Functional coding variation in the presynaptic dopamine transporter associated with neuropsychiatric disorders drives enhanced motivation and context-dependent impulsivity in mice.
Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val. We developed DAT Val559 knock-in mice as a construct valid model of dopaminergic alterations that drive multiple clinical phenotypes, and here evaluate the impact of lifelong expression of the variant on impulsivity and motivation utilizing the 5- choice serial reaction time task (5-CSRTT) and Go/NoGo as well as tests of time estimation (peak interval analysis), reward salience (sucrose preference), and motivation (progressive ratio test). Our findings indicate that the DAT Val559 variant induces impulsivity behaviors that are dependent upon the reward context, with increased impulsive action observed when mice are required to delay responding for a reward, whereas mice are able to withhold responding if there is a probability of reward for a correct rejection. Utilizing peak interval and progressive ratio tests, we provide evidence that impulsivity is likely driven by an enhanced motivational phenotype that also may drive faster task acquisition in operant tasks. These data provide critical validation that DAT, and more generally, DA signaling perturbations can drive impulsivity that can manifest in specific contexts and not others, and may rely on motivational alterations, which may also drive increased maladaptive reward seeking.
['Davis|Gwynne L|GL|', 'Stewart|Adele|A|', 'Stanwood|Gregg D|GD|', 'Gowrishankar|Raajaram|R|', 'Hahn|Maureen K|MK|', 'Blakely|Randy D|RD|']
D000818:Animals D002755:Choice Behavior D004195:Disease Models, Animal D050483:Dopamine Plasma Membrane Transport Proteins D005518:Food Preferences D007175:Impulsive Behavior D008297:Male D001523:Mental Disorders D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009042:Motivation D009154:Mutation D012054:Reinforcement, Psychology D013395:Sucrose D013549:Sweetening Agents D014633:Valine
Dopamine transporter Motivation Impulsivity Attention-deficit hyperactivity disorder Instrumental learning Transgenic model