Bone growth in juvenile rhesus monkeys is influenced by 5HTTLPR polymorphisms and interactions between 5HTTLPR polymorphisms and fluoxetine

Abstract

Male rhesus monkeys received a therapeutic oral dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine daily from 1 to 3 years of age. Puberty is typically initiated between 2 and 3 years of age in male rhesus and reproductive maturity is reached at 4 years. The study group was genotyped for polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (SERT) genes that affect serotonin neurotransmission. Growth was assessed with morphometrics at 4 month intervals and radiographs of long bones were taken at 12 month intervals to evaluate skeletal growth and maturation. No effects of fluoxetine, or MAOA or SERT genotype were found for growth during the first year of the study. Linear growth began to slow during the second year of the study and serotonin reuptake transporter (SERT) long polymorphic region (5HTTLPR) polymorphism effects with drug interactions emerged. Monkeys with two SERT 5HTTLPR L alleles (LL, putative greater transcription) had 25–39% less long bone growth, depending on the bone, than monkeys with one S and one L allele (SL). More advanced skeletal maturity was also seen in the LL group, suggesting earlier onset of puberty. An interaction between 5HTTLPR polymorphisms and fluoxetine was identified for femur and tibia growth; the 5HTTLPR effect was seen in controls (40% less growth for LL) but not in the fluoxetine treated group (10% less growth for LL). A role for serotonin in peripubertal skeletal growth and maturation has not previously been investigated but may be relevant to treatment of children with SSRIs.

Peripheral fibroblast metabolic pathway alterations in juvenile rhesus monkeys undergoing long-term fluoxetine administration

“…The cohort of male rhesus monkeys ( Macaca mulatto ) that were sampled for this study has been described previously (He et al, 2014; Golub et al, 2015). At approximately 1 year of age animals were selected from the outdoor colony at the CNPRC, relocated to indoor caging, and assigned to treatment (fluoxetine) or control (vehicle) groups.…”

“…The long postnatal period during which the primate brain matures provides an appropriate animal model for investigating juvenile brain development and its response to drugs. Juvenile macaque monkeys, the most common laboratory NHP, are becoming a preferred model for studying short- and long-term effects of psychoactive agents used in children (Popke et al 2001; Patterson et al, 2010; Rodriguez et al, 2010; Soto et al, 2012; Shrestha et al, 2014; Golub et al, 2015). …”

Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions

“…The ages of the rhesus macaque subjects in the present study (one to four years of age) correspond roughly to four to twelve year-old children. Previous reports from this project have described dose selection (Golub and Hogrefe, 2014), metabolomic biomarkers of drug action (He et al, 2014), bone growth (Golub et al, 2015), sleep disturbance (Golub and Hogrefe, 2016), and social interaction (Golub et al, 2016). …”

Selective serotonin reuptake inhibitors and dental implant failure—A significant concern in elders?

“…A substantial influence of the serotonin reuptake transporter genotype on the SSRI induced slowing of long bone development has been shown. 10 Similarly, genetic 5-HT variations have been related to differences in bone turnover. 11 Next, different SSRI drugs and doses may differ in their effect on bone.…”

“…Serotonin receptor affinity tends to significant genetic variation. A substantial influence of the serotonin reuptake transporter genotype on the SSRI induced slowing of long bone development has been shown . Similarly, genetic 5‐HT variations have been related to differences in bone turnover .…”