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

Published:September 15, 2011DOI:


      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.


      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.


      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.


      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.

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        • Cartwright C.
        • Hollander E.
        SSRIs in the treatment of obsessive-compulsive disorder.
        Depress Anxiety. 1998; 8: 105-113
        • Fineberg N.A.
        • Gale T.M.
        Evidence-based pharmacotherapy of obsessive-compulsive disorder.
        Int J Neuropsychopharmacol. 2005; 8: 107-129
      1. Mavissakalian M, Jones B, Olson S, Perel JM (190): The relationship of plasma clomipramine and N-desmethylclomipramine to response in obsessive-compulsive disorder. Psychopharmacol Bull 26:119-122.

        • Goodman W.K.
        • Price L.H.
        • Delgado P.L.
        • Palumbo J.
        • Krystal J.H.
        • Nagy L.M.
        • et al.
        Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder.
        Arch Gen Psychiatry. 1990; 47: 577-585
        • Bourin M.
        • Lambert O.
        Pharmacotherapy of anxious disorders.
        Hum Psychopharmacol. 2002; 17: 383-400
        • Hoenig K.
        • Hochrein A.
        • Quednow B.B.
        • Maier W.
        • Wagner M.
        Impaired prepulse inhibition of acoustic startle in obsessive-compulsive disorder.
        Biol Psychiatry. 2005; 57: 1153-1158
        • Swerdlow N.R.
        • Benbow C.H.
        • Zisook S.
        • Geyer M.A.
        • Braff D.L.
        A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder.
        Biol Psychiatry. 1993; 33: 298-301
        • Graham F.K.
        Presidential Address, 1974.
        Psychophysiology. 1975; 12: 238-248
        • Gross-Isseroff R.
        • Cohen R.
        • Sasson Y.
        • Voet H.
        • Zohar J.
        Serotonergic dissection of obsessive compulsive symptoms: A challenge study with m-chlorophenylpiperazine and sumatriptan.
        Neuropsychobiology. 2004; 50: 200-205
        • Koran L.M.
        • Pallanti S.
        • Quercioli L.
        Sumatriptan, 5-HT(1D) receptors and obsessive-compulsive disorder.
        Eur Neuropsychopharmacol. 2001; 11: 169-172
        • Stein D.J.
        • Van Heerden B.
        • Wessels C.J.
        • Van Kradenburg J.
        • Warwick J.
        • Wasserman H.J.
        Single photon emission computed tomography of the brain with Tc-99m HMPAO during sumatriptan challenge in obsessive-compulsive disorder: Investigating the functional role of the serotonin auto-receptor.
        Prog Neuropsychopharmacol Biol Psychiatry. 1999; 23: 1079-1099
        • Boshuisen M.L.
        • den Boer J.A.
        Zolmitriptan (a 5-HT1B/1D receptor agonist with central action) does not increase symptoms in obsessive compulsive disorder.
        Psychopharmacology (Berl). 2000; 152: 74-79
        • Baxter Jr, L.R.
        • Schwartz J.M.
        • Mazziotta J.C.
        • Phelps M.E.
        • Pahl J.J.
        • Guze B.H.
        • Fairbanks L.
        Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder.
        Am J Psychiatry. 1988; 145: 1560-1563
        • Nordahl T.E.
        • Benkelfat C.
        • Semple W.E.
        • Gross M.
        • King A.C.
        • Cohen R.M.
        Cerebral glucose metabolic rates in obsessive compulsive disorder.
        Neuropsychopharmacology. 1989; 2: 23-28
        • Swedo S.E.
        • Schapiro M.B.
        • Grady C.L.
        • Cheslow D.L.
        • Leonard H.L.
        • Kumar A.
        • et al.
        Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder.
        Arch Gen Psychiatry. 1989; 46: 518-523
        • Breiter H.C.
        • Rauch S.L.
        • Kwong K.K.
        • Baker J.R.
        • Weisskoff R.M.
        • Kennedy D.N.
        • et al.
        Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder.
        Arch Gen Psychiatry. 1996; 53: 595-606
        • Cottraux J.
