Behavioural and in vivo pharmacology

Contact:

PD Dr. Ute Krügel
Rudolf Boehm Institute of Pharmacology and Toxicology
Härtelstrasse 16-18
04107 Leipzig, Germany
Phone: +49-(0)341-9713007
Fax: +49-(0)341-9724609
e-mail: ute.kruegel@medizin.uni-leipzig.de

Research interests:

1. Involvement of metabotropic P2Y receptors in the mediation of cognitive processing and behavioural functions

Purines and pyrimidines are potent extracellular signals acting at cell surface receptors, at ionotropic P2X and metabotropic P2Y receptors. P2Y receptors are expressed early in the embryonic brain and are widely distributed at neurones and glia cells. By activation of different G-proteins coupled to various signal transduction pathways P2Y receptors can modulate long lasting trophic effects (e.g. cell proliferation) or pre- and postsynaptic stimulation with subsequent release of neurotransmitters or ADP/ATP itself.
Behavioural methods, microdialysis and telemetric EEG experiments at freely moving rats have shown that an endogenous extracellular tone of ADP/ATP modulates the release of dopamine and glutamate in various areas of the mesolimbic-mesocortical system. This network generates or suppresses motivation-related behaviour, a cost-benefit driven decision for food, social recognition or stimulatory drugs on the base of preceding cognitive processing of exogenous and endogenous stimuli. We investigate the regulatory features of P2Y receptor subtypes in emotional and cognitive dysfunction in rats, knockout mice and transient knock down models by siRNA of mental diseases, e.g. depression and psychomotor disturbances.

2. Behavioural conditioning of immune functions - central neurotransmission and peripheral immune regulation

The immune system can be modified via behavioural conditioning, documenting the brain’s abilities to sense immune-derived signals or immune status, to associate them with concurrently relevant exteroceptive stimuli, and to reinstate such immune responses on demand. Behavioural conditioned immunosuppressive effects in rats employing cyclsoporine A as an unconditioned stimulus are clinically relevant since they prolong heart allograft survival and attenuate allergic responses. These conditioned effects are mediated centrally via the insular cortex and the amygdala as well as on the peripheral efference via the splenic nerve, through noradrenaline and β-adrenoceptor-dependent mechanisms.
We intend to analyze the kinetics of the behavioural conditioned immunopharmacological response together with the reconditionability of the immunosuppression. In addition, the afferent pathways between the peripheral immune system and the CNS in the context of the conditioning process are in our focus. In particular, it will be analyzed, when and how the changes in the peripheral immune system are detected by the brain as well as the involvement of central neurotransmitters and/or cytokines involved in this associative learning process is investigated. These experiments will form a basis for the evaluation of whether conditioning paradigms can be utilized to complement immunomodulatory drug regimes in clinical situations.

3. Purinergic regulation of food intake – modulation of leptin-mediated anorexia

Anorexia is part of acute-phase responses to illness and may be deleterious over time. Behavioural, microdialysis and EEG investigations have shown that central receptors sensitive to extracellular ATP (P2YRs) are involved in the regulation of food intake in various brain regions. Leptin is a possible mediator of anorexia. Central leptin induces hypophagia and a decrease in extracellular basal and feeding induced dopamine, probably related to the motivation to take food in. The stimulation of P2Y1Rs abolished the impairment of leptin-induced feeding pattern mediated by an increase of dopaminergic signalling. In agreement, we found a co-localisation of the leptin receptor (ObR) on tyrosine hydroxylase-positive fibres in the NAc and on cell bodies in the VTA. By chronic food restriction, the P2YR mRNA expression was increased in the same time course as the mRNA of the leptin receptor subsequent to a drop down of plasma leptin, suggested to provide an increase the mesolimbic sensitivity directed to achieve satisfaction and reward. The investigations contribute to a better understanding of brain detection of peripheral metabolic and humoral state.

4. P2 receptors and neuronal injury

Extracellular adenosine 5'-triphosphate (ATP) is an activity-dependent signaling molecule regulating glia-glia and glia-neuron communication. The release of ATP is a widespread physiological process. Further, high excitotoxic amounts of ATP may exit cells through damaged plasma membrane in settings of inflammation, ischemia or mechanical injury. P2 receptor activation could either be a cause or a consequence of neuronal cell death/ glial activation and may result in detrimental and/or beneficial effects. Important P2 receptor-mediated neurodegenerative and neuroprotective processes and their beneficial modulation by therapeutic manipulations are in the focus. Morphological and structural changes of the injured or ischemic brain are under investigation by immunocytochemical methods or MRT. Functional consequences after cortical and subcortical trauma and after occlusion of the arteria cerebri media of rat or transgenic mice are monitored by EEG recording, by motor function and coordination and by cognitive capabilities.

The group:

Anne-Kathrin Krause (technician)

External and local collaborations:

Dr. Anton Bespalov, Abbott GmbH & Co. KG, Ludwigshafen
Dr. Raphael Doenlen, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
PD Heike Endepols, Max Planck Inst. for Neurological Research, Cologne
Dr. Alexandra Lämmer, Dept. of Neurology, University of Erlangen-Nuremberg, Nuremberg
Dr. Gustavo Pacheco-Lopez, ETH Zurich, Switzerland
PD Dr. M. Pissarek, Research Centre Juelich, Inst. of Neurosciences and Biophysics, Juelich
Prof. Dr. Manfred Schedlowski, Inst. of Medical Psychology and Behavioral Immunobiology, Essen
Dipl. hum. biol. Timo Wirth, Inst. of Medical Psychology and Behavioral Immunobiology, Essen

PD Dr. Heike Franke, Inst. of Pharmacology and Toxicology, Leipzig
Prof. Wilfried Gründer, Inst. for Medical Physics and Biophysics, Leipzig
Prof. Thomas Kahn, Dept. of Diagnostic and Interventional Radiology, Leipzig
PD Dr. R. Regenthal, Inst. for Clinical Pharmacology, Leipzig