Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine

NEUROPHARMACOLOGY

卷:128

Article

Kopra, Jaakko¹  Villarta-Aguilera, Marian¹  Savolainen, Mari¹  Weingerl, Samo¹  Myohanen, Timo T.¹  Rannanpaa, Saara¹  Salvatore, Michael E.^2,3  Andressoo, Jaan-Olle^4,5,6  Piepponen, T. Petteri¹ 

[1] Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapy, FIN-00014 Helsinki, Finland

[2] Univ North Texas, Hlth Sci Ctr, Inst Hlth Aging, Ft Worth, TX 76107 USA

[3] Univ North Texas, Hlth Sci Ctr, Ctr Neurosci Discovery, Ft Worth, TX 76107 USA

[4] Univ Helsinki, Inst Biotechnol, FIN-00014 Helsinki, Finland

[5] Univ Helsinki, Fac Med, FIN-00014 Helsinki, Finland

[6] Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-14152 Huddinge, Sweden

关键词: Amphetamine;    Conditioned place preference;    Dopamine;    GDNF;    MEN2B;    Striatum;   

DOI  :  10.1016/j.neuropharm.2017.10.010

来源: Elsevier

【 摘 要 】

Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum. We utilized two knock-in mouse strains to delineate contributions of GDNF and Ret signaling using MEN2B mice (constitutively active GDNF receptor Ret), and GDNF hypermorphic mice (enhanced endogenous GDNF expression). The duration of amphetamine-induced CPP was greatly enhanced in MEN2B mice, but not in the GDNF hypermorphic mice. The enhanced duration of CPP was correlated with increased tyrosine hydroxylase (TH) expression and dopamine content in the ventral striatum. Together, our results suggest that downstream components of GDNF signaling, in this case Ret, may mediate persistent drug-seeking behavior through increased TH expression and dopamine levels in the mesolimbic dopamine neurons. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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