title: The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats.
abstract: Drugs that are able to shift effort-related decision making in intact rats towards high-effort response options are largely unknown. Here, we examined the effects of two candidate drugs, MRZ-9547 and its l-enantiomer MRZ-9546 on progressive ratio (PR) responding using two different tasks, a standard PR task that involves increasing ratio requirements and a PR/chow feeding choice task in which animals can lever press for preferred food pellets under a PR schedule or approach freely available less preferred lab chow. Furthermore, we assessed the mechanisms of action of both drugs using in vitro-assay methods and in vivo-microdialysis. Results reveal that MRZ-9547 is a selective dopamine transporter (DAT) inhibitor that moderately stimulated striatal dopamine release. MRZ-9546 was a much less potent DAT inhibitor. Furthermore, MRZ-9547 dose dependently increased the tendency to work for food reinforcement both in the standard PR task and the PR/chow feeding choice task, MRZ-9546 was considerably less active. Relative to MRZ-9547, other DAT-interfering drugs had only moderate (methylphenidate) or marginal (modafinil, d-amphetamine) stimulant effects on PR responding in either task. Collectively, our data demonstrate that the DAT inhibitor MRZ-9547 can markedly stimulate PR responding and shift effort-related decision making in intact rats towards high-effort response options. An analysis of effort-related decision making in rodents could provide an animal model for motivational dysfunctions related to effort expenditure such as fatigue, e.g. in Parkinson's disease or major depression. Our findings suggest that DAT inhibitors such as MRZ-9547 could be potentially useful for treating energy-related symptoms in neurological or neuropsychiatric disorders.
authors: Institute of Biology, Department of Animal Physiology,University of Stuttgart,D-70550 Stuttgart,Germany.
authors: S
authors: S
authors: Sommer
authors: Merz Pharmaceuticals GmbH,D-60318, Frankfurt am Main,Germany.
authors: W
authors: W
authors: Danysz
authors: Merz Pharmaceuticals GmbH,D-60318, Frankfurt am Main,Germany.
authors: H
authors: H
authors: Russ
authors: Merz Pharmaceuticals GmbH,D-60318, Frankfurt am Main,Germany.
authors: B
authors: B
authors: Valastro
authors: Brains On-Line B.V.,De Mudden 16, 9747 AW Groningen,The Netherlands.
authors: G
authors: G
authors: Flik
authors: Institute of Biology, Department of Animal Physiology,University of Stuttgart,D-70550 Stuttgart,Germany.
authors: W
authors: W
authors: Hauber
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D000077408:Modafinil; D009042:Motivation / Q000187:drug effects*; D009483:Neuropsychological Tests; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D008774:Methylphenidate; D000077408:Modafinil; D003913:Dextroamphetamine; D004298:Dopamine