The effects of 5-hydroxytryptophan on attention and central serotonin neurochemistry in the rhesus macaque

Abstract

Psychiatric disorders, particularly depression and anxiety, are often associated with impaired serotonergic function. However, serotonergic interventions yield inconsistent effects on behavioral impairments. To better understand serotonin’s role in these pathologies, we investigated the role of serotonin in a behavior frequently impaired in depression and anxiety, attention. In this study, we used a quantitative, repeated, within-subject, design to test how L-5-hydroxytryptophan (5-HTP), the immediate serotonin precursor, modulates central serotoninergic function and attention in macaques. We observed that intramuscular 5-HTP administration increased cisternal cerebrospinal fluid (CSF) 5-HTP and serotonin. In addition, individuals’ baseline looking duration, during saline sessions, predicted the direction and magnitude in which 5-HTP modulated attention. We found that 5-HTP decreased looking duration in animals with high baseline attention, but increased looking duration in low baseline attention animals. Furthermore, individual differences in 5-HTP’s effects were also reflected in how engaged individuals were in the task and how they allocated attention to salient facial features—the eyes and mouth—of stimulus animals. However, 5-HTP constricted pupil size in all animals, suggesting that the bi-directional effects of 5-HTP cannot be explained by serotonin-mediated changes in autonomic arousal. Critically, high and low baseline attention animals exhibited different baseline CSF concentrations of 5-HTP and serotonin, an index of extracellular functionally active serotonin. Thus, our results suggest that baseline central serotonergic functioning may underlie and predict variation in serotonin’s effects on cognitive operation. Our findings may help inform serotonin’s role in psychopathology and help clinicians predict how serotonergic interventions will influence pathologies.

Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research

“…This is notable since receptor autoradiography in mice fails to detect OXTR in the nucleus accumbens, demonstrating the principle that OXTR on terminals are not detectable by autoradiography and therefore one cannot deduce all possible sites of OT action based on autoradiography. In rhesus monkeys intramuscular administration of the immediate serotonin precursor L-5-hydroxytryptophan (5-HTP) not only increased levels of serotonin in the CSF, but also interacted with individual variations in baseline attention and baseline levels of CSF serotonin to differentially modulate attentional changes (WeinbergWolf et al, 2018). Interestingly 5-HTP decreased the duration of looking at static images of conspecifics in animals with high baseline attention, but increased looking duration in low baseline attention animals (Weinberg-Wolf et al, 2018).…”

“…In rhesus monkeys intramuscular administration of the immediate serotonin precursor L-5-hydroxytryptophan (5-HTP) not only increased levels of serotonin in the CSF, but also interacted with individual variations in baseline attention and baseline levels of CSF serotonin to differentially modulate attentional changes (WeinbergWolf et al, 2018). Interestingly 5-HTP decreased the duration of looking at static images of conspecifics in animals with high baseline attention, but increased looking duration in low baseline attention animals (Weinberg-Wolf et al, 2018). Subcutaneous injections of a selective 5-HTP 1A agonist in male Titi monkeys decreased the social behaviors directed at a female pair-mate (Larke, Maninger, Ragen, Mendoza, & Bales, 2016), further implicating serotonergic activity in the regulation of primate social behavior.…”

Differences in how macaques monitor others: Does serotonin play a central role?

“…The inset shows the raw looking duration to social (filled bars) and non‐social images (open bars) for low and high baseline animals during saline (blue) and 5‐HTP (red) sessions. Adapted and reproduced with permission from Weinberg‐Wolf et al ()). (C) Average time courses of 5‐HTP's bi‐directional effect on attention to the mouth for low and high baseline animals.…”

“…Saline data shown in blue, and 40 mg/kg 5‐HTP in red. Adapted and reproduced with permission from Weinberg‐Wolf et al (). (d) Average time courses of 5‐HTP's effect on attention to conspecific eyes for low and high baseline animals.…”

Phasic activation of dorsal raphe serotonergic neurons increases pupil-linked arousal

“…However, the role of other modulatory pathways in the control of pupil-linked arousal has not been as thoroughly investigated, but evidence suggests that noradrenaline may not be alone [7,17,18]. Administration of serotonergic drugs seems to affect pupil size [19][20][21][22][23], but these effects have not been investigated in detail. Here, we show that transient serotonin (5-HT) activation, like noradrenaline, causes pupil-size changes.…”