title: Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice.
abstract: 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.
authors.affiliation: Committee on Neurobiology, University of Chicago, IL 60637, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Shanahan
authors.forename: Lady P
authors.initials: LP
authors.lastname: Velez
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Masten
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Dulawa
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000633:toxicity; D000161:Acoustic Stimulation / Q000009:adverse effects; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000818:Animals; D002997:Clomipramine / Q000494:pharmacology / Q000627:therapeutic use; D003891:Desipramine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007211:Indoles / Q000633:toxicity; D020120:Iodocyanopindolol / Q000493:pharmacokinetics; D007554:Isotopes / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009433:Neural Inhibition / Q000187:drug effects; D009771:Obsessive-Compulsive Disorder / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D017397:Prefrontal Cortex / Q000378:metabolism*; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000633:toxicity; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D018759:Adrenergic Uptake Inhibitors; D000319:Adrenergic beta-Antagonists; D002997:Clomipramine; D003891:Desipramine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007211:Indoles; D020120:Iodocyanopindolol; D007554:Isotopes; D044302:Receptor, Serotonin, 5-HT1B; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole