title: Dampened Amphetamine-Stimulated Behavior and Altered Dopamine Transporter Function in the Absence of Brain GDNF.
abstract: 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.
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland, and.
authors.forename: Jaakko J
authors.identifier: 0000-0002-4872-3326
authors.initials: JJ
authors.lastname: Kopra
authors.affiliation: Institute of Biotechnology and.
authors.forename: Anne
authors.identifier: 0000-0001-5082-4006
authors.initials: A
authors.lastname: Panhelainen
authors.affiliation: Department of Integrative Medical Biology, Umeå University, Umeå 90187, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Af Bjerkén
authors.affiliation: Institute of Biotechnology and.
authors.forename: Lauriina L
authors.identifier: 0000-0002-7861-7962
authors.initials: LL
authors.lastname: Porokuokka
authors.affiliation: Institute of Biotechnology and.
authors.forename: Kärt
authors.identifier: 0000-0003-1777-5614
authors.initials: K
authors.lastname: Varendi
authors.affiliation: Institute of Biotechnology and.
authors.forename: Soophie
authors.initials: S
authors.lastname: Olfat
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland, and.
authors.forename: Heidi
authors.initials: H
authors.lastname: Montonen
authors.affiliation: Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland, and.
authors.forename: T Petteri
authors.identifier: 0000-0002-2318-1612
authors.initials: TP
authors.lastname: Piepponen
authors.affiliation: Institute of Biotechnology and.
authors.forename: Mart
authors.identifier: 0000-0001-5543-7160
authors.initials: M
authors.lastname: Saarma
authors.affiliation: Institute of Biotechnology and jaan-olle.andressoo@helsinki.fi.
authors.forename: Jaan-Olle
authors.identifier: 0000-0002-0271-3157
authors.initials: JO
authors.lastname: Andressoo
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000661:Amphetamine
keywords: GDNF; amphetamine; cyclic voltammetry; dopamine; dopamine transporter; striatum