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Frauke Ohl

Publications and source records attributed to Frauke Ohl.

13 recordsLinked to original sources
PubMed2006

A pharmacological model for psychosis based on N-methyl-D-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities.

BACKGROUND: The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) in healthy humans and their ability to exacerbate psychotic symptoms in schizophrenic patients have promoted a view of schizophrenia as being related to altered glutamatergic neurotransmission. METHODS: This prompted us and others to develop animal models for psychosis based on a glutamatergic approach. Pharmacological induction of a state of impaired glutamatergic neurotransmission based on chronic, low-dose application of MK-801, a highly selective noncompetitive NMDA antagonist, revealed marked parallels between schizophrenia and our animal model. RESULTS: MK-801 altered the expression of NR1 splice variants and NR2 subunits of the NMDA receptor in a pattern partially resembling the alterations detected in schizophrenia. Ultrastructurally, the number of gamma-aminobutyric-acid (GABA)ergic parvalbumin-positive interneurons was relatively decreased, a finding which again parallels observations in post mortem brain from schizophrenic patients. As a functional consequence, local inhibition of pyramidal cells which is largely mediated by recurrent axon collaterals, originating from GABAergic interneurons, was altered. Not unexpectedly, these animals showed cognitive deficits resembling findings in schizophrenic humans. CONCLUSIONS: These convergent lines of evidence suggest that our approach has a significant potential of serving as a model of the pathobiology of several aspects of psychosis and consequently could contribute to the development of new therapeutic strategies.

Animals↗
PubMed2006

Effects of light or dark phase testing on behavioural and cognitive performance in DBA mice.

Behavioural experiments in mice are often carried out during the resting phase of these nocturnal animals. Ignoring the fact that mice are more active during the dark period, results from resting-phase testing has also been used to characterize these animals. Since the influence of the light/dark cycle on testing is likely to be a relevant factor for the analysis of behavioural results, the aim of this study was to evaluate the effects of the relative time of the day as well as light conditions during testing on behavioural and cognitive performance in inbred mice. Naïve DBA/2N (DBA) mice were tested in the modified hole board (mHB) either during the dark phase under red light or during the light phase under white light. Different behavioural dimensions and cognitive functions were evaluated in parallel. Depending on the testing conditions, the results showed significant differences in behavioural activity, with DBA mice being less inhibited during dark phase. The same experimental group made fewer memory errors in a visuo-spatial task and showed a faster habituation compared with the group tested during the dark phase. From the results we conclude that testing during the light phase induces a pronounced behavioural inhibition as well as a cognitive disruption in DBA mice, which should be taken into account when cognitively testing these animals.

Animals↗
PubMed2005

Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919).

RATIONALE: The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets. OBJECTIVE: To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model. RESULTS: Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775. CONCLUSION: NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways.

Animals↗
PubMed2005

Listening to mutant mice: a spotlight on the role of CRF/CRF receptor systems in affective disorders.

Genetically engineered mice were originally generated to delineate the role of a specific gene product in behavioral or neuroendocrine phenotypes, rather than to produce classic animal models of depression. To learn more about the neurobiological mechanisms underlying a clinical condition such as depression, it has proven worthwhile to investigate changes in behaviors characteristic of depressed humans, such as anxiety, regardless of whether or not these alterations may also occur in other disorders besides depression. The majority of patients with mood and anxiety disorders have measurable shifts in their stress hormone regulation as reflected by elevated secretion of central and peripheral stress hormones or by altered hormonal responses to neuroendocrine challenge tests. In recent years, these alterations have been increasingly translated into testable hypotheses addressing the pathogenesis of illness. Refined molecular technologies and the creation of genetically engineered mice have allowed to specifically target individual genes involved in regulation of corticotropin releasing factor (CRF) system elements (e.g. CRF and CRF-related peptides, their receptors, binding protein). Studies performed in such mice have complemented and extended our knowledge. The cumulative evidence makes a strong case implicating dysfunction of these systems in the pathogenesis of depression and leads us beyond the monoaminergic synapse in search of eagerly anticipated strategies to discover and develop better therapies for depression.

Animals↗
PubMed2005

Differences in serotonergic neurotransmission between rats displaying high or low anxiety/depression-like behaviour: effects of chronic paroxetine treatment.

