Increased impulsive behavior and risk proneness following lentivirus-mediated dopamine transporter over-expression in rats' nucleus accumbens

Abstract

Abstract-Multiple theories have been proposed for sensation seeking and vulnerability to impulse-control disorders [Zuckerman M, Kuhlman DM (2000) Personality and risk-taking: Common biosocial factors. J Pers 68:999 -1029], and many of these rely on a dopamine system deficit. Available animal models reproduce only some behavioral symptoms and seem devoid of construct validity. We used lentivirus tools for over-expressing or silencing the dopamine transporter (DAT) and we evaluated the resulting behavioral profiles in terms of motivation and self-control. Wistar adult rats received stereotaxic inoculation of a lentivirus that allowed localized intra-accumbens delivery of a DAT gene enhancer/ silencer, or the green fluorescent protein, GFP. These animals were studied for intolerance to delay, risk proneness and novelty seeking. As expected, controls shifted their demanding from a large reward toward a small one when the delivery of the former was increasingly delayed (or uncertain). Interestingly, in the absence of general locomotor effects, DAT over-expressing rats showed increased impulsivity (i.e. a more marked shift of demanding from the large/ delayed toward the small/soon reward), and increased risk proneness (i.e. a less marked shift from the large/uncertain toward the small/sure reward), compared with controls. Rats with enhanced or silenced DAT expression did not show any significant preference for a novel environment. In summary, consistent with literature on comorbidity between attentiondeficit/hyperactivity disorder and pathological gambling, we demonstrate that DAT over-expression in rats' nucleus accumbens leads to impulsive and risk prone phenotype. Thus, a reduced dopaminergic tone following altered accumbal DAT function may subserve a sensation-seeker phenotype and the vulnerability to impulse-control disorders.

MR Imaging-Detectable Metabolic Alterations in Attention Deficit/Hyperactivity Disorder: From Preclinical to Clinical Studies

“…The behavioral and neurochemical features of each of these models, with a focus on the features that they share, have been recently reviewed by Fan et al 24 The Lenti-dopamine transporter is an innovative and promising animal model, developed through brain inoculation of selfinactivating, regulatable lentiviruses, targeting the dopamine transporter gene and protein expression. 25,26 Specifically, these animals could serve as a model for symptoms observed in cases of comorbidity between ADHD and pathologic gambling. The Lenti-dopamine transporter model was indeed analyzed in vivo by 1 H-MR spectroscopy.…”

“…An altered accumbal dopamine transporter function, resulting in a modified dopaminergic tone, may subserve a sensation-seeker phenotype and the vulnerability to impulse-control disorders. 25,26 Compared with dopamine transporter-knockout and dopamine transporter-knockdown rodents, the principal advantages of Lenti-dopamine transporter rats are localization and inducibility. Further studies on these rats will explore directly the effects of dopamine transporter-targeting drugs currently used in clinics, such as methylphenidate.…”

Lentiviral Vector-Mediated Gene Transfer and RNA Silencing Technology in Neuronal Dysfunctions

“…Adriani et al [167] tested the role of striatal dopamine function in ADHD using lentiviruses driving the expression of DAT or siRNAs targeted against DAT mRNA in the Nucleus Accumbens of rats. These tools enabled us to evaluate behavioral changes, associated with very local DAT over-expression or suppression [167].…”

Impulsivity and home-cage activity are decreased by lentivirus-mediated silencing of serotonin transporter in the rat hippocampus

“…We have recently used this approach exploiting brain inoculation of lentiviruses targeting the dopamine transporter (DAT): its overexpression in rats' nucleus accumbens leads to an impulsive and risk-prone phenotype [1,2]. Similarly, we prepared a novel vector designed to suppress the serotonin transporter (SERT) gene expression.…”