Clinically effective OCD treatment prevents 5-HT1B receptor-induced repetitive behavior and striatal activation

Serotonin-1B receptor (5-HT1BR) agonist treatment induces obsessive-compulsive disorder (OCD)-like behaviors including locomotor stereotypy, prepulse inhibition deficits, and delayed alternation disruptions, which are selectively prevented by clinically effective OCD treatment. However, the role of 5-HT1BRs in modulating other repetitive behaviors or OCD-like patterns of brain activation remains unclear.

We assessed the effects of 5-HT1BR agonism on digging, grooming, and open field behaviors in mice. We also quantified effects on neuronal activation in brain regions overactivated in OCD. Finally, we assessed whether effects of the 5-HT1BR challenge could be blocked by clinically effective, but not ineffective, drug treatments.

Mice were tested in open field, dig, and splash tests after acute treatment with saline, 1, 3, 5, or 10 mg/kg RU24969 (5-HT1B/1A agonist). Behavioral effects of RU24969 were also tested following co-treatment with vehicle, 1 mg/kg WAY100635 (5-HT1A antagonist) and 5 or 10 mg/kg GR127935 (5HT1B/D antagonist). Separate mice were behaviorally assessed following chronic pretreatment with vehicle with 10 mg/kg fluoxetine or 20 mg/kg desipramine and acute treatment with saline or 10 mg/kg RU24969. Brains were analyzed for Fos expression in the orbitofrontal cortex, the dorsal striatum, and the cerebellum.

RU24969 induced robust locomotor stereotypy and decreased rearing, digging, and grooming. Effects were blocked by GR127935 but not by WAY100635. RU24969 also increased Fos expression in the dorsal striatum. Chronic fluoxetine, but not desipramine, alleviated 5-HT1BR-induced effects.

We report novel 5-HT1BR-induced behaviors and striatal activation that were alleviated only by clinically effective pharmacological OCD treatment. Studying the mechanisms underlying these effects could provide insight into OCD pathophysiology.