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, 111 (26), E2751-9

Dopamine Transporters Govern Diurnal Variation in Extracellular Dopamine Tone

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Dopamine Transporters Govern Diurnal Variation in Extracellular Dopamine Tone

Mark J Ferris et al. Proc Natl Acad Sci U S A.

Abstract

The majority of neurotransmitter systems shows variations in state-dependent cell firing rates that are mechanistically linked to variations in extracellular levels, or tone, of their respective neurotransmitter. Diurnal variation in dopamine tone has also been demonstrated within the striatum, but this neurotransmitter is unique, in that variation in dopamine tone is likely not related to dopamine cell firing; this is largely because of the observation that midbrain dopamine neurons do not display diurnal fluctuations in firing rates. Therefore, we conducted a systematic investigation of possible mechanisms for the variation in extracellular dopamine tone. Using microdialysis and fast-scan cyclic voltammetry in rats, as well as wild-type and dopamine transporter (DAT) knock-out mice, we demonstrate that dopamine uptake through the DAT and the magnitude of subsecond dopamine release is inversely related to the magnitude of extracellular dopamine tone. We investigated dopamine metabolism, uptake, release, D2 autoreceptor sensitivity, and tyrosine hydroxylase expression and activity as mechanisms for this variation. Using this approach, we have pinpointed the DAT as a critical governor of diurnal variation in extracellular dopamine tone and, as a consequence, influencing the magnitude of electrically stimulated dopamine release. Understanding diurnal variation in dopamine tone is critical for understanding and treating the multitude of psychiatric disorders that originate from perturbations of the dopamine system.

Keywords: caudate-putamen; circadian; nucleus accumbens.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Extracellular dopamine (A) and metabolites HVA (B) and DOPAC (C), expressed as percent of baseline, oscillate across the light/dark cycle with peaks and trough of DA and HVA occurring midway through the dark and light phases, respectively. The DOPAC cycle is phase-shifted to the right of dopamine by ∼6 h (D). DA, HVA, and DOPAC are best fit to a third-order regression curve that is significantly different from linearity (***P < 0.001).
Fig. 2.
Fig. 2.
Maximal rate of DA uptake (Vmax) in the caudate (A), NAc core (B), and shell (C) engenders an inverted u-shaped trend when plotted starting one hour into the light phase (ZT1; main effect of ZT, ***P < 0.001, **P < 0.01). Tukey’s multiple comparisons (ΔΔΔP < 0.001, ΔP < 0.05 relative to ZT6; ΦΦP < 0.01, ΦP < 0.05 relative to ZT13). Vmax demonstrates an inverse relationship to extracellular dopamine levels ([DA]ext) in the caudate (D). The green line represents the best-fit model for Vmax and the red line represents the best-fit model for [DA]ext.
Fig. 3.
Fig. 3.
Electrically-stimulated dopamine release ([DA]o) in the caudate (A), NAc core (B), and shell (C) engenders an inverted u-shaped trend when plotted starting 1 h into the light phase (ZT1; main effect of ZT, ***P < 0.001, **P < 0.01). Tukey’s multiple comparisons (ΔP < 0.05 relative to ZT6; ΦP < 0.05 relative to ZT13). (D) [DA]o demonstrates an inverse relationship to extracellular dopamine levels ([DA]ext) in the caudate. The blue line represents the best-fit model for [DA]o and the red line represents the best-fit model for [DA]ext.
Fig. 4.
Fig. 4.
Electrically stimulated DA release ([DA]o) in the caudate following 30 nM (A) and 100 nM (B) quinpirole, expressed as a percent of predrug [DA]o engenders a decreasing linear trend when plotted starting one hour into the light phase (ZT1; main effect of ZT, **P < 0.01). Tukey’s multiple comparisons (##P < 0.01 relative to ZT1; ΔΔP < 0.01, ΔP < 0.05 relative to ZT6). (C) The relative sensitivity of caudate D2 autoreceptors to inhibit [DA]o is plotted against extracellular DA in the caudate.
Fig. 5.
Fig. 5.
Extracellular dopamine [DA]ext in the caudate of WT mice (A) oscillates across the light/dark cycle. The red line signifies a fourth-order regression best-fit model that was significantly different from linearity (***P < 0.001). DAT KO mice (B), demonstrated no light/dark cycle oscillation in [DA]ext. TH expression (green line) and activity (blue line; as measured by l-DOPA accumulation after administration of NSD-1015) oscillates in both WT (C) and DAT KO (D) mice in a manner similar to [DA]ext in WT mice.
Fig. 6.
Fig. 6.
Stimulated dopamine release [DA]o is higher during the light in WT (green, **P < 0.01), but not DAT KO (blue) mice. Cocaine eliminated variation in [DA]o when administered for 48 consecutive hours in vivo via minipump (orange bars) but augmented the difference in [DA]o between the light and dark in WT mice when applied acutely to brain slices (**P < 0.01, *P < 0.05; ΔP < 0.05 red vs. green ZT6).

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