        • Gerard D.
        • Cinotti L.
        • Froment J.C.
        • Deiber M.P.
        • Le Bars D.
        • et al.
        A controlled positron emission tomography study of obsessive and neutral auditory stimulation in obsessive-compulsive disorder with checking rituals.
        Psychiatry Res. 1996; 60: 101-112
        • Benkelfat C.
        • Nordahl T.E.
        • Semple W.E.
        • King A.C.
        • Murphy D.L.
        • Cohen R.M.
        Local cerebral glucose metabolic rates in obsessive-compulsive disorder.
        Arch Gen Psychiatry. 1990; 47: 840-848
        • Saxena S.
        • Brody A.L.
        • Maidment K.M.
        • Dunkin J.J.
        • Colgan M.
        • Alborzian S.
        • et al.
        Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in obsessive-compulsive disorder.
        Neuropsychopharmacology. 1999; 21: 683-693
        • Swedo S.E.
        • Pietrini P.
        • Leonard H.L.
        • Schapiro M.B.
        • Rettew D.C.
        • Goldberger E.L.
        • et al.
        Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder.
        Arch Gen Psychiatry. 1992; 49: 690-694
        • Dulawa S.C.
        • Geyer M.A.
        Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice.
        Neuropharmacology. 2000; 39: 2170-2179
        • Dulawa S.C.
        • Hen R.
        • Scearce-Levie K.
        • Geyer M.A.
        Serotonin 1B receptor modulation of startle reactivity, habituation, and prepulse inhibition in wild-type and serotonin1B knockout mice.
        Psychopharmacology (Berl). 1997; 132: 125-134
        • Chaouloff F.
        • Courvoisier H.
        • Moisan M.P.
        • Mormede P.
        GR 127935 reduces basal locomotor activity and prevents RU 24969-, but not D-amphetamine-induced hyperlocomotion, in the Wistar-Kyoto hyperactive (WKHA) rat.
        Psychopharmacology (Berl). 1999; 141: 326-331
        • Oberlander C.
        • Blaquiere B.
        • Pujol J.F.
        Distinct functions for dopamine and serotonin in locomotor behaviour: Evidence using the 5-HT1 agonist RU 24969 in globus pallidus-lesioned rats.
        Neurosci Lett. 1986; 67: 113-118
        • Rempel N.L.
        • Callaway C.W.
        • Geyer M.A.
        Serotonin 1B receptor activation mimics behavioral effects of presynaptic serotonin release.
        Neuropsychopharmacology. 1993; 8: 201-211
        • Shanahan N.A.
        • Holick Pierz K.A.
        • Masten V.L.
        • Waeber C.
        • Ansorge M.
        • Gingrich J.A.
        • et al.
        Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice.
        Biol Psychiatry. 2009; 65: 401-408
        • Montgomery S.
        Pharmacological treatment of obsessive-compulsive disorder.
        in: Hollander E. Zohar J. Marazziti D. Olivier B. Current Insights in Obsessive Disorder. Wiley, New York1994: 215-226
        • Blier P.
        The pharmacology of putative early-onset antidepressant strategies.
        Eur Neuropsychopharmacol. 2003; 13: 57-66
        • Dulawa S.C.
        • Holick K.A.
        • Gundersen B.
        • Hen R.
        Effects of chronic fluoxetine in animal models of anxiety and depression.
        Neuropsychopharmacology. 2004; 29: 1321-1330
        • Thomsen P.H.
        • Jensen J.
        Obsessive-compulsive disorder: Admission patterns and diagnostic stability.
        Acta Psychiatr Scand. 1994; 90: 19-24
        • Bebbington P.E.
        Epidemiology of obsessive-compulsive disorder.
        Br J Psychiatry Suppl. 1998; 35: 2-6
        • Fireman B.
        • Koran L.M.
        • Leventhal J.L.
        • Jacobson A.
        The prevalence of clinically recognized obsessive-compulsive disorder in a large health maintenance organization.
        Am J Psychiatry. 2001; 158: 1904-1910
        • Geyer M.A.
