Tetrahydrobiopterin administration facilitates amphetamine-induced dopamine release and motivation in mice

H. Fanet, F. Ducrocq, M. Tournissac, A. Oummadi, A. Lo, P. Bourrassa, V. De Smedt-Peyrusse, B. Azzougen, L. Capuron, S. Layé, F. Moussa, P. Trifilieff, F. Calon, S. Vancassel
Behavioural Brain Research. 2020-02-01; 379: 112348
DOI: 10.1016/j.bbr.2019.112348

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Fanet H(1), Ducrocq F(2), Tournissac M(3), Oummadi A(2), Lo A(4), Bourrassa P(3), De Smedt-Peyrusse V(5), Azzougen B(2), Capuron L(5), Layé S(6), Moussa F(4), Trifilieff P(5), Calon F(3), Vancassel S(7).

Author information:
(1)INRA, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux, France; Université de Bordeaux, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux, France; Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada; Neurosciences Axis, Centre de Recherche du CHU de Québec-Université Laval, Quebec City, QC, Canada; OptiNutriBrain International Associated Laboratory (NurtriNeuro France-INAF Canada), Quebec City, Canada.
(2)INRA, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux, France; Université de Bordeaux, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux, France.
(3)Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada; Neurosciences Axis, Centre de Recherche du CHU de Québec-Université Laval, Quebec City, QC, Canada; OptiNutriBrain International Associated Laboratory (NurtriNeuro France-INAF Canada), Quebec City, Canada.
(4)LETIAM, Lip(Sys)2′ EA7357, IUT d’Orsay, Université Paris Sud 11, Plateau de Moulon, Orsay, France; Biochemistry and Neuropediatrics Department, Groupe Hospitalier Trousseau Laroche-Guyon, 26 Avenue du Dr Arnold Netter, Paris, France.
(5)INRA, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux, France.
(6)INRA, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux, France; OptiNutriBrain International Associated Laboratory (NurtriNeuro France-INAF Canada), Quebec City, Canada.
(7)INRA, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux, France; OptiNutriBrain International Associated Laboratory (NurtriNeuro France-INAF Canada), Quebec City, Canada. Electronic address: .

Dopamine (DA) is a critical neurotransmitter involved in motivational processes. Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis. Decreases in BH4 levels are observed in several DA-related neuropsychiatric diseases involving impairment in motivation. Yet, whether BH4 could be used to treat motivational deficits has not been comprehensively investigated. To investigate the effects of exogenous BH4 administration on the dopaminergic system and related behaviors, we acutely injected mice with BH4 (50 mg/kg). Passage of BH4 through the blood brain barrier and accumulation in brain was measured using the in situ brain perfusion technique. DA release was then recorded using in-vivo micro-dialysis and motivation was evaluated through operant conditioning paradigms in basal condition and after an amphetamine (AMPH) injection. First, we showed that BH4 crosses the blood-brain barrier and that an acute peripheral injection of BH4 is sufficient to increase the concentrations of biopterins in the brain, without
affecting BH4- and DA-related protein expression. Second, we report that this increase in BH4 enhanced AMPH-stimulated DA release in the nucleus accumbens. Finally, we found that BH4-induced DA release led to improved performance of a motivational task. Altogether, these findings suggest that BH4, through its action on the dopaminergic tone, could be used as a motivational enhancer.

Copyright © 2019 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.bbr.2019.112348
PMID: 31711897


Auteurs Bordeaux Neurocampus