Disturbances in serotonergic neurotransmission have been suggested to be closely interlinked with hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, and are likely to be involved in the pathophysiology of anxiety disorders and major depression. We therefore investigated markers of serotonergic transmission and their modulation by chronic paroxetine in rats selectively bred for high (HAB) or low (LAB) anxiety-related behaviour, both under basal conditions and in response to emotional stress. Hippocampal serotonin 1 A (5-HT1A) receptor mRNA expression was reduced in HAB rats, whereas 5-HT concentrations in hippocampal microdialysates did not differ between HAB and LAB rats under basal conditions. In the hippocampus, overall expression of serotonin transporter binding sites was increased in HAB compared with LAB rats. Exposure to emotional stress failed to increase intrahippocampal 5-HT release in HAB rats whereas LAB rats displayed a physiological, albeit small rise. Chronic paroxetine treatment markedly increased the stress-induced rise in hippocampal 5-HT in HAB, but not LAB rats. This effect may be (at least in part) related to a greater down-regulation of hippocampal serotonin transporter binding sites by paroxetine in HABs compared with LABs, while 5-HT1A receptor expression remained unaffected in this brain area. The findings indicate reduced hippocampal serotonergic transmission in HAB rats as compared with LAB rats, which is evident both at the presynaptic (5-HT release) and the postsynaptic (5-HT1A receptor) level. Chronic paroxetine enhanced the presynaptic responsivity in HAB rats, but not LAB rats, pointing to a preferential efficacy of paroxetine in rats with enhanced anxiety/depression-related behaviour.

Analysis of Variance↗
PubMed2004

Regular voluntary exercise reduces anxiety-related behaviour and impulsiveness in mice.

We embarked on a study to delineate the behavioural changes in mice after 4 weeks of voluntary exercise. As an initial behavioural characterization, we exposed the control and exercising mice to a modified hole board and an open field test. As compared to control mice, exercising animals showed clear signs of increased behavioural inhibition (e.g. a longer latency to enter unprotected areas), suggesting increased anxiety in these animals. In addition, the exercising mice were reluctant to spend time in the open field's centre during the beginning of the 30-min open field test, but compensated for this at later times. Paradoxically, the exercising animals showed more rearings on the board of the modified hole board, indicating decreased anxiety. Thus, the behavioural inhibition seen in exercising mice is likely to represent decreased stress responsiveness at the behavioural level which can also be interpreted as reduced impulsiveness. To clarify whether voluntary exercise evolves in more or less anxiety-related behaviour, we exposed animals to the elevated plus-maze and the dark-light box, two selective tests for unconditioned anxiety. Clearly, compared to the control animals, exercising mice spent significantly more time on the open arm of the plus-maze and spent double the amount of time in the light compartment of the dark-light box. Taken together, we conclude that long-term voluntary exercise appears to result in decreased anxiety-related behaviour and impulsiveness. Thus, our observations fit into the concept that regular exercise strengthens endogenous stress coping mechanisms, thereby protecting the organism against the deleterious effects of stress.

Adaptation, Psychological↗
PubMed2004

Activity patterns as a correlate for sleep-wake behaviour in mice.

Sleep-wake behaviour in mice is known to interact with various behavioural dimensions. Therefore, it is necessary to control for such dimensions when evaluating sleep in mice. The characterisation of sleep in rodents usually is based on EEG signals. Since this method demands the invasive implantation of electrodes, it cannot be integrated into general behavioural phenotyping procedures. Thus, non- or minimum-invasive methods are needed for the analysis of sleep-wake behaviour. Although physiological parameters, like for instance general locomotor activity, allow for the assessment of sleep-wake behaviour in mice, existing methods lack reliability especially in measuring stationary and three-dimensional activities. In this study, a small magnet was implanted subcutaneously near the neck muscles of mice and each movement of the magnet was registered via a sensor plate. For validation of the described method, the effects of sleep deprivation were evaluated by both the magnet and the EEG in parallel. Our results show that the data obtained via the subcutaneously implanted magnet represent a reliable and sensitive measurement of quantitative aspects of sleep-wake behaviour: spatial variation as well as stationary activities could be dissociated from sleep. Qualitative sleep characteristics were not detected. In summary, this minimum invasive method allows for the detection of quantitative alterations in sleep-wake behaviour in mice, thus, offering a useful, rapid pre-screen in animal sleep research.

Animals↗
PubMed2003

Behavioural screening in mutagenised mice--in search for novel animal models of psychiatric disorders.

Complementary to the 'gene-driven' analysis of gene function, 'phenotype-driven' approaches can be performed and may be equally important. Despite the current availability of a long list of mouse mutants, there remains an appreciable need for behavioural phenotypes in mouse models permitting to learn more about the aetiology of psychiatric disorders. This lack can be compensated by phenotype-driven ethyl-nitrosourea (ENU)-mutagenesis programs which aim at identifying novel phenotypes without any a priori assumptions, thus, representing a unique possibility to create novel animal models which approximate the underlying genetic aetiology. The power of mouse mutagenesis critically depends on the phenotyping procedures performed. In the case of ENU-mutants, behavioural phenotyping is especially challenging, as behavioural profiles have to be identified in single individuals. For high-throughput screening, approaches have been made to establish standardised screening protocols including a combination of well-validated, easy to perform behavioural tests. Different strategies are being introduced, which are used in ENU-mutagenesis screens to identify behavioural mutants representing possible endophenotypes of psychiatric diseases.