        • Dulawa S.C.
        Assessment of murine startle response, prepulse inhibition, and habituation.
        in: Crawley J. Skolnick P. Current Protocols in Neuroscience. Jon Wiley & Sons, New York2004
        • Mansbach R.S.
        • Geyer M.A.
        • Braff D.L.
        Dopaminergic stimulation disrupts sensorimotor gating in the rat.
        Psychopharmacology (Berl). 1988; 94: 507-514
        • Holick K.A.
        • Lee D.C.
        • Hen R.
        • Dulawa S.C.
        Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor.
        Neuropsychopharmacology. 2008; 33: 406-417
        • Cryan J.F.
        • Page M.E.
        • Lucki I.
        Noradrenergic lesions differentially alter the antidepressant-like effects of reboxetine in a modified forced swim test.
        Eur J Pharmacol. 2002; 436: 197-205
        • Borsini F.
        • Lecci A.
        • Sessarego A.
        • Frassine R.
        • Meli A.
        Discovery of antidepressant activity by forced swimming test may depend on pre-exposure of rats to a stressful situation.
        Psychopharmacology (Berl). 1989; 97: 183-188
        • Waeber C.
        • Palacios J.M.
        Non 5-HT1A/5-HT1C [3H]5-HT binding sites in the hamster, opossum, and rabbit brain show similar regional distribution but different sensitivity to beta-adrenoceptor antagonists.
        Synapse. 1992; 12: 261-270
        • Paulus M.P.
        • Geyer M.A.
        Quantitative assessment of the microstructure of rat behavior: I, f(d), the extension of the scaling hypothesis.
        Psychopharmacology (Berl). 1993; 113: 177-186
        • Martinez-Price D.L.
        • Geyer M.A.
        Subthalamic 5-HT(1A) and 5-HT(1B) receptor modulation of RU 24969-induced behavioral profile in rats.
        Pharmacol Biochem Behav. 2002; 71: 569-580
        • Cheetham S.C.
        • Heal D.J.
        Evidence that RU 24969-induced locomotor activity in C57/B1/6 mice is specifically mediated by the 5-HT1B receptor.
        Br J Pharmacol. 1993; 110: 1621-1629
        • Peroutka S.J.
        Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex.
        J Neurochem. 1986; 47: 529-540
        • Saxena S.
        • Rauch S.L.
        Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder.
        Psychiatr Clin North Am. 2000; 23: 563-586
        • Chudasama Y.
        • Robbins T.W.
        Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: Further evidence for the functional heterogeneity of the rodent frontal cortex.
        J Neurosci. 2003; 23: 8771-8780
        • Bechara A.
        • Tranel D.
        • Damasio H.
        Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions.
        Brain. 2000; 123: 2189-2202
        • Geyer M.A.
        • Markou A.
        Animal models of psychiatric disorders.
        in: Bloom F. Kupfer D. Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York1995: 787-798
        • Korff S.
        • Stein D.J.
        • Harvey B.H.
        Stereotypic behaviour in the deer mouse: Pharmacological validation and relevance for obsessive compulsive disorder.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 348-355
        • Greene-Schloesser D.M.
        • Van der Zee E.A.
        • Sheppard D.K.
        • Castillo M.R.
        • Gregg K.A.
        • Burrow T.
        • et al.
        Predictive validity of a non-induced mouse model of compulsive-like behavior.
        Behav Brain Res. 2011; 221: 55-62
        • Shmelkov S.V.
        • Hormigo A.
        • Jing D.
        • Proenca C.C.
        • Bath K.G.
        • Milde T.
        • et al.
        Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice.
        Nat Med. 2010; 16: 598-602
        • Sugimoto Y.
        • Tagawa N.
        • Kobayashi Y.
        • Hotta Y.
        • Yamada J.
        Effects of the serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran on marble burying behavior in mice.
        Biol Pharm Bull. 2007; 30: 2399-2401
        • Welch J.M.
        • Lu J.
        • Rodriguiz R.M.
        • Trotta N.C.
        • Peca J.
        • Ding J.D.
        • et al.
        Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice.
        Nature. 2007; 448: 894-900
        • Wang L.
        • Simpson H.B.
        • Dulawa S.C.
        Assessing the validity of current mouse genetic models of obsessive-compulsive disorder.
        Behav Pharmacol. 2009; 20: 119-133
        • Hoffman K.L.
        • Rueda Morales R.I.
        Toward an understanding of the neurobiology of ”just right” perceptions: Nest building in the female rabbit as a possible model for compulsive behavior and the perception of task completion.
        Behav Brain Res. 2009; 204: 182-191
        • Korff S.
        • Harvey B.H.
        Animal models of obsessive-compulsive disorder: Rationale to understanding psychobiology and pharmacology.
        Psychiatr Clin North Am. 2006; 29: 371-390
        • Bejerot S.
        An autistic dimension: A proposed subtype of obsessive-compulsive disorder.
        Autism. 2007; 11: 101-110
        • Leyfer O.T.
        • Folstein S.E.
        • Bacalman S.
        • Davis N.O.
        • Dinh E.
        • Morgan J.
        • et al.
        Comorbid psychiatric disorders in children with autism: Interview development and rates of disorders.
        J Autism Dev Disord. 2006; 36: 849-861
        • Ozaki N.
        • Goldman D.
        • Kaye W.H.
        • Plotnicov K.
        • Greenberg B.D.
        • Lappalainen J.
        • et al.
        Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype.
        Mol Psychiatry. 2003; 8: 933-936
        • Bolton P.F.
        • Pickles A.
        • Murphy M.
        • Rutter M.
        Autism, affective and other psychiatric disorders: Patterns of familial aggregation.
        Psychol Med. 2004; 28: 385-395
        • Micali N.
        • Chakrabarti S.
        • Fombonne E.
        The broad autism phenotype: Findings from an epidemiological survey.
        Autism. 2004; 8: 21-37
        • Hollander E.
        • King A.
        • Delaney K.
        • Smith C.J.
        • Silverman J.M.
        Obsessive-compulsive behaviors in parents of multiplex autism families.
        Psychiatry Res. 2003; 117: 11-16
        • Frankland P.W.
        • Wang Y.
        • Rosner B.
        • Shimizu T.
        • Balleine B.W.
        • Dykens E.M.
        • et al.
        Sensorimotor gating abnormalities in young males with fragile × syndrome and Fmr1-knockout mice.
        Mol Psychiatry. 2004; 9: 417-425
        • McAlonan G.M.
        • Daly E.
        • Kumari V.
        • Critchley H.D.
        • van Amelsvoort T.
        • Suckling J.
        • et al.
        Brain anatomy and sensorimotor gating in Asperger's syndrome.
        Brain. 2002; 125: 1594-1606
        • Hollander E.
        • Novotny S.
        • Allen A.
        • Aronowitz B.
        • Cartwright C.
        • DeCaria C.
        The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder.
        Neuropsychopharmacology. 2000; 22: 163-167
        • Novotny S.
        • Hollander E.
        • Allen A.
        • Mosovich S.
        • Aronowitz B.
        • Cartwright C.
        • et al.
        Increased growth hormone response to sumatriptan challenge in adult autistic disorders.
        Psychiatry Res. 2000; 94: 173-177
        • Novotny S.
        • Hollander E.
        • Phillips A.
        • Allen A.
        • Wasserman S.
        • Iyengar R.
        Increased repetitive behaviours and prolactin responsivity to oral m-chlorophenylpiperazine in adults with autism spectrum disorders.
        Int J Neuropsychopharmacol. 2004; 7: 249-254
        • Brodkin E.S.
        • McDougle C.J.
        • Naylor S.T.
        • Cohen D.J.
        • Price L.H.
        Clomipramine in adults with pervasive developmental disorders: A prospective open-label investigation.
        J Child Adolesc Psychopharmacol. 1997; 7: 109-121
        • Bachevalier J.
        • Loveland K.A.
        The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism.
        Neurosci Biobehav Rev. 2006; 30: 97-117
        • Dawson G.
