Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward

Abstract

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).

Keywords: Addiction; Molecular biology; Neuroscience.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Intercorrelations among rest-activity rhythm parameters.

Pearson’s correlation coefficients between objective and subjective measures of rest-activity rhythms used in the present study.

Figure 2. Rhythm components and DA receptor availability.

Timing and amplitude of rest-activity rhythms are associated with caudate D1R and NAc D2/3R, respectively. Results from voxel-wise analyses controlling for age, sex and BMI. Acrophase represents time of day with peak activity (left, middle). Zero-order correlations between rhythm components and DA receptor levels from ROI analyses (right). The solid lines indicate the lines of best fit and the dashed lines indicate the 95% confidence intervals.

Figure 3. Association between DA receptor availability and subjective drug effects (peak).

The maximum drug effects (peak) were used as outcome measures. We subtracted placebo from MP ratings to estimate MP-induced subjective drug effects (y axes). D1R in the caudate (upper panel) and D2/3R in the nucleus accumbens (NAc) (lower panel) (x axes). The solid lines indicate the lines of best fit and the dashed lines indicate the 95% confidence intervals.