The glucocorticoid receptor as a potential target to reduce cocaine abuse.
Several findings suggest that glucocorticoid hormones are involved in determining the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor. In this study, we show that the selective inactivation of the GR gene in the brains of mice profoundly flattened the dose-response function for cocaine intravenous self-administration and suppressed sensitization, two experimental procedures considered relevant models of addiction. Furthermore, administration of a GR antagonist dose-dependently reduced the motivation to self-administer cocaine. Importantly, the absence of GR did not modify the basal behavioral and molecular effects of cocaine but selectively modified the excessive response to the drug spontaneously present in certain vulnerable individuals or induced by repeated drug exposure in others. In conclusion, we provide the first genetic evidence that the GR gene can modulate cocaine abuse. This suggests that targeting GR function in the brain could provide new therapeutic strategies to treat cocaine addiction for which there is no available treatment.
Deroche-Gamonet
Véronique
V
Institut National de la Santé et de la Recherche Médicale, Unité 588, Bordeaux 33077, France.
Sillaber
Inge
I
Aouizerate
Bruno
B
Izawa
Ryozuke
R
Jaber
Mohamed
M
Ghozland
Sandy
S
Kellendonk
Christoph
C
Le Moal
Michel
M
Spanagel
Rainer
R
Schütz
Günther
G
Tronche
François
F
Piazza
Pier Vincenzo
PV
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012646:Self Administration
D006727:Hormone Antagonists; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003042:Cocaine