Serotonin and Brain: Evolution, Neuroplasticity, and Homeostasis

Azmitia, Efrain C.

doi:10.1016/s0074-7742(06)77002-7

Cited by 129 publications

(96 citation statements)

References 109 publications

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“…Serotonin evolved in mitochondria [27], and, in many cell types, cellular uptake of serotonin depends on mitochondrial activity [36,37,38,39,40], which suggests serotonin supports many biological processes. Indeed, serotonin regulates growth, development, reproduction, neuronal activity, digestion, immune function, thermoregulation, tissue repair, maintenance, electrolyte balance, mitochondrial function, and the storage, mobilization and distribution of energetic resources [3,27,41]. By blocking the transporter in the brain and periphery, selective serotonin reuptake inhibitors (SSRIs), which are the most widely prescribed ADs, could potentially degrade many adaptive processes [3,42].…”

Section: Introductionmentioning

confidence: 99%

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

Maslej

Bolker²,

Russell³

et al. 2017

Psychother Psychosom

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Background: Antidepressants (ADs) are commonly prescribed medications, but their long-term health effects are debated. ADs disrupt multiple adaptive processes regulated by evolutionarily ancient biochemicals, potentially increasing mortality. However, many ADs also have anticlotting properties that can be efficacious in treating cardiovascular disease. We conducted a meta-analysis assessing the effects of ADs on all-cause mortality and cardiovascular events in general-population and cardiovascular-patient samples. Methods: Two reviewers independently assessed articles from PubMed, EMBASE, and Google Scholar for AD-related mortality controlling for depression and other comorbidities. From these articles, we extracted information about cardiovascular events, cardiovascular risk status, and AD class. We conducted mixed-effect meta-analyses testing sample type and AD class as moderators of all-cause mortality and new cardiovascular events. Results: Seventeen studies met our search criteria. Sample type consistently moderated health risks. In general-population samples, AD use increased the risks of mortality (HR = 1.33, 95% CI: 1.14-1.55) and new cardiovascular events (HR = 1.14, 95% CI: 1.08-1.21). In cardiovascular patients, AD use did not significantly affect risks. AD class also moderated mortality, but the serotonin reuptake inhibitors were not significantly different from tricyclic ADs (TCAs) (HR = 1.10, 95% CI: 0.93-1.31, p = 0.27). Only “other ADs” were differentiable from TCAs (HR = 1.35, 95% CI: 1.08-1.69). Mortality risk estimates increased when we analyzed the subset of studies controlling for premedication depression, suggesting the absence of confounding by indication. Conclusions: The results support the hypothesis that ADs are harmful in the general population but less harmful in cardiovascular patients.

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Section: Introductionmentioning

confidence: 99%

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

Maslej

Bolker²,

Russell³

et al. 2017

Psychother Psychosom

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“…16,17 Serotonin, in addition to being a classic neurotransmitter, is known from an extensive literature to have positive developmental, neuroprotective, and regenerative effects. [18][19][20] The majority of serotonergic raphe terminals corelease neuropeptides that have trophic or protective actions, most prominently galanin in the case of the midbrain raphe. 21,22 The hindbrain raphe nuclei constitute an analogous descending system, whose neurons release serotonin and neuropeptides such as thyrotropin-releasing hormone and substance P in widespread spinal cord segments and laminae.…”

Section: Introductionmentioning

confidence: 99%

Midbrain Raphe Stimulation Improves Behavioral and Anatomical Recovery from Fluid-Percussion Brain Injury

Gonzalez

Blaya

Alonso

et al. 2013

Journal of Neurotrauma

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The midbrain median raphe (MR) and dorsal raphe (DR) nuclei were tested for their capacity to regulate recovery from traumatic brain injury (TBI). An implanted, wireless self-powered stimulator delivered intermittent 8-Hz pulse trains for 7 days to the rat's MR or DR, beginning 4-6 h after a moderate parasagittal (right) fluid-percussion injury. MR stimulation was also examined with a higher frequency (24 Hz) or a delayed start (7 days after injury). Controls had sham injuries, inactive stimulators, or both. The stimulation caused no apparent acute responses or adverse long-term changes. In watermaze trials conducted 5 weeks post-injury, early 8-Hz MR and DR stimulation restored the rate of acquisition of reference memory for a hidden platform of fixed location. Short-term spatial working memory, for a variably located hidden platform, was restored only by early 8-Hz MR stimulation. All stimulation protocols reversed injury-induced asymmetry of spontaneous forelimb reaching movements tested 6 weeks post-injury. Post-mortem histological measurement at 8 weeks post-injury revealed volume losses in parietal-occipital cortex and decussating white matter (corpus callosum plus external capsule), but not hippocampus. The cortical losses were significantly reversed by early 8-Hz MR and DR stimulation, the white matter losses by all forms of MR stimulation. The generally most effective protocol, 8-Hz MR stimulation, was tested 3 days post-injury for its acute effect on forebrain cyclic adenosine monophosphate (cAMP), a key trophic signaling molecule. This procedure reversed injury-induced declines of cAMP levels in both cortex and hippocampus. In conclusion, midbrain raphe nuclei can enduringly enhance recovery from early disseminated TBI, possibly in part through increased signaling by cAMP in efferent targets. A neurosurgical treatment for TBI using interim electrical stimulation in raphe repair centers is suggested.

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“…the production, secretion, and inactivation of the biogenic amine 5-HT (1). A critical and conserved mechanism to regulate 5-HT signaling involves the action of the presynaptic 5-HT transporter, SERT (2).…”

mentioning

confidence: 99%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/ 6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J ؋ DBA/2J ‫؍‬ BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.A complex set of phylogentically conserved traits relies upon the production, secretion, and inactivation of the biogenic amine 5-HT (1). A critical and conserved mechanism to regulate 5-HT signaling involves the action of the presynaptic 5-HT transporter, SERT (2). SERTs are not only responsible for the clearance of 5-HT after release, but also recycle synaptic 5-HT to sustain adequate stores for 5-HT release (3).The recognition of the central role played by SERT in 5-HT inactivation has been reinforced by studies where mouse SERT (mSERT) has been eliminated (4), suppressed (5, 6), or enhanced (7). Although investigations with these models provide critical support for a role of SERT in presynaptic 5-HT clearance and homeostasis, inferences linking SERT to neural signaling and behavior are complicated by significant compensatory changes in other genes (8). Conversely, a lack of recognition for background genetic diversity in mouse strains likely limits the full elaboration of phenotypes associated with SERT genetic variation (9). Indeed, SERT knockout mice display different phenotypes depending on their genetic background (10).An alternative approach is the identification of traits that are sensitive to naturally occurring polymorphisms using genetic reference populations, such as BXD recombinant inbred (RI) lines (11). BXD RI lines are isogenic, homozygous mosaics of C57BL/6J and DBA/2J inbred strains, previ...

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Serotonin and Brain: Evolution, Neuroplasticity, and Homeostasis

Cited by 129 publications

References 109 publications

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis

Midbrain Raphe Stimulation Improves Behavioral and Anatomical Recovery from Fluid-Percussion Brain Injury

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

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