Dampened Amphetamine-Stimulated Behavior and Altered Dopamine Transporter Function in the Absence of Brain GDNF
| Autor: | Jaan-Olle Andressoo, Soophie Olfat, Sara af Bjerkén, Heidi Montonen, Jaakko Kopra, Mart Saarma, Lauriina L. Porokuokka, Kärt Varendi, Anne Panhelainen, T. Petteri Piepponen |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Mice 129 Strain animal diseases Dopamine Plasma Membrane Transport Proteins Substantia nigra Reuptake Mice Random Allocation 03 medical and health sciences 0302 clinical medicine Dopamine Uptake Inhibitors Dopamine Internal medicine medicine Glial cell line-derived neurotrophic factor Animals Glial Cell Line-Derived Neurotrophic Factor Research Articles Dopamine transporter Mice Knockout biology urogenital system General Neuroscience Dopaminergic Brain 3. Good health Mice Inbred C57BL Amphetamine 030104 developmental biology Endocrinology nervous system biology.protein Psychology Neuroscience 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | The Journal of Neuroscience. 37:1581-1590 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1673-16.2016 |
| Popis: | Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases, including drug addiction and Parkinson's disease. Because of its well established dopaminotrophic effects, the therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) has been studied extensively in various disorders with disturbed dopamine homeostasis. However, the outcomes from preclinical and clinical studies vary, highlighting a need for a better understanding of the physiological role of GDNF on striatal dopaminergic function. Nevertheless, the current lack of appropriate animal models has limited this understanding. Therefore, we have generated novel mouse models to study conditionalGdnfdeletion in the CNS during embryonic development and reduction of striatal GDNF levels in adult mice via AAV-Cre delivery. We found that both of these mice have reduced amphetamine-induced locomotor response and striatal dopamine efflux. Embryonic GDNF deletion in the CNS did not affect striatal dopamine levels or dopamine release, but dopamine reuptake was increased due to increased levels of both total and synaptic membrane-associated dopamine transporters. Collectively, these results suggest that endogenous GDNF plays an important role in regulating the function of dopamine transporters in the striatum.SIGNIFICANCE STATEMENTDelivery of ectopic glial cell line-derived neurotrophic factor (GDNF) promotes the function, plasticity, and survival of midbrain dopaminergic neurons, the dysfunction of which contributes to various neurological and psychiatric diseases. However, how the deletion or reduction of GDNF in the CNS affects the function of dopaminergic neurons has remained unknown. Using conditionalGdnfknock-out mice, we found that endogenous GDNF affects striatal dopamine homeostasis and regulates amphetamine-induced behaviors by regulating the level and function of dopamine transporters. These data regarding the physiological role of GDNF are relevant in the context of neurological and neurodegenerative diseases that involve changes in dopamine transporter function. |
| Databáze: | OpenAIRE |
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