Serotonin 1A Agonism Selectively Inhibits Affiliation in the Titi Monkey: Relevance to Social Deficits and Hyperserotonemia in Autism

Background:  Hyperserotonemia is present in roughly one third of individuals with autism, and central deficits in serotonin and oxytocin are associated with autism. Early in life, serotonin in blood may be activating 1A autoreceptors in the brainstem involved in a negative feedback loop which decreases serotonin activity in higher brain areas. Rodent models of hyperserotonemia indicate that it leads to an autistic-like phenotype, yet the processes involved in the suppression of social behavior in this model remain unclear, and comparative work in non-human primates is needed.

Objectives:  To model the effects of activation of the serotonin 1A negative feedback loop on affiliative behavior in male pair-bonded titi monkeys, in order to examine how serotonin autoreceptor activity is involved in social behavior. We also sought to characterize changes in peripheral oxytocin, vasopressin, and cortisol due to serotonin 1A agonism, and to correlate these peripheral measures with social behaviors of interest.

Methods:  8 adult male titi monkeys in established pair bonds were administered 0.1 mg/kg 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, a selective serotonin 1A receptor agonist) or saline vehicle daily for 15 consecutive days. Blood samples were taken 15 and 45 minutes post injection on days 1, 3, 8, 10 and 15. Behavior was recorded daily for 30 minutes with the pair-mate and coded for locomotor, sexual, arousal and affiliative behaviors. Blood plasma was assayed for oxytocin, vasopressin and cortisol.

Results:  8-OH-DPAT significantly inhibited affiliative behavior, including reductions in approaching the pair mate (F_1,209 = 18.42, p<.0001 ), initiation of physical contact (F_1,208 =14.54 , p<.001), duration of passive contact (F_1,209 = 4.85, p<.05), and lipsmacking (F_1,211 = 72.64, p<.0001). Oxytocin was significantly increased relative to the saline group (F_1,61 =4.71, p<.05) and a significant time by treatment interaction was found for cortisol (F_1,64= 5.6,  p<.05).

Conclusions:  Excess serotonergic autoreceptor activity decreases affiliative behavior in male titi monkeys, indicating that this process can directly impact social behavior absent a developmental context. Serotonin 1A autoreceptor agonism resulting from hyperserotonemia may be a significant factor leading to the social deficits seen in autism.

Funding: Autism Science Foundation Pre-doctoral fellowship, NIH HD053555, Office of Research Infrastructure Programs, grant P51OD011107, and the Good Nature Institute.