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

Ho, Emily V.; Thompson, Summer L.; Katzka, William; Sharifi, Mitra F.; Knowles, James A.; Dulawa, Stephanie C.

doi:10.1007/s00213-015-4086-8

Cited by 24 publications

(45 citation statements)

References 37 publications

(51 reference statements)

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“…While some have suggested that the female Fmr1 KOs should be included in studies with males based on similarity, here we highlight the marked phenotypic differences, and as such, future research could focus on how these phenotypes could, and should, be treated separately. For instance, repetitive behavior phenotypes are commonly treated using several different types of drugs, including 5‐HT1BR agonists (Ho et al., 2016), 5HT1A partial antagonists (Chugani et al., 2016) and more recently, antioxidants (Hardan et al., 2012). Through the routine exclusion of females from biomedical studies, opportunities are missed to explore potential treatments and how sex may impact the efficacy of such treatments.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Fmr1 results in sex‐specific changes in behavior

et al. 2017

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ObjectiveIn this study, we used a systemic Fmr1 knockout in order to investigate both genotype‐ and sex‐specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear‐related learning and memory.BackgroundFragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes.MethodsUsing wild‐type and systemic homozygous Fmr1 knockout mice, we assessed a variety of behavioral paradigms in adult animals, including the open field test, elevated plus maze, nose‐poke assay, accelerating rotarod, social partition task, three‐chambered social task, and two different fear conditioning paradigms. Tests were ordered such that the most invasive tests were performed last in the sequence, and testing paradigms for similar behaviors were performed in separate cohorts to minimize testing effects.ResultsOur results indicate several sex‐specific changes in Fmr1 knockout mice, including male‐specific increases in activity levels, and female‐specific increases in repetitive behaviors on both the nose‐poke assay and motor coordination on the accelerating rotarod task. The results also indicated that Fmr1 deletion results in deficits in fear learning and memory across both sexes, and no changes in social behavior across two tasks.ConclusionThese findings highlight the importance of including female subjects in preclinical studies, as simply studying the impact of genetic mutations in males does not yield a complete picture of the phenotype. Further research should explore these marked phenotypic differences among the sexes. Moreover, given that treatment strategies are typically equivalent between the sexes, the results highlight a potential need for sex‐specific therapeutics.

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Section: Discussionmentioning

confidence: 99%

Deletion of Fmr1 results in sex‐specific changes in behavior

et al. 2017

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“…Cohort 3 consisted of 6 KO and 6 WT male mice (2–4 months), and were used for biochemical studies of the PSD. Sample sizes were selected based on estimates from our previous work 36 – 38 .…”

Section: Methodsmentioning

confidence: 99%

Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability

Coba

Ramaker

et al. 2018

Sci Rep

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The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KO mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD.

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“…5HT 1A agonists reduce stereotypy (Korff et al, 2008; Tucci et al, 2013, 2014b), while 5-HT 1A receptor activation promotes adenylyl cyclase sensitization (Hensler et al, 1996), supporting a role for 5HT 1A/B G i dependent adenylate cyclase-cAMP coupling in OCD (Marazziti et al, 2001; Perez et al, 2001) and its response to treatment. Indeed, clinically effective OCD treatments prevent 5-HT 1B receptor-induced repetitive behavior and striatal activation (Ho et al, 2015). Furthermore, elevated cAMP in H mice could be related to increased 5HT 1A -adenylate cyclase-cAMP signaling with reduced hydrolysis by PDE4 (Korff et al, 2009).…”

Section: Insights Into Ocd From the Deer Mouse: A Platform For Resmentioning

confidence: 99%

Obsessive-compulsive disorder: Insights from animal models

Szechtman

Ahmari

Beninger

et al. 2017

Neuroscience & Biobehavioral Reviews

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Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.

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

Abstract: 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.

Cited by 24 publications

References 37 publications

Deletion of Fmr1 results in sex‐specific changes in behavior

Deletion of Fmr1 results in sex‐specific changes in behavior

Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability

Obsessive-compulsive disorder: Insights from animal models

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