Motivational effects on interval timing in dopamine transporter (DAT) knockdown mice.

We examined interval timing in mice that underexpress the dopamine transporter (DAT) and have chronically higher levels of extracellular dopamine (Zhuang et al., 2001). The dopaminergic system has been proposed as a neural substrate for an internal clock, with transient elevations of dopaminergic activity producing underestimation of temporal intervals. A group of DAT knockdown (KD) and littermate wild type (WT) mice were tested with a dual peak procedure. Mice obtained reinforcement by pressing one of two levers after a fixed amount of time (30 or 45 s) had elapsed since lever extension. Only one lever was available at a time, and each lever was associated with a single duration. On occasional probe trials, the DAT KD mice began responding earlier in the interval than WT mice, but showed maximal responding and terminated responding around the same time as the WT mice. Administration of raclopride (0.2, 0.6, and 1.2 mg/kg), a D2 antagonist, eliminated most of the differences between DAT KD and WT mice, suggesting that the effects of chronic DAT downregulation on interval timing were mediated by the D2 receptors. Another cohort of DAT KD mice was trained on a visual attention task, and no deficits were observed, confirming that the changes in timed behavior were not attentionally mediated. Our data are consistent with the view that tonic dopamine affects the sensitivity of an organism to external reward signals, and that this increased motivation for reward of DAT KD mice lowers the threshold for initiating responding in a timing task.