nitrosourea)-driven target-selected mutagenesis. Optimal mutagenesis conditions have been determined in three different rat strains and a universal, rapid, and cost-effective dideoxy resequencing-based screening setup was established for mutation discovery. The effectiveness of the approach is illustrated by the identification of 120 induced mutations in a set of genes of interest, including six that result in unique rat knockout models due to the introduction of premature stop codo...
In one of his earlier papers, Lex Cools stated that the &... more In one of his earlier papers, Lex Cools stated that the 'concept of an impaired balance between the in series connected […] dopamine system, […] 5-HT system and […] noradrenaline system offers a single coherent and integrated theory of schizophrenia' (Cools, 1975). Since then, considerable attention has focused on the interaction between dopamine and 5-HT and it is now well accepted that most antipsychotics (especially the second-generation drugs) modulate both dopaminergic and serotonergic receptors. However, the vast majority of research has focused on the 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present paper, we review the literature pertaining to the 5-HT3 receptor, the only ionotropic 5-HT receptor. We discuss both the interactions between 5-HT3 receptors and dopamine, and the animal and human literature investigating the role of 5-HT3 receptors in schizophrenia. The results show that the interactions between 5-HT3 receptors and dopamine are complex, but that 5-HT3 receptors do not have a strong influence on the positive symptoms of schizophrenia. However, when added to standard antipsychotic medication, several recent studies have found that 5-HT3 receptor antagonists can induce a statistically significantly improvement in negative and cognitive symptoms. The implications of these findings in relation to animal modelling and drug development are discussed.
A combination of genetic factors and early life events is thought to determine the vulnerability ... more A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997
Variability in susceptibility to diseases is a well known phenomenon that has been attributed to ... more Variability in susceptibility to diseases is a well known phenomenon that has been attributed to genetic and environmental factors. At the level of the immune system, the reactivity of two types of T helper cells (Th1 and Th2 cells) plays an important role in determining disease susceptibility. Inflammatory (autoimmune) diseases are stimulated by cytokines produced by Th1 cells. Th2 cytokines stimulate antibody production (e.g., IgE) and eosinophilia as observed in allergic reactions or during parasitic infections. We describe here that the reactivity in a Th1 or a Th2 disease model significantly differs between individual rats that show group-specific differences in reactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as well as in their behavioral responses to stress. We used two outbred lines of Wistar rats, apomorphine-susceptible rats that have a relatively hyperreactive HPA axis (APO-SUS) and apomorphine-unsusceptible rats that have a relatively hyporeactive HPA axis (...
Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depre... more Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. As individual differences exist in central serotonin neurotransmission, the impact of ATD may vary accordingly. In this experiment, we investigated the hypothesis that male serotonin transporter knockout (SERT(-/-)), rats marked by a lower SERT function, are more vulnerable to the effects of ATD in an object recognition task than male wildtype (SERT(+/+)) and heterozygous (SERT(+/-)) rats. Twelve male SERT(+/+), SERT(+/-), and SERT(-/-) rats were treated with standard dose and low-dose ATD using a gelatine-based protein-carbohydrate mixture lacking tryptophan. In the control treatment, L: -tryptophan was added to the mixture. Four hours after treatment, the rats were subjected to the object recognition task. In addition, the effects of ATD on plasma amino acid concentrations ...
The rat is one of the most important model organisms for biomedical and pharmacological research.... more The rat is one of the most important model organisms for biomedical and pharmacological research. However, the generation of novel models for studying specific aspects of human diseases largely depends on selection for specific traits using existing rat strains, thereby solely depending on naturally occurring variation. This study aims to provide the tools to manipulate the rat genome in a more directed way. We developed robust, automated, and scaleable reverse genetic methodology based on ENU (N-ethyl-N-nitrosourea)-driven target-selected mutagenesis. Optimal mutagenesis conditions have been determined in three different rat strains and a universal, rapid, and cost-effective dideoxy resequencing-based screening setup was established for mutation discovery. The effectiveness of the approach is illustrated by the identification of 120 induced mutations in a set of genes of interest, including six that result in unique rat knockout models due to the introduction of premature stop codo...
In one of his earlier papers, Lex Cools stated that the &... more In one of his earlier papers, Lex Cools stated that the 'concept of an impaired balance between the in series connected […] dopamine system, […] 5-HT system and […] noradrenaline system offers a single coherent and integrated theory of schizophrenia' (Cools, 1975). Since then, considerable attention has focused on the interaction between dopamine and 5-HT and it is now well accepted that most antipsychotics (especially the second-generation drugs) modulate both dopaminergic and serotonergic receptors. However, the vast majority of research has focused on the 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present paper, we review the literature pertaining to the 5-HT3 receptor, the only ionotropic 5-HT receptor. We discuss both the interactions between 5-HT3 receptors and dopamine, and the animal and human literature investigating the role of 5-HT3 receptors in schizophrenia. The results show that the interactions between 5-HT3 receptors and dopamine are complex, but that 5-HT3 receptors do not have a strong influence on the positive symptoms of schizophrenia. However, when added to standard antipsychotic medication, several recent studies have found that 5-HT3 receptor antagonists can induce a statistically significantly improvement in negative and cognitive symptoms. The implications of these findings in relation to animal modelling and drug development are discussed.
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Papers by Bart Ellenbroek