title: Impairment of acquisition of intravenous cocaine self-administration  by RNA-interference of dopamine D1-receptors in the nucleus  accumbens shell.
abstract: Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of c-Fos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement.
authors.affiliation: Institute of Neuroscience, National Research Council of Italy, 09124 Cagliari, Italy.
authors.forename: Augusta
authors.initials: A
authors.lastname: Pisanu
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecca
authors.forename: Valentina
authors.initials: V
authors.lastname: Valentini
authors.forename: Amine
authors.initials: A
authors.lastname: Bahi
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dreyer
authors.forename: Fabio
authors.initials: F
authors.lastname: Cacciapaglia
authors.forename: Andrea
authors.initials: A
authors.lastname: Scifo
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piras
authors.forename: Cristina
authors.initials: C
authors.lastname: Cadoni
authors.forename: Gaetano
authors.initials: G
authors.lastname: Di Chiara
mesh_terms: D061605:Administration, Intravenous; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012055:Reinforcement Schedule; D012646:Self Administration; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D017447:Receptors, Dopamine D1; D049452:Green Fluorescent Proteins; D003932:Heroin; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine