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Abstract

Obsessive-compulsive disorder (OCD) is a psychiatric illness characterized by obsessions, compulsions, or both. Obsessions are intrusive thoughts, urges, or images that are ego dystonic and cause distress to the patient. Compulsions are repetitive behaviors or mental acts that are typically associated with obsessions. Limbic cortico-striato-thalamo-cortical circuitry is dysregulated in OCD and is thought to contribute to OCD symptomatology. However, effective treatment options are still lacking. Serotonin reuptake inhibitors (SRIs), made up of the selective SRIs and clomipramine, are the only effective pharmacological monotherapy for OCD. However, only about half of patients respond to SRIs, and symptom response is partial even in responders. Thus, a better understanding of OCD neurobiology will be needed in order to develop improved treatment options for this debilitating disorder.,Here, we used animal modeling as a tool to study mechanisms underlying OCD-relevant behavior. In chapter 2, we dissected signaling pathways underlying pharmacologically induced OCD-like behavior in the established 5-HT1BR-induced model of aspects of OCD. We found distinct effects of the canonical and noncanonical signaling pathways on OCD-like behavior, which could have implications for development of more selective therapeutics. In chapter 3, we assessed effects of the putative fast-acting anti-OCD treatment ketamine on the 5-HT1BR-induced model. We found dose-dependent effects of ketamine pretreatment on OCD-like behavior, with the lowest dose showing ameliorative effects on 5-HT1BR-induced OCD-like behavior. These findings reinforce the preliminary human results suggesting efficacy of ketamine as a treatment for OCD. These results also demonstrate that the 5-HT1BR- induced model is capable of identifying novel anti-OCD treatments. In chapter 4, we assessed putative OCD risk gene BTBD3 for OCD-relevant phenotypes using a global Btbd3 knockout mouse and viral-mediated knockdown of Btbd3 expression in Btbd3 floxed mice. We found robust effects of Btbd3 expression on OCD-relevant behaviors, and that the hippocampus is a major driver of these effects. These results are the first to demonstrate a role for BTBD3 in behavior. These findings support the human data suggesting that BTBD3 may play a role in OCD etiology.,Together, these findings provide novel insights into mechanisms underlying OCD-relevant behaviors.

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