Recent advances in understanding adverse effects associated with drugs targeting the serotonin receptor, 5-HT GPCR

Abstract

It has been acknowledged that more women suffer from adverse effects of drugs than men globally. A group of drugs targeting serotonin [5-hydroxytryptamine] (5-HT) binding G-protein-coupled receptors (GPCRs) have been reported to preferentially affect women more than men, causing adverse effects such as breast cancer and infertility. 5-HT GPCR-targeted drugs in the central nervous system (CNS) manage psychiatric conditions, such as depression or bipolar and in the peripheral nervous system (PNS) treat migraines. Physiological characteristics such as specific types of hormones, higher body fat density and smaller body mass in women result in disparities in pharmacodynamics of drugs, thus explaining sex-related differences in the observed adverse effects. In this review, we discuss the side effects of drugs targeting 5-HT GPCRs based on serotonin's roles in the CNS and PNS. We have systematically reviewed adverse effects of drugs targeting 5-HT GPCR using information from the Food and Drug Administration and European Medicines Agency. Further information on drug side effects and receptor targets was acquired from the SIDER and DrugBank databases, respectively. These drugs bind to 5-HT GPCRs in the CNS, namely the brain, and PNS such as breasts, ovaries and testes, potentially causing side effects within these areas. Oestrogen affects both the biosynthesis of 5-HT and the densities of 5-HT GPCRs in given tissues and cells. 5-HT GPCR-targeting drugs perturb this process. This is likely a reason why women are experiencing more adverse effects than men due to their periodic increase and the relatively high concentrations of oestrogen in women and, thus a greater incidence of the oestrogen-mediated 5-HT system interference. In addition, women have a lower concentration of serotonin relative to men and also have a relatively faster rate of serotonin metabolism which might be contributing to the former. We discuss potential approaches that could mitigate at least some of the adverse effects experienced by women taking the 5-HT GPCR-targeting drugs.

Keywords: CNS—central nervous system; GPCR (G protein coupled receptor); PNS—peripheral nervous system; oestrogen (E) 2; prolactin; serotonin 5-HT; tryptophane hydroxyrase (TPH).

Figure 1

Schematic diagram of the serotonin synthesis pathway following an increase in oestradiol in the peripheral nervous tissue. The increase in E2 leads to the activation of ERβ causing it to dimerize. Dimerized ERβ interacts with SP1 to inhibit HTR1A receptor transcription. Secondly, ERβ causes transcription of the HTR2A receptor gene, increasing 5-HT2a receptor protein in the cell. An increase in 5-HT2a results in an increase in tryptophan hydroxylase 2 (TPH2) mRNA and subsequently TPH2 protein. The dotted line represents an indirect induction of TPH2 by 5HT2a. Dimerized ERβ directly induces TPH2 transcription leading to TPH2 protein synthesis. TPH2 catalyses the conversion of tryptophan into 5-hydroxytryptophan, which is then converted into serotonin (5-hydroxytryptamine) via aromatic l-amino acid decarboxylase (AADC). Serotonin binding with 5-HT2a leads to positive feedback increasing TPH2 and resulting in serotonin production. Created with BioRender.com.

Figure 2

Relative hormone level during the four estrus phases. Cycling of oestrogen levels during the menstrual cycle was compared to the expression of HTR2A and HTR1A encoding 5-HT2a and 5-HT1a receptors, respectively. Oestrogen receptor (ER) also regulates TPH1 encoding one of the serotonin biosynthesis genes. Created with BioRender.com.

Figure 3

Physiological function of serotonin in reproductive organs. Diagrams present the function of serotonin in the uterus, fallopian tube, ovaries, cervix, breasts, testis and penis. Created with BioRender.com.