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

• Published in: Psychopharmacology Vol. 233; no. 1; pp. 57 - 70
• Main Authors: Ho, Emily V., Thompson, Summer L., Katzka, William R., Sharifi, Mitra F., Knowles, James A., Dulawa, Stephanie C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2016; Springer; Springer Nature B.V
• Subjects: Analysis; Animal behavior; Animals; Biomedical and Life Sciences; Biomedicine; Care and treatment; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Desipramine - pharmacology; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Female; Fluoxetine - pharmacology; Health aspects; Indoles - toxicity; Mice; Mice, Inbred C57BL; Murinae; Neurobiology; Neurophysiology; Neurosciences; Obsessive compulsive disorder; Obsessive-Compulsive Disorder - chemically induced; Obsessive-Compulsive Disorder - drug therapy; Obsessive-Compulsive Disorder - metabolism; Original Investigation; Pharmacology/Toxicology; Physiological aspects; Psychiatry; Psychopharmacology; Receptor, Serotonin, 5-HT1B - metabolism; Rodents; Serotonin; Serotonin 5-HT1 Receptor Agonists - pharmacology; Serotonin 5-HT1 Receptor Antagonists - pharmacology; Serotonin 5-HT1 Receptor Antagonists - therapeutic use; Serotonin Receptor Agonists - toxicity; Stereotyped Behavior - drug effects; Stereotyped Behavior - physiology; Treatment Outcome; Triptans; United States; Striatum; Exploratory behavior; Serotonin 1B receptor; Mouse model; Fos; Serotonin reuptake inhibitor; Repetitive behavior
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-015-4086-8

Rationale 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. Objectives 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. Methods 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. Results 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. Conclusions 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.