Evidence that sleep deprivation downregulates dopamine D2R in ventral striatum in the human brain

Abstract

Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [(11)C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([(11)C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [(11)C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

Figure 1.

SPM results showing the regions where D2/D3R BP_ND was greater for RW than for SD (RW > SD; p < 0.005 uncorrected), both for the placebo and the MP conditions, and for both combined.

Figure 2.

A, SPM results showing the regions where D2/D3R BP was greater for placebo than for MP [placebo (PL) > MP; p < 0.005 uncorrected], which reflect MP-induced DA increased, both for the RW and the SD conditions and for the results for the comparison of MP-induced changes between RW and SD (RW > SD; p < 0.05 uncorrected). Neither the comparison of MP-induced changes for the contrast RW > SD nor that for SD > RW were significant. B, Scattergrams for the percentage change in BP_ND with MP (with respect to placebo) both for RW and SD in caudate, putamen, and VS.

Figure 3.

Correlations between changes in D2/D3R BP and changes in self-reports of alertness and sleepiness. A, Correlations for the D2R changes in VS and self-reports between RW and SD (placebo measures). B, Correlations for the D2R changes in caudate (CD) and putamen (PT) and self-reports between placebo (PL) and MP for the SD condition.

Figure 4.

Results for the microdialysis experiments measuring extracellular DA levels in nucleus accumbens between 10:00 A.M. and 4:00 P.M. both for a group of rats (SD) subjected the preceding night to paradoxical sleep deprivation (placed on a small platform surrounded by water) and in a group of rats (controls) subjected to a similar environment during the night except that they were placed on a larger a platform that allowed them to sleep. Values correspond to means and standard errors.