Switching brain serotonin with oxytocin

Abstract

Serotonin (5-HT) and oxytocin (OXT) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism. We asked whether these chemical messengers interact in the regulation of emotion-based behavior by administering OXT or placebo to 24 healthy subjects and mapping cerebral 5-HT system by using 2′-methoxyphenyl-(N-2′-pyridinyl)-p-[ ]MPPF nondisplaceable binding potential (BP ND ) in the dorsal raphe nucleus (DRN), the core area of 5-HT synthesis, and in the amygdala/hippocampal complex, insula, and orbitofrontal cortex. Importantly, the amygdala appears central in the regulation of 5-HT by OXT: [ 18 F]MPPF BP ND changes in the DRN correlated with changes in right amygdala, which were in turn correlated with changes in hippocampus, insula, subgenual, and orbitofrontal cortex, a circuit implicated in the control of stress, mood, and social behaviors. OXT administration is known to inhibit amygdala activity and results in a decrease of anxiety, whereas high amygdala activity and 5-HT dysregulation have been associated with increased anxiety. The present study reveals a previously unidentified form of interaction between these two systems in the human brain, i.e., the role of OXT in the inhibitory regulation of 5-HT signaling, which could lead to novel therapeutic strategies for mental disorders. B rain chemistry strongly influences our behavior. Among neuromodulators, serotonin (5-HT) and oxytocin (OXT) are important for the regulation and expression of several behaviors such as human affects and socialization. Both systems have been implicated in the control of stress, anxiety, and social cooperation (1, 2). Moreover, their dysfunction is associated with major psychiatric disorders such as depression (3, 4) and autism (5,6). Recent animal studies demonstrated that specific anatomical links exist between these two molecules. Serotonergic fibers originating from the dorsal and medial raphe nuclei of the brainstem project toward magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus, where OXT is released (7). In this region, 5-HT fibers overlap and follow the distribution of OXT cells (8). Importantly, in the raphe nuclei, the core area of 5-HT synthesis, serotonergic neurons display OXT receptors and OXT modulates the release of 5-HT (9). Recent results have also shown that administration of OXT during the postnatal period increases the length of serotonergic axons in the hypothalamus and in the amygdala (10). In return, 5-HT is able to modulate OXT release while interacting with different 5-HT receptors in the hypothalamus (11). Also, the administration of fenfluramine, a serotonergic agonist, to healthy subjects increases plasma OXT level (12). These findings indicate that OXT and 5-HT share anatomical substrates, which may constitute a functional interface in the regulation of emotionbased behaviors. Behaviorally, OXT and 5-HT modulate reactions to social contexts and threatening stimuli in humans and animals (13,14). For instance, oversens...

Adaptations for social cognition in the primate brain

“…In the laboratory, variation in 5-HTTLPR predicts elevated arousal and decreased social interest in assays of social attention and social reward [134]. Moreover, there is new evidence that serotonin and OT interact in brain circuits implicated in emotion regulation and social behaviour in humans [135], thus linking two neuromodulatory systems previously implicated in arousal and social function. Thus, although the definitive studies on the repeatability, fitness consequences and heritability of personality styles and social skills in the wild remain to be conducted, current evidence suggests that individual variation in social behaviour arises, in part, from the adaptive influence of genes on neural circuits and neuromodulatory systems mediating social function [136].…”

The effect of oxytocin on the level and monoamines turnover in the brain of isolated mice of highand low-aggressive lines

“…Здесь и далее на рис. 4,5,7,9,10: левая сторона -левая сторона мозга, правая сторо-на -правая сторона мозга; Ф -после введения физраствора, О -после введения окситоцина; p = 0,054 по содержанию ДА в левой коре между мышами контрольной (получавшие физра-створ) и опытной (получавшие окситоцин) группы Исследование уровня моноаминов в симметрич-ных структурах мозга мышей-изолянтов высоко-и низкоагрессивной линий выявило существенные различия как по базовому проявлению асимметрии, вызванной изоляцией (без влияния препаратов), так и по способности окситоцина влиять на функциони-рование моноаминергических систем мозга.…”

“…В пользу данного предположения свидетельствовали как данные о наличии оксито-циновых рецепторов на серотонинергических ней-ронах [7], так и наши результаты, полученные на мышах линии C57Bl/6 [2,5]. Однако действие ок-ситоцина на серотонинергическую систему у белых беспородных мышей проявлялось слабо: эффек-ты окситоцина заключались в повышении 5-ГИУК в правом стриатуме и в исчезновении исходного преобладания 5-ОТ в левой коре.…”

The potential of oxytocin as a therapeutic target for psychiatric disorders

“…OXT fibers project to numerous other brain regions, among them the amygdala, the nucleus accumbens and dorsal raphe nucleus, thus building local networks with GABAergic, dopaminergic and serotonergic circuits. [12][13][14] For instance, during birth, OXT mediates the reduction of intracellular chloride concentrations, leading to a shift in GABAergic currents from excitatory to inhibitory. [14] Intriguingly, it is suggested that autism might partly be caused by an incomplete execution of this shift.…”

“…It is speculated that OXT brings about its anxiolytic effect partly via modulation of 5-HT activity within the amygdala, providing new possibilities for therapeutic strategies. [12] Furthermore, there is good evidence for interactions of OXT with the dopaminergic system, especially within the nucleus accumbens, where OXT promotes the rewarding effects of, for example, social interactions. [13] Moreover, there is also evidence for OXT interactions with the glutamatergic system, specifically with mGluR5 in the septum.…”