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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).

Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter to correct a presumed deficit in extracellular serotonin signaling during depression. These agents bring clinical relief to many who take them; however, a significant and growing number of individuals are resistant to SSRIs. There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown. In this work, we use fast in vivo serotonin measurement tools to investigate the nexus between serotonin, inflammation, and SSRIs. Upon acute systemic lipopolysaccharide (LPS) administration in male and female mice, we find robust decreases in extracellular serotonin in the mouse hippocampus. We show that these decreased serotonin levels are supported by increased histamine activity (because of inflammation), acting on inhibitory histamine H3 heteroreceptors on serotonin terminals. Importantly, under LPS-induced histamine increase, the ability of escitalopram to augment extracellular serotonin is impaired because of an off-target action of escitalopram to inhibit histamine reuptake. Finally, we show that a functional decrease in histamine synthesis boosts the ability of escitalopram to increase extracellular serotonin levels following LPS. This work reveals a profound effect of inflammation on brain chemistry, specifically the rapidity of inflammation-induced decreased extracellular serotonin, and points the spotlight at a potentially critical player in the pathology of depression, histamine. The serotonin/histamine homeostasis thus, may be a crucial new avenue in improving serotonin-based treatments for depression. SIGNIFICANCE STATEMENT Acute LPS-induced inflammation (1) increases CNS histamine, (2) decreases CNS serotonin (via inhibitory histamine receptors), and (3) prevents a selective serotonin reuptake inhibitor (SSRI) from effectively increasing extracellular serotonin. A targeted depletion of histamine recovers SSRI-induced increases in extracellular hippocampal serotonin.

Fast-scan cyclic voltammetry at carbon fiber microelectrodes measures low concentrations of analytes in biological systems. There are ongoing efforts to simplify FSCV analysis and several custom platforms are available for filtering and multi-modal analysis of FSCV signals but there is no single, easily accessible platform that has capacity for all these features. Here we present The Analysis Kid: a free, open-source cloud application that does not require a specialized runtime environment and is easily accessible via common browsers. We show that a user-friendly interface can analyze multi-platform file formats to provide multimodal visualization of FSCV color plots with digital background subtraction. We highlight key features that allow interactive calibration and parametric analysis via peak finding algorithms to automatically detect the maximum amplitude, area under the curve and clearance rate of the signal. Finally, The Analysis Kid enables semi-automatic fitting of data with Michaelis Menten kinetics with single or dual reuptake models. The Analysis Kid can be freely accessed at https://analysis-kid.herokuapp.com/. The web application code is found, under an MIT license, at https://github.com/sermeor/The-Analysis-Kid.

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.

Between 30% and 60% of HIV seropositive individuals develop symptoms of clinical depression and/or apathy. Dopamine and serotonin are associated with motivational alterations; however, histamine is less well studied. In the present study, we used fast-scan cyclic voltammetry in HIV-1 transgenic (Tg) rats to simultaneously analyze the kinetics of nucleus accumbens dopamine (DA), prefrontal cortical serotonin (5-HT), and hypothalamic histamine (HA). For voltammetry, subjects were 15 HIV-1 Tg (7 male, 8 female) and 20 F344/N (11 male, 9 female) adult rats. Both serotonergic and dopaminergic release and reuptake kinetics were decreased in HIV-1 Tg animals relative to controls. In contrast, rates of histamine release and reuptake increased in HIV-1 Tg rats. Additionally, we used immunohistochemical (IHC) methods to identify histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus. For IHC, subjects were 9 HIV-1 Tg (5 male, 4 female) and 9 F344/N (5 male, 4 female) adult rats. Although the total number of TMN histaminergic cells did not differ between HIV-1 Tg rats and F344/N controls, a significant sex effect was found; with females having an increased number of histaminergic neurons, relative to males. Collectively, these findings illustrate neurochemical alterations that potentially underlie or exacerbate the pathogenesis of clinical depression and/or apathy in HIV-1.

Fast-scan cyclic voltammetry at carbon fiber microelectrodes measures low concentrations of analytes in biological systems. There are ongoing efforts to simplify FSCV analysis and several custom platforms are available for filtering and multi-modal analysis of FSCV signals but there is no single, easily accessible platform that has capacity for all these features. Here we present The Analysis Kid: a free, open-source cloud application that does not require a specialized runtime environment and is easily accessible via common browsers. We show that a user-friendly interface can analyze multi-platform file formats to provide multimodal visualization of FSCV color plots with digital background subtraction. We highlight key features that allow interactive calibration and parametric analysis via peak finding algorithms to automatically detect the maximum amplitude, area under the curve and clearance rate of the signal. Finally, The Analysis Kid enables semi-automatic fitting of data with Michaelis Menten kinetics with single or dual reuptake models. The Analysis Kid can be freely accessed at https://analysis-kid.herokuapp.com/. The web application code is found, under an MIT license, at https://github.com/sermeor/The-Analysis-Kid.

Our understanding of the world around us has been greatly enhanced by our ability to detect and quantify analytes in the environment and in biology. It is highly beneficial to perform analysis at the site of interest as many situations do not afford the luxury of time required for samples to be collected and sent off for analysis. Some processes necessitate immediate detection to facilitate rapid action. As an example, harmful environmental phenomena can result from dynamic events such as the recent spate of tropical cyclones in the Caribbean and Southeastern region of the United States. These storms have mobilized nutrients, facilitating large-scale algal blooms that are damaging to marine ecosystems and human health. The rapid delivery of analytical information during such events is the key to quickly mitigating detrimental effects. Another example is analytically monitoring the quality of drinking water in the context of avoiding residential crises such as in Flint, MI where residents were exposed to h...