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Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (synaptic plasticity and neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here. We measure hippocampal serotonin in mice with voltammetry and study the effects of acute challenges of antidepressants. We find that pseudo-equivalent doses of these drugs similarly raise ambient serotonin levels, despite their differing pharmacodynamics because of differences in Uptake 1 and 2, rapid SERT trafficking and modulation of serotonin by histamine. These antidepressants have different pharmacodynamics but have strikingly similar effects on extracellular serotonin. Our findings suggest that serotonin is a common thread that links clinically effective antidepressants, synergizing different theories of depression (synaptic plasticity, neurogenesis and the monoamine hypothesis).

Histamine is well known for mediating peripheral inflammation, but histamine is also found in high concentrations in the brain where amongst other roles, this amine is thought to be neuromodulator. Neuromodulation is critical for brain function, yet histamine dynamics are very difficult to measure and thus several fundamental aspects of the mechanisms that control the extracellular and modulatory behavior of this messenger remain undefined. In this work we undertake the first in-depth characterization of in vivo histamine dynamics in real time using fast-scan cyclic voltammetry at carbon fiber microelectrodes. We measure electrically evoked histamine in the mouse hypothalamus and find that histamine release is sensitive to pharmacological manipulation at the level of synthesis, packaging, autoreceptor control of release, and metabolism. We find two breakthrough aspects of histamine modulation. First, there are differences in H3 receptor regulation of histamine between sexes showing that histamine release in female mice is more much tightly regulated than in male mice under H3 or inflammatory drug challenge. We hypothesize that this finding may contribute to hormone-mediated neuroprotection mechanisms in female mice. Second, we find that a high dose of a commonly available antihistamine, the H1 receptor inverse agonist diphenhydramine, rapidly decreases serotonin levels. This high dose is considered overdose; however, this finding highlights the sheer significance of better consideration of the modulatory nuances of histamine on serotonin.We, thus, present the first in depth in vivo characterization of fast histamine dynamics and highlight two breakthrough regulatory aspects of this elusive modulator. The implications of our study are new avenues to better understand and treat histamine related disorders of the brain (such as neuroinflammation), emphasizing that sex and modulation (of serotonin) are critical factors to consider when studying/designing new histamine targeting therapeutics.