Serotonin 5-HT_1B receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin...

Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT_1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT_1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT_1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT_1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969.

We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT_1B receptor binding and 5-HT_1B-mediated sensorimotor deficits.

Specific binding to 5-HT_1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT_1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined.

While enhanced SERT function increased 5-HT_1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum.

While reducing 5-HT_1B receptors may attenuate sensorimotor gating deficits, increased 5-HT_1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.