Knockdown of the D2 Autoreceptor from the Ventral Tegmental Area Increases Temporal Impulsivity

Abstract

Impulsivity associated with abnormal dopamine function occurs in a variety of disorders, including addiction. Temporal impulsivity is characterized by the preference for smaller rewards sooner over larger rewards after a delay, caused by excessive discounting of future rewards. Addicts have abnormally high discounts rates and prefer the smaller rewards sooner. While impulsivity has been inversely correlated with D2 receptor availability in the midbrain, it is difficult to mechanistically link the two due to the diverse neuroanatomical localization of the receptors, which are found in multiple brain regions, neuronal subtypes, and compartments within the neurons. To test the hypothesis that Ventral Tegmental Area (VTA) D2 autoreceptor hypofunction is linked to impulsivity, we have developed a method to knockdown D2 autoreceptors from the VTA. By injecting a viral vector to deliver short interfering RNAs (shRNA) targeting the D2 receptor in rats, D2 receptor knockdown is restricted to the VTA. This leaves postsynaptic D2 intact in the nucleus accumbens, prefrontal cortex, and other corticomesolimbic structures, all which have some influence in impulsive action. Rats were trained in a delayed discounting (DD) task to assess choice impulsivity until a stable discounting curve was obtained. Rats then received bilateral VTA infusions of the D2 shRNA or a scrambled control virus. Over time the discounting curve of the VTA D2 knockdown rats shifted to the left, indicating a preference for the smaller, immediate reward, whereas the curve for control rats remained stable. Together these results demonstrate that a decrease in D2 autoreceptors enhances temporal impulsivity.