Striatal dopamine D1 receptors control motivation to respond,but not interval timing,during the timing task

Dopamine plays a critical role in behavioral tasks requiring interval timing (time perception in a seconds-to-minutes range). Although some studies demonstrate the role of dopamine receptors as a controller of the speed of the internal clock, other studies demonstrate their role as a controller of motivation. Both D1 dopamine receptors (D1DRs) and D2 dopamine receptors (D2DRs) within the dorsal striatum may play a role in interval timing because the dorsal striatum contains rich D1DRs and D2DRs. However, relative to D2DRs, the precise role of D1DRs within the dorsal striatum in interval timing is unclear. To address this issue, rats were trained on the peak-interval 20-sec procedure, and D1DR antagonist SCH23390 was infused into the bilateral dorsocentral striatum before behavioral sessions. Our results showed that the D1DR blockade drastically reduced the maximum response rate and increased the time to start responses with no effects on the time to terminate responses. These findings suggest that the D1DRs within the dorsal striatum are required for motivation to respond, but not for modulation of the internal clock speed.

Animals, including humans, can regulate their behavior according to temporal information. This suggests animals can perceive the passage of time (i.e., time perception). Without accurate time perception, we cannot speak, appreciate and play music, drive cars, and play sports. The current paper focussed on time perception in a seconds-to-minutes range; i.e., interval timing (Buhusi and Meck 2005). Interval timing is essential for an optimal foraging (Kacelnik and Bateson 1996) and associative learning (Gallistel and Gibbon 2000).In rodents, interval timing is frequently examined using the peak-interval (PI) procedure (Catania 1970; Roberts 1981). This task consists of randomly ordered two types of trials; i.e., fixed-interval (FI) and probe trials, separated by intertrial intervals (ITIs). During each FI trial, a reward is delivered for the first response made after a criterion time (e.g., 20 sec) has elapsed from the start of the trial, but not for responses made before the criterion time. Probe trials usually last for three times more than the criterion time in FI trials (e.g., 60 sec), and the reward is omitted. During an individual probe trial, rats typically start responding before the criterion time and stop it after the criterion time. The average rate of responses throughout the multiple probe trials in a session increases as the criterion time approaches, reaches a peak around the criterion time, and then decreases. The location of the peak of the response rate function (peak time), the spread of the function (peak spread), and the height of the peak (peak rate) are indices for timing accuracy, timing precision, and motivation to respond, respectively.Many studies have demonstrated that systemic injections of drugs affecting dopamine (DA) receptors impact interval timing in various ways. Some studies suggest that DA modulates the speed of the internal clock (Meck 1996). Systemic injection of DA receptor agonist decreases peak times, while that of DA receptor antagonist increases peak times. Importantly, the degree to which responding is altered is proportional to the duration being timed (Maricq et al. 1981; Maricq and Church 1983; Meck 1983, 1996; Matell et al. 2006). Therefore, it is necessary to use multiple target durations of a PI procedure (e.g., 20 and 40 sec) while examining the occurrence of any changes in clock speed mechanisms adequately. A recent study showed that transient activation or inhibition of DA neurons in the substantia nigra pars compacta (SNc) was sufficient to induce overestimation or underestimation of time in a temporal discrimination task, respectively (Soares et al. 2016). These results suggest that DA neurons in the SNc and DA receptors modulate the speed of the internal clock (“the dopamine-clock hypothesis”). Other studies, however, suggest that DA is involved in motivation during the interval timing task (Balcı 2014). Systemic injection of dopamine D1 receptors (D1DRs) antagonist SCH23390 reduced the peak rate (Drew et al. 2003), whereas systemic injection of DA agonist D-amphetamine increased the peak rate but reduced peak time and start time of responding without affecting stop time of responding (Taylor et al. 2007). The results of these studies are similar to those of studies that investigated the effect of manipulation of motivation on interval timing (Balcı 2014). Manipulations that decrease motivation (e.g., decreasing reward magnitude, prefeeding, and reward devaluation) reduced the peak rate, and sometimes delayed the start time (Roberts 1981; Ludvig et al. 2007; Galtress and Kirkpatrick 2009; Delamater et al. 2014, 2018). In contrast, opposite manipulations on motivation (e.g., increasing reward magnitude) caused earlier initiation of responding and a higher peak rate (Galtress and Kirkpatrick 2009). These findings support the idea that DA contributes to modulating motivation (Ikemoto et al. 2015). Therefore, DA might modulate motivation also during the timing task (“the dopamine-motivation hypothesis”).DA receptors within the dorsal striatum (dSTR) can be responsible for the effect of systemically injected DA agents on interval timing. Lesioning of the dSTR and damaged DA neurons in the SNc projecting to the dSTR caused the severe impairment of interval timing (Meck 2006b; Gouvêa et al. 2015; Mello et al. 2015), and optogenetic manipulation of DA neurons in the SNc affected the performance of the temporal discrimination task (Soares et al. 2016). These results strengthen the notion that the DA pathway from the SNc to the dSTR and the modulation of DA receptors in the dSTR are important for interval timing. Therefore, systemically injected DA agents might affect interval timing task through the DA receptors in the dSTR. Consistently, the affinity of DA agents for D2 dopamine receptors (D2DRs), but not D1DRs, correlated with the degree to produce the rightward shift of the temporal bisection function (Meck 1986), and systemic injection of D2DR blocker, but not D1DR blocker, affected interval timing in the PI procedure (Drew et al. 2003). These findings suggest that the change in the activity of D2DRs is implicated in the effect of DA on interval timing.Some studies, however, suggest that also the D1DRs within the dSTR might also play an important role in interval timing. A study showed that stimulation of the D1DR by systemic injection changed interval timing behavior (Cheung et al. 2007). D1DRs, as well as D2DRs, are highly expressed in the medium spiny neurons in the dSTR (Gerfen and Surmeier 2011). Thus, it is the possible that D1DRs in the dSTR also play an important role in interval timing. Notably, a recent study reported that D1DR blockade in the dSTR increased the time of stop responding (De Corte et al. 2019), and the findings cannot be explained by either “dopamine-clock hypothesis” nor “dopamine-motivation hypothesis.” Therefore, further studies are needed to clarify the role of D1DRs within the dSTR in interval timing.The present study aimed to examine further the role of D1DRs within the dorsal striatum in interval timing using the PI procedure. After a limited amount of training (Cheng et al. 2007), rats were infused with D1DR antagonist SCH23390 into the bilateral dSTR. Our findings support the “dopamine-motivation hypothesis” of D1DRs in the dSTR.