Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine.
The transcription factor DeltaFosB accumulates in substance P-dynorphin-containing striatal neurons with repeated cocaine use. Here, we show that inducible transgenic DeltaFosB overexpression in this same striatal cell type facilitates acquisition of cocaine self-administration at low-threshold doses, consistent with increased sensitivity to the pharmacological effects of the drug. Importantly, DeltaFosB also enhances the degree of effort mice will exert to maintain self-administration of higher doses on a progressive ratio schedule of reinforcement, whereas levels of cocaine intake are not altered on less demanding fixed-ratio schedules. Acquisition and extinction of behavior reinforced by food pellets is not altered in DeltaFosB-overexpressing mice, indicating that DeltaFosB does not alter the capacity to learn an instrumental response or cause response perseveration in the absence of reinforcement. These data suggest that accumulation of DeltaFosB contributes to drug addiction by increasing the incentive properties of cocaine, an effect that could increase the risk for relapse long after cocaine use ceases.
Colby
Christina R
CR
Division of Molecular Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508, USA.
Whisler
Kim
K
Steffen
Cathy
C
Nestler
Eric J
EJ
Self
David W
DW
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004334:Drug Administration Schedule; D004399:Dynorphins / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009042:Motivation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D012054:Reinforcement, Psychology; D012646:Self Administration; D013373:Substance P / Q000096:biosynthesis; D019076:Transgenes / Q000502:physiology
D016760:Proto-Oncogene Proteins c-fos; D013373:Substance P; D004399:Dynorphins; D003042:Cocaine; D004318:Doxycycline