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

Committee on Neurobiology, University of Chicago, IL 60637, USA.
Biological psychiatry (Impact Factor: 10.26). 09/2011; 70(11):1039-48. DOI: 10.1016/j.biopsych.2011.07.032
Source: PubMed


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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Available from: Stephanie C Dulawa, Dec 14, 2013
    • "Earlier studies in the deer mouse have indeed highlighted cortico-striatal differences between HS and [NS/LS] animals but with respect to other biological parameters, although favouring a greater disturbance in the frontal-cortex [1,3]. Interestingly, in a different mouse model of OCD that also focused on rigid locomotor behaviour [50] , stimulation of orbito-frontal 5HT 1B/D -receptors was associated with the expression of rigid hyperlocomotion and perseveration along a certain set of locomotor paths, leading the authors to conclude that activation of orbitofrontal, but not striatal, 5HT 1B/D receptors is necessary for the expression of OCD-like behaviour. Although SERT binding described here confirms a perturbation in striatal serotonin functioning, it is important to note that the two models differ with respect to the etiological mechanisms underlying compulsive-like behaviour. "
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    ABSTRACT: Obsessive-compulsive disorder (OCD) is characterized by recurrent thoughts and repetitive motor actions. Hyposerotonergic signalling in the cortico-striatal circuitry is believed to be central to the pathology of OCD, while many patients only respond to chronic treatment with high dose selective serotonin (5HT) reuptake inhibitors (SSRIs). Confined deer mice spontaneously develop two forms of stereotypy, namely vertical jumping and pattern running. The purpose of this investigation was to reappraise these behaviours and strengthen the validity of deer mouse stereotypy as an animal model of OCD within a framework of three study questions: 1) can the time spent executing stereotypical behaviours be employed as a measure of extent of stereotypy, 2) does deer mouse stereotypy only respond to chronic, but not sub-chronic treatment with a high-dose SSRI, and 3) is deer mouse stereotypy associated with altered cortico-striatal SERT binding?The current study demonstrates that treatment naïve high stereotypical (HS) deer mice spend significantly more time executing stereotypical behaviours while significantly less time is spent indulging in stereotypy following chronic, but not sub-chronic,treatment with escitalopram. Furthermore, HS deer mice present with a significant decrease in striatal SERT density compared to the non-stereotypical (NS) controls. Building on previous validation studies, we conclude that deer mouse stereotypy is a valid naturalistic animal model of OCD with robust face, construct and predictive validity.
    No preview · Article · Sep 2013 · Behavioural brain research
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    • "Specifically, the mechanisms of action responsible for the SRI effect on obsessive-compulsive symptoms are not completely understood . Results from animal studies suggest that downregulation of 5-HT1BR expression in the orbitofrontal cortex is necessary to reduce repetitive behaviors in mice (Shanahan et al., 2011). This down-regulation is a delayed effect of chronic exposure to SRI and also has a cumulative effect. "
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    ABSTRACT: Unlabelled: In major depression, early response to treatment has been strongly associated with final outcome. We aimed to investigate the ability of early improvement (4 weeks) to predict treatment response at 12 weeks in DSM-IV-defined obsessive-compulsive disorder (OCD) patients treated with serotonin reuptake inhibitors (SRI). We conducted an SRI practical trial with 128 subjects. Inclusion criteria: age range 18-65 years-old, baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score ≥ 16, and absence of previous adequate pharmacological treatment. Systematic assessments were performed at baseline, 4 and 12 weeks of treatment. Treatment response at 12 weeks was defined as a 35% or greater reduction in baseline Y-BOCS score. Stepwise logistic regression was used to test the relationship between early improvement and treatment response at 12 weeks, taking into account additional potential predictive factors. Different thresholds of early improvement were tested and their predictive power was calculated. Early improvement, defined as a 20% or greater reduction from baseline Y-BOCS score at 4 weeks, predicted response at 12 weeks with 75.6% sensitivity and 61.9% specificity. According to a logistic regression including demographic and clinical features as explaining variables, early improvement was the best predictor of treatment response (OR = 1.05, p < 0.0001). Only 19.8% of patients who did not improve at 4 weeks were responders after 12 weeks. In contrast, 55.3% of the individuals who showed early improvement were responders at 12 weeks (Pearson Chi-Square = 17.06, p < 0.001). Early improvement predicted OCD treatment response with relatively good sensitivity and specificity, such that its role in early decision-making warrants further investigation in wider samples. Trial registration: Identifier NCT00680602.
    Full-text · Article · Aug 2013 · Journal of Psychiatric Research
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    • "In summary, we show that 5-HT1B receptor activation disrupts DAT accuracy , and chronic fluoxetine pretreatment prevents these 5- HT1B-induced deficits. Our previous work showing that chronic fluoxetine treatment downregulates 5-HT1B receptor expression in the orbitofrontal cortex (Shanahan et al. 2011) provides a likely mechanism for fluoxetine's prevention of 5-HT1B-induced deficits in DAT performance. Moreover, 5-HT1B-induced deficits in DAT performance may provide a mouse model for DAT deficits in OCD patients since OCD patients exhibit delayed alternation deficits , and chronic SRI treatment alleviates OCD symptoms. "
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    ABSTRACT: Rationale Obsessive-compulsive disorder (OCD) patients show overactivation of the orbitofrontal cortex and deficits in cognitive tasks that require proper orbitofrontal functioning including delayed alternation tests of spatial working memory. We recently showed that OCD-like behavior is induced in mice by activating orbitofrontal serotonin 1B receptors (5-HT1Bs). However, the role of 5-HT1Bs in delayed alternation remains unclear. Objectives We examined the effects of 5-HT1B receptor activation on delayed alternation task (DAT) performance. We also assessed the ability of an effective OCD treatment, fluoxetine, to prevent 5-HT1B-induced deficits in DAT performance. Methods Mice were tested on the DAT after acute treatment with saline, 3 or 6 mg/kg RU24969 (5-HT1B/1A agonist), 0.3 or 3 mg/kg 8-OH-DPAT (5-HT1A agonist), or co-injection with 3 mg/kg RU24969 and 5 mg/kg GR127935 (5-HT1B/1D antagonist). Separate mice were pretreated chronically (28 days) with 10 mg/kg fluoxetine and then tested on the DAT after acute treatment with 3 mg/kg RU24969, 0.3 mg/kg 8-OH-DPAT, or saline. Results Both doses of RU24969 decreased accuracy and increased latency on the DAT, and GR127935 blocked RU24969-induced effects on accuracy. The 0.3 mg/kg 8-OH-DPAT did not affect the DAT performance, whereas 3 mg/kg increased omissions on the DAT. Finally, RU24969-induced DAT deficits were absent in fluoxetine-pretreated mice. Conclusions We show that 5-HT1B receptor activation disrupts DAT performance in mice, and chronic fluoxetine pretreatment blocks these 5-HT1B-induced deficits. Our findings suggest that 5-HT1B receptors play an important role in modulating orbitofrontal-dependent delayed alternation. Moreover, 5-HT1B-induced DAT deficits may provide a mouse model for DAT deficits in OCD.
    Full-text · Article · Feb 2013 · Psychopharmacology
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