Serotonin 5-HT_1B receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant.

ABSTRACT:

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

SUBMITTER: O'Reilly KC 

PROVIDER: S-EPMC8728944 | biostudies-literature |

REPOSITORIES: biostudies-literature