        • Munson J.
        • Estes A.
        • Osterling J.
        • McPartland J.
        • Toth K.
        • et al.
        Neurocognitive function and joint attention ability in young children with autism spectrum disorder versus developmental delay.
        Child Dev. 2002; 73: 345-358
        • Salmond C.H.
        • de Haan M.
        • Friston K.J.
        • Gadian D.G.
        • Vargha-Khadem F.
        Investigating individual differences in brain abnormalities in autism.
        Philos Trans R Soc Lond B Biol Sci. 2003; 358: 405-413
        • Engel G.
        • Gothert M.
        • Hoyer D.
        • Schlicker E.
        • Hillenbrand K.
        Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites.
        Naunyn Schmiedebergs Arch Pharmacol. 1986; 332: 1-7
        • Johanning H.
        • Plenge P.
        • Mellerup E.
        Serotonin receptors in the brain of rats treated chronically with imipramine or RU24969: Support for the 5-HT1B receptor being a 5-HT autoreceptor.
        Pharmacol Toxicol. 1992; 70: 131-134
        • Wu S.Y.
        • Wang M.Y.
        • Dun N.J.
        Serotonin via presynaptic 5-HT1 receptors attenuates synaptic transmission to immature rat motoneurons in vitro.
        Brain Res. 1991; 554: 111-121
        • Bennett-Clarke C.A.
        • Leslie M.J.
        • Chiaia N.L.
        • Rhoades R.W.
        Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons.
        Proc Natl Acad Sci U S A. 1993; 90: 153-157
        • Blier P.
        • de Montigny C.
        Current advances and trends in the treatment of depression.
        Trends Pharmacol Sci. 1994; 15: 220-226
        • Briley M.
        • Moret C.
        The possibility of 5-HT1B autoreceptors in the action of serotonergic antidepressant drugs.
        in: Briley M. Montgomery S.A. Antidepressant Therapy: At the Dawn of the Third Millenium. Martin Dunitz, London1998: 37-54
        • Bergqvist P.B.
        • Bouchard C.
        • Blier P.
        Effect of long-term administration of antidepressant treatments on serotonin release in brain regions involved in obsessive-compulsive disorder.
        Biol Psychiatry. 1999; 45: 164-174
        • el Mansari M.
        • Bouchard C.
        • Blier P.
        Alteration of serotonin release in the guinea pig orbito-frontal cortex by selective serotonin reuptake inhibitors.
        Neuropsychopharmacology. 1995; 13: 117-127
        • Bramley J.R.
        • Sollars P.J.
        • Pickard G.E.
        • Dudek F.E.
        5-HT1B receptor-mediated presynaptic inhibition of GABA release in the suprachiasmatic nucleus.
        J Neurophysiol. 2005; 93: 3157-3164
        • Matsuoka T.
        • Hasuo H.
        • Akasu T.
        5-Hydroxytryptamine 1B receptors mediate presynaptic inhibition of monosynaptic IPSC in the rat dorsolateral septal nucleus.
        Neurosci Res. 2004; 48: 229-238
        • Simpson H.B.
        Pharmacological treatment of obsessive-compulsive disorder.
        Curr Top Behav Neurosci. 2010; 2: 527-543
        • Franklin K.B.J.
        • Paxinos G.
        The Mouse Brain in Stereotaxic Coordinates.
        3rd ed. Academic Press, San Diego, CA2007

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      • Pathophysiological Modeling of Obsessive-Compulsive Disorder: Challenges, and Progress
        Biological PsychiatryVol. 70Issue 11
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          Animal models of disease can enormously advance our understanding of pathophysiology and the development of new treatments. Insight into Parkinson's disease, for example, has been greatly advanced by the demonstration that recapitulating pathologic degeneration of substantia nigra dopaminergic neurons produces behavioral changes reminiscent of the disorder and by subsequent pathophysiologic and therapeutic investigations in this model (1). Genetic models of Alzheimer's and Huntington's diseases have likewise been enormously fruitful in shining light on the pathophysiology of these conditions and identifying new therapeutic targets (1).
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