Essential Role for Orbitofrontal Serotonin 1B Receptors in Obsessive-Compulsive Disorder-Like Behavior and Serotonin Reuptake Inhibitor Response in Mice

Autor: Virginia L. Masten, Stephanie C. Dulawa, Lady P. Velez, Nancy A. Shanahan
Rok vydání: 2011
Předmět:
Agonist
Obsessive-Compulsive Disorder
medicine.medical_specialty
Clomipramine
Indoles
Time Factors
medicine.drug_class
Serotonin reuptake inhibitor
Adrenergic beta-Antagonists
Prefrontal Cortex
behavioral disciplines and activities
Mice
Isotopes
Internal medicine
Desipramine
mental disorders
medicine
Animals
Drug Interactions
Iodocyanopindolol
Serotonin Uptake Inhibitors
Swimming
Biological Psychiatry
Serotonin transporter
8-Hydroxy-2-(di-n-propylamino)tetralin
Mice
Inbred BALB C
Adrenergic Uptake Inhibitors
Dose-Response Relationship
Drug
biology
Neural Inhibition
humanities
Serotonin Receptor Agonists
Disease Models
Animal
Endocrinology
Acoustic Stimulation
Guanosine 5'-O-(3-Thiotriphosphate)
Exploratory Behavior
Receptor
Serotonin
5-HT1B
biology.protein
Female
Orbitofrontal cortex
Serotonin
Psychology
Selective Serotonin Reuptake Inhibitors
medicine.drug
Zdroj: Biological Psychiatry. 70:1039-1048
ISSN: 0006-3223
DOI: 10.1016/j.biopsych.2011.07.032
Popis: Background Perseveration and sensorimotor gating deficits are core features of obsessive-compulsive disorder (OCD). Serotonin 1B receptor (5-HT1BR) agonists exacerbate OCD symptoms in patients and induce perseveration and sensorimotor gating deficits in mice. Serotonin reuptake inhibitors (SRIs), but not noradrenaline reuptake inhibitors (NRIs), reduce OCD symptoms following 4 to 8 weeks of treatment. Using mice, we compared the effects of chronic SRI versus NRI treatment on 5-HT1BR-induced OCD-like behavior and 5-HT1BR sensitivity in orbitofrontal-subcortical OCD circuits. Furthermore, we localized the 5-HT1BR population that mediates OCD-like behavior. Methods Mice chronically received the SRI clomipramine or the NRI desipramine and were examined for 5-HT1BR-induced OCD-like behavior or 5-HT1BR binding and G-protein coupling in caudate putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior following 4, 14, 21, 28, or 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5-HT1BR agonist infusion or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment. Results Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time course that parallels the delayed therapeutic onset in OCD patients and downregulated 5-HT1BR expression in the orbitofrontal cortex. Intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment. Conclusions These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice and that SRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs. Our findings suggest an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment.
Databáze: OpenAIRE
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