Assessment of Addictive Behavior in Rats with Partial Knockout of the Dopamine Transporter Gene

Animals with knockout of the dopamine transporter gene (DAT-KO) display hyperdopaminergic phenotypes, including attention-deficit/hyperactivity-like behaviors. A previous behavioral analysis of heterozygous rats with partial knockout (DAT-HET) suggested increased susceptibility to addictive behaviors. The aim of this study was to investigate elements of addictive behaviors and the mechanisms underlying dopamine release in DAT-HET rats. Offspring derived from DAT-knockout breeding underwent genotyping and behavioral assessment using the marble burying test, a manipulative behavior test using nesting material, and a modified version of the Iowa Gambling Task. Feeding behavior was studied using a binge-eating model. Reinforcing properties were investigated using intracranial self-stimulation under fixed-ratio (FR) and variable-ratio (VR) schedules. Dopamine (DA) release and clearance dynamics were assessed using fast-scan cyclic voltammetry (FSCV). DAT-HET rats exhibited moderate hyperactivity, increased impulsive choice, and compulsive responses. Male DAT-HET rats also showed increased compulsive overeating compared with wild-type (WT) rats of both sexes and female DAT-HET rats. In addition, DAT-HET rats demonstrated a preference for VR self-stimulation, which resembles risk- and thrill-seeking behavior in humans. In DAT-KO rats, impaired DA clearance resulted from complete loss of dopamine transporter function. In DAT-HET rats, increased DA release amplitude was observed, and dopamine persisted longer in the extracellular space than in WT rats. These findings underscore the importance of the DAT-HET model for studying impulsivity, compulsivity, and factors underlying the predisposition to addictive behavior.