Histamine is well known for mediating peripheral inflammation; however, this amine is also found in high concentrations in the brain where its roles are much less known. In vivo chemical dynamics are difficult to measure, thus fundamental aspects of histamine’s neurochemistry remain undefined. In this work, we undertake the first in-depth characterization of real time in vivo histamine dynamics using fast electrochemical tools. We find that histamine release is sensitive to pharmacological manipulation at the level of synthesis, packaging, autoreceptors and metabolism. We find two breakthrough aspects of histamine modulation. First, differences in H3 receptor regulation between sexes show that histamine release in female mice is much more 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, a high dose of a commonly available antihistamine, the H1 receptor inverse agonist diphenhydramine, rapidly decreases serotonin levels. This finding highlights the sheer significance of pharmaceuticals on neuromodulation. Our study opens the path to better understanding and treating 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.

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.

Histamine is well known for mediating peripheral inflammation, however, histamine is found in high concentrations in the brain where amongst other roles, this amine is a neuromodulator. Histamine modulation is critical for brain function, yet dynamic histamine chemistry is 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 an in-depth characterization of in vivo histamine dynamics 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 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 antagonist diphenhydramine, rapidly decreased 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 when studying/designing histamine targeting pharmaceuticals. We, thus, present the first in depth in vivo characterization of fast histamine dynamics and presents two breakthrough regulatory aspects of this elusive modulator.

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.