Role of orbitofrontal cortex neuronal ensembles in the expression of incubation of heroin craving.
In humans, exposure to cues previously associated with heroin use often provokes relapse after prolonged withdrawal periods. In rats, cue-induced heroin seeking progressively increases after withdrawal (incubation of heroin craving). Here, we examined the role of orbitofrontal cortex (OFC) neuronal ensembles in the enhanced response to heroin cues after prolonged withdrawal or the expression of incubation of heroin craving. We trained rats to self-administer heroin (6 h/d for 10 d) and assessed cue-induced heroin seeking in extinction tests after 1 or 14 withdrawal days. Cue-induced heroin seeking increased from 1 to 14 d and was accompanied by increased Fos expression in ∼12% of OFC neurons. Nonselective inactivation of OFC neurons with the GABA agonists baclofen + muscimol decreased cue-induced heroin seeking on withdrawal day 14 but not day 1. We then used the Daun02 inactivation procedure to assess a causal role of the minority of selectively activated Fos-expressing OFC neurons (that presumably form cue-encoding neuronal ensembles) in cue-induced heroin seeking after 14 withdrawal days. We trained c-fos-lacZ transgenic rats to self-administer heroin and 11 d later reexposed them to heroin-associated cues or novel cues for 15 min (induction day), followed by OFC Daun02 or vehicle injections 90 min later; we then tested the rats in extinction tests 3 d later. Daun02 selectively decreased cue-induced heroin seeking in rats previously reexposed to the heroin-associated cues on induction day but not in rats exposed previously to novel cues. Results suggest that heroin-cue-activated OFC neuronal ensembles contribute to the expression of incubation of heroin craving.
Behavioral Neuroscience Branch, Intramural Research Program/National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland 21224, USA.
Sanya
S
Fanous
Evan M
EM
Goldart
Florence R M
FR
Theberge
Jennifer M
JM
Bossert
Yavin
Y
Shaham
Bruce T
BT
Hope
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal; D002047:Buprenorphine / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects*; D003463:Cues; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D066298:In Vitro Techniques; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
D058786:GABA-B Receptor Agonists; C576267:N-(4''-(galactopyranosyl)-3''-nitrobenzyloxycarbonyl)daunomycin; D009292:Narcotic Antagonists; D016761:Oncogene Proteins v-fos; D009118:Muscimol; D002047:Buprenorphine; D003932:Heroin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010751:Phosphopyruvate Hydratase; D001418:Baclofen; D003630:Daunorubicin