Oxytocin and Serotonin Brain Mechanisms in the Nonhuman Primate

Abstract

Oxytocin (OT) is increasingly studied for its therapeutic potential in psychiatric disorders, which are associated with the deregulation of several neurotransmission systems. Studies in rodents demonstrated that the interaction between OT and serotonin (5-HT) is critical for several aspects of social behavior. Using PET scan in humans, we have recently found that 5-HT 1A receptor (5-HT_1AR) function is modified after intranasal oxytocin intake. However, the underlying mechanism between OT and 5-HT remains unclear. To understand this interaction, we tested 3 male macaque monkeys using both [¹¹C]DASB and [¹⁸F]MPPF, two PET radiotracers, marking the serotonin transporter and the 5-HT_1AR, respectively. Oxytocin (1 IU in 20 μl of ACSF) or placebo was injected into the brain lateral ventricle 45 min before scans. Additionally, we performed postmortem autoradiography. Compared with placebo, OT significantly reduced [¹¹C]DASB binding potential in right amygdala, insula, and hippocampus, whereas [¹⁸F]MPPF binding potential increased in right amygdala and insula. Autoradiography revealed that [¹¹C]DASB was sensitive to physiological levels of 5-HT modification, and that OT does not act directly on the 5-HT_1AR. Our results show that oxytocin administration in nonhuman primates influences serotoninergic neurotransmission via at least two ways: (1) by provoking a release of serotonin in key limbic regions; and (2) by increasing the availability of 5-HT_1AR receptors in the same limbic areas. Because these two molecules are important for social behavior, our study sheds light on the specific nature of their interaction, therefore helping to develop new mechanisms-based therapies for psychiatric disorders.SIGNIFICANCE STATEMENT Social behavior is largely controlled by brain neuromodulators, such as oxytocin and serotonin. While these are currently targeted in the context of psychiatric disorders such as autism and schizophrenia, a new promising pharmaceutical strategy is to study the interaction between these systems. Here we depict the interplay between oxytocin and serotonin in the nonhuman primate brain. We found that oxytocin provokes the release of serotonin, which in turn impacts on the serotonin 1A receptor system, by modulating its availability. This happens in several key brain regions for social behavior, such as the amygdala and insula. This novel finding can open ways to advance treatments where drugs are combined to influence several neurotransmission networks.

Keywords: PET scan; nonhuman primate; oxytocin; serotonin.

Figure 1.

Anatomical MRI from Monkey V (left) and Monkey J (right) at the end of the experiment. Red ellipse indicates the path of the needle.

Figure 2.

OT decreased DASB BP_ND. Top, T-map SPM analysis (voxel significance level p < 0.0001, uncorrected) showing the effects of OT on DASB BP_ND compared with placebo (placebo > OT). Effects were localized in the right amygdala (cluster a), right insula (cluster b), and right hippocampus (cluster c). On the sagital slice (right image) are also small nonsignificant clusters and an anterior extension of the amygdala activity. Bottom, Bar plot illustrating the mean values (n = 14) in the OT and PLA sessions. Such differences were not found in the left hemisphere or in other regions with high DASB binding potential, such as the thalamus. Error bars indicate SEM.

Figure 3.

OT increases MPPF BP_ND. Top, T-map SPM analysis (voxel significance level p < 0.01, uncorrected) showing the effects of OT on MPPF BP_ND compared with placebo (OT > placebo). Effects were localized in the right amygdala (left) and the right insula (right). Middle, Scale bar indicates T score. Bottom, Mean BP_ND inside amygdala and insula clusters, for each scan (n = 16, extracted from SPM and normalized per individual). The average increase of BP_ND after OT is 33.3% in the amygdala and 32.8% in the insula (compared with the ∼5% obtained in humans). Error bars indicate SEM.

Figure 4.

DASB is sensitive to serotonin concentration. Adjacent macaque coronal slices incubated with DASB and increasing concentrations of 5-HT. DASB labeling of the serotonin transporter decreases in a dose-dependent manner. Graph shows PSL values (mean of two duplicates) of the hippocampus.

Figure 5.

MPPF is insensitive to OT concentration. Adjacent macaque coronal slices incubated with MPPF and increasing concentrations of OT did not show any effects of OT on 5-HT_1A-r MPPF labeling.