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Pharmacologically induced hyperserotonemia: Perinatal treatments of rats with 5- hydroxytryptophan and tranylcypromine

Introduction: Serotonin (5-hydroxytryptamine, 5HT) is present both, in brain and peripheral tissues where it mediates various physiological functions. It also regulates perinatal development of serotonergic neurons and target tissues. Alterations in 5HT neurotransmission are indicated as biological substrates in several neuropsychiatric disorders, including autism. The most consistent 5HT-related finding in autistic disorder is hyperserotonemia (elevated blood 5HT concentration), but the mechanism of its development and its relation to central 5HT dysfunction are still unclear. It is assumed that high blood 5HT levels, resulting from dysregulation of the peripheral 5HT-homeostasis, could reach the brain, before the formation of the blood-brain barrier, and inhibit accurate development of 5HT neurons. The aim of this study was to pharmacologically induce hyperserotonemia during the period of most intensive development of 5HT neurons using either the immediate 5HT precursor, 5- hydroxytryptophan (5HTP), or the non-selective irreversible MAO inhibitor tranylcypromine (TCP). Materials and methods: After mating and confirmation of pregnancy, female Wistar rats were treated with 25 mg/kg 5HTP, 2 mg/kg TCP, or saline, subcutaneously from gestational day 13 until delivery. 24 hours after birth, survived pups continued to receive the respective treatment until postnatal day (PND) 21. Blood 5HT concentrations were determined by ELISA at PND 21 and PND 70. Also, the number of born and survived pups in each litter was recorded, body mass increase over time was monitored, and the level of anxiety produced by separation of pups from their mother was examined at PND 17. Results: Treatment with both compounds, in comparison with saline treatment, resulted in significantly elevated blood 5HT concentrations at PND 21. While treatment with 5HTP induced only temporary increase in peripheral 5HT concentrations, the effects of TCP lasted into adulthood. Compared to the control group, both experimental groups had smaller litters, significantly lower pup survival rate, and slower weight gain during the post-weaning free-feeding period. Significant effect of treatment on separation anxiety was also observed, with 5HTP and TCP acting in the opposite direction: 5HTP- treated rats returned to their dams faster, and TCP- treated rats slower than the saline-treated rats. Conclusions: Our results indicate that the perinatal treatments of rats with 5HTP and TCP during the critical phase of brain development have caused hyperserotonemia, as well as physiological disturbances in pups and young rats. The observed effects are likely caused by the disregulation of the peripheral 5HT homeostasis, but disturbances in the central 5HT compartment are also indicated. The extent of the changes in the central serotonergic compartment in adult rats will be explored in further studies.

Serotonin ; autism ; brain development ; blood serotonin levels ; physiological consequences

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