Occupancy of brain dopamine d(3) receptors and drug craving: a translational approach

Manolo Mugnaini; Laura Iavarone; Palmina Cavallini; Cristiana Griffante; Beatrice Oliosi; Chiara Savoia; John Beaver; Eugenii A Rabiner; Fabrizio Micheli; Christian Heidbreder; Anne Andorn; Emilio Merlo Pich; Massimo Bani

doi:10.1038/npp.2012.171

Occupancy of brain dopamine d(3) receptors and drug craving: a translational approach

Manolo Mugnaini, Laura Iavarone, Palmina Cavallini, Cristiana Griffante, Beatrice Oliosi, Chiara Savoia, John Beaver, Eugenii A Rabiner, Fabrizio Micheli, Christian Heidbreder, Anne Andorn, Emilio Merlo Pich, Massimo Bani

NIHR Maudsley Biomedical Research Centre (BRC)

Research output: Contribution to journal › Article › peer-review

69 Citations (Scopus)

Abstract

Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.

Original language	English
Pages (from-to)	302-312
Number of pages	11
Journal	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Volume	38
Issue number	2
Early online date	12 Sept 2012
DOIs	https://doi.org/10.1038/npp.2012.171
Publication status	Published - 2013

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Mugnaini, M., Iavarone, L., Cavallini, P., Griffante, C., Oliosi, B., Savoia, C., Beaver, J., Rabiner, E. A., Micheli, F., Heidbreder, C., Andorn, A., Merlo Pich, E., & Bani, M. (2013). Occupancy of brain dopamine d(3) receptors and drug craving: a translational approach. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 38(2), 302-312. https://doi.org/10.1038/npp.2012.171

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title = "Occupancy of brain dopamine d(3) receptors and drug craving: a translational approach",

abstract = "Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.",

author = "Manolo Mugnaini and Laura Iavarone and Palmina Cavallini and Cristiana Griffante and Beatrice Oliosi and Chiara Savoia and John Beaver and Rabiner, {Eugenii A} and Fabrizio Micheli and Christian Heidbreder and Anne Andorn and {Merlo Pich}, Emilio and Massimo Bani",

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Mugnaini, M, Iavarone, L, Cavallini, P, Griffante, C, Oliosi, B, Savoia, C, Beaver, J, Rabiner, EA, Micheli, F, Heidbreder, C, Andorn, A, Merlo Pich, E & Bani, M 2013, 'Occupancy of brain dopamine d(3) receptors and drug craving: a translational approach', Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 38, no. 2, pp. 302-312. https://doi.org/10.1038/npp.2012.171

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T1 - Occupancy of brain dopamine d(3) receptors and drug craving: a translational approach

AU - Mugnaini, Manolo

AU - Iavarone, Laura

AU - Cavallini, Palmina

AU - Griffante, Cristiana

AU - Oliosi, Beatrice

AU - Savoia, Chiara

AU - Beaver, John

AU - Rabiner, Eugenii A

AU - Micheli, Fabrizio

AU - Heidbreder, Christian

AU - Andorn, Anne

AU - Merlo Pich, Emilio

AU - Bani, Massimo

PY - 2013

Y1 - 2013

N2 - Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.

AB - Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.

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DO - 10.1038/npp.2012.171

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SN - 1740-634X

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JO - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Occupancy of brain dopamine d(3) receptors and drug craving: a translational approach

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