title: Social withdrawal and gambling-like profile after lentiviral manipulation of DAT expression in the rat accumbens.
abstract: Dysfunction of brain dopamine transporter (DAT) has been associated with sensation seeking and impulse-control disorders. We recently generated a new animal model by stereotaxical inoculation of lentiviral vectors, which allowed localized intra-accumbal delivery of modulators for DAT gene: GFP (green fluorescent protein) control, silencers (Sil), a regulatable enhancer (DAT+), or both (DAT+Sil). Wistar male rats were followed both for socio-emotional profiles and for propensity to seek risky, uncertain rewards. Elevated anxiety and affiliation towards an unfamiliar partner emerged in Sil rats. Interestingly, in DAT+Sil rats (and Sil rats to a lesser extent) levels of playful social interaction were markedly reduced compared to controls. These DAT+Sil rats displayed a marked 'gambling-like' profile (i.e. preference for a large/uncertain over a small/sure reward), which disappeared upon doxycycline-induced switch-off onto DAT enhancer, but consistently reappeared with doxycycline removal. MRI-guided 1H-MRS (at 4.7 T) examinations in vivo (under anaesthesia) revealed changes in the bioenergetic metabolites (phosphocreatine and total creatine) for DAT+Sil rats, indicating a functional up-regulation of dorsal striatum (Str) and conversely a down-regulation of ventral striatum (i.e. nucleus accumbens, NAc). A combined profile of (1) enhanced proneness to gambling and (2) strong social withdrawal is thus associated with altered DAT-induced balance within forebrain dopamine systems. In fact, risk of developing a gambling-prone, social-avoidant psychopathology might be associated with (1) dominant semi-automatic strategies and/or habits, developed within Str circuits, and (2) reduced NAc function, with poorer feedback adjustment on decisions by aversive experiences.
authors.affiliation: Sections of Behavioral Neuroscience and of Molecular & Cellular Imaging, Department Cell Biology & Neurosciences, Istituto Superiore di Sanità, Roma, Italy. Walter.Adriani@iss.it
authors.forename: Walter
authors.initials: W
authors.lastname: Adriani
authors.forename: Frederic
authors.initials: F
authors.lastname: Boyer
authors.forename: Damiana
authors.initials: D
authors.lastname: Leo
authors.forename: Rossella
authors.initials: R
authors.lastname: Canese
authors.forename: Franca
authors.initials: F
authors.lastname: Podo
authors.forename: Carla
authors.initials: C
authors.lastname: Perrone-Capano
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dreyer
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laviola
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D004199:Disease Vectors; D007174:Disruptive, Impulse Control, and Conduct Disorders / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005715:Gambling / Q000378:metabolism*; D016086:Lentivirus / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012918:Social Alienation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004298:Dopamine