Animals↗
PubMed2003

Impact of high and low anxiety on cognitive performance in a modified hole board test in C57BL/6 and DBA/2 mice.

We investigated the interaction between behavioural dimensions and cognitive performance in the inbred mouse strains C57BL/6 and DBA/2, which have previously been found to differ in cognitive performance and emotionality. Because it has never been evaluated whether cognitive performance and emotional behaviour are interrelated in these strains, we analysed various behavioural dimensions and cognitive functions in parallel using the modified hole board test. We could show that naive BL6 and DBA mice distinctly differed in terms of anxiety-related behaviour. Principal component analysis on the phenotyping data showed that anxiety-related behaviour was described by identical parameters and was not correlated to locomotion in the two strains. During cognitive testing, DBA mice habituated faster and performed better than BL6 mice. Principal component analysis indicated a close correlation between anxiety-related behaviour and cognitive performance in DBA mice, being associated with a highly successful cognitive performance. In BL6 mice, cognition was correlated to general exploration. This correlation turned out to be less successful in performing the modified hole board test. Our findings support the idea that high anxiety may interact with specific cognitive processing, thus offering a promising animal model for future preclinical research on the interaction of anxiety and cognition.

Animals↗
PubMed2002

Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model.

The neuroendocrine and behavioral effects of chronic paroxetine treatment were investigated in two rat lines selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) emotionality. In addition to a characteristic behavioral phenotype with markedly passive stress-coping strategies, HAB rats show a hypothalamic vasopressinergic hyperdrive that is causally related to hypothalamic-pituitary-adrenocortical dysregulation as demonstrated in the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. A total of 8 weeks of chronic paroxetine treatment induced a more active coping strategy in the forced swim test in HAB rats only. In contrast, paroxetine-treated LAB rats did not change their swimming behavior. To investigate the neuroendocrine alterations linked to these behavioral changes, a combined DEX/CRH test was performed. In HAB rats, the paroxetine-induced behavioral changes towards more active coping strategies were accompanied by a normalization of the CRH-stimulated increase in corticotropin (ACTH) and corticosterone secretion. Concomitantly, the hypothalamic vasopressinergic hyperdrive was found to be reduced in HAB but not LAB rats, as indicated by a decrease in vasopressin mRNA expression, whereas vasopressin 1a receptor binding was unaffected. These findings provide the first evidence that the vasopressinergic system is likely to be critically involved in the behavioral and neuroendocrine effects of antidepressant drugs. This novel mechanism of action of paroxetine on vasopressin gene regulation renders vasopressinergic neuronal circuits a promising target for the development of more causal antidepressant treatment strategies.

Animals↗
PubMed2002

Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity.

The undesired side-effects of haloperidol treatment include a number of extrapyramidal side-effects which have been proposed to result from drug-induced damage to the basal ganglia. The drug also causes irregular movements and locomotor patterns in experimental animals. Here we show that haloperidol treatment in rats is associated with increases in the expression of p53 and the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2/Bcl-x(L)) proteins in the hippocampus and caudate putamen (CPu). In addition, haloperidol induces the DNA binding activity of the redox-sensitive nuclear factor-kappa B (NF-kappaB) and concomitantly upregulates the levels of the phosphorylated form of IkappaBalpha protein in vivo. Similar responses are observed when a mouse hippocampal cell line (HT-22) is treated with haloperidol and/or vitamin E. Interestingly, all of these biochemical effects of haloperidol are significantly attenuated when animals or cultured cells are pretreated with alpha-tocopherol (vitamin E). Consistent with this, vitamin E is demonstrated to substantially reduce the haloperidol-induced impairment of locomotor activity in rats. Collectively, the data indicate the usefulness of vitamin E as an adjunct to haloperidol treatment and provide initial clues about the underlying molecular mechanisms involved in these effects.

Animals↗
PubMed2002

Cognitive performance in rats differing in their inborn anxiety.

There is profound evidence that cognitive processes and anxiety are interrelated. To learn more about this interaction, the authors tested rats bred for either high (HABs) or low (LABs) anxiety-related behavior in a modified hole board task. This task allows parallel investigation of various cognitive processes and possibly related behavioral dimensions, both under baseline conditions and during cognitively stressful situations. The authors provide evidence that the degree of anxiety is differentially associated with enhanced performance for distinct informational processes in rats. As HABs and LABs did not differ in their anxiety-related behavior after habituation, that is, in a familiar environment during appetitive learning, the authors conclude that anxiety behavior in naive HABs may be due to differential cognitive processing.

Animals↗