Research on this topic directly measured changes in monoaminergic neurotransmission in animal models, or studied SD effects in humans with challenge methods, brain imaging, or pharmacogenetic approaches. These methods allowed definition of convergent effects in animal and humans, either healthy or depressed, of SD on serotonin (5-HT), noradrenaline (NA), and dopamine (DA). In animal models, SD increase 5-HT neurotransmission87 by enhancing the activity of 5-HT neurons in the dorsal raphe nucleus,88 increasing brain extracellular 5-HT89 and 5-1 IT turnover,90-92 reducing the sensitivity Inhibitors,research,lifescience,medical of 5-IIT1A
inhibitory autoreceptors,88,93 and increasing the behavioral responsiveness to 5-HT precursors.94 In a similar way, SD was shown to increase synaptic levels of NA95 and tyrosine hydroxylase and NA transporter mRNA in the locus Inhibitors,research,lifescience,medical coeruleus,96 and to increase DA activity and behavioral response to DA agonists,97,98 with an increase of DA receptor
binding sites during the early stages of SD (following 12 to 24 hours awake)99 and a subsequent subsensitivity after more prolonged wake,100 suggesting downregulation after prolonged stimulation. Clinical psychobiology confirmed these effects in depressed humans and linked them with the efficacy of chronotherapeutics. SD increased the Inhibitors,research,lifescience,medical prolactin response to intravenous tryptophan infusion101 and decreased plasma levels of prolactin, which is inhibited by DA agonists, thus suggesting DA hyperactivity during SD.102,103 D2 receptor occupancy decreased in responders to SD, thus suggesting an Inhibitors,research,lifescience,medical enhanced
DA release in responders,104 levels of homovanillic acid in the spinal fluid predicted the clinical effects of SD,105 and eye-blink Inhibitors,research,lifescience,medical rate after SD increased in responders, suggesting DA activation.106 The NA metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and MHPG sulfate107 increased after SD pro-portionally to severity of depression108 and clinical response to treatment.109 Human why pharmacogenetics confirmed that gene variants that click here improve neurotransmission by increasing receptor or transporter density, or decreasing neurotransmitter degradation, also improve the clinical efficacy of SD in bipolar depression when given alone or combined with bright light therapy. This was proven for genotypes influencing the density of the 5-1 IT transporter110-112 and of the 5-IIT2A receptor,113 or the efficiency of the catechol-O-methyltransferase (COMT) in clearing NA and DA from the synapse.114 Interestingly, the role of these genetic influences has effect sizes comparable to those observed on response to antidepressant drugs,115-117 thus strongly suggesting a shared mechanism of action of chronotherapeutics and monoaminergic drugs.