Dopamine transporters govern diurnal variation in extracellular dopamine tone

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. circadian | caudate-putamen | nucleus accumbens T he dopamine transporter (DAT) is a transmembrane protein that removes dopamine (DA) from the extracellular space to terminate signaling at pre-and postsynaptic receptors. Extensive evidence indicates that aberrant DAT function may be involved in many neuropsychiatric illnesses, including attention deficit hyperactivity disorder (1, 2), depression (3, 4), substance abuse disorders (5, 6), schizophrenia (7-9), and anxiety disorders (10, 11). Our current understanding of the role of the DAT under physiologically normal conditions is that of a homeostatic regulator. This basic hypothesis was confirmed in work using DAT knock-out (KO) mice, where extracellular DA levels ([DA] ext ) and corresponding locomotor activity are substantially higher than in WT animals (12, 13). In addition, up-or down-regulation of the DAT is regarded as a compensatory plasticity to "normalize" [DA] ext in the context of repeated exposure to abused drugs (5,14,15).Despite this progress in understanding DAT function, much less work has been dedicated to understanding the role of the DAT and other presynaptic modulators of [DA] Despite the limited mechanistic understanding of the complex relationship between [DA] ext and nerve terminal function, behaviors known to be governed by DA are strongly influenced by diurnal cycles. For example, behaviors that measure reinforcement and reward, such as psychostimulant self-administration and conditioned place preference, fluctuate markedly a...

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