Fear extinction in an obsessive-compulsive disorder animal model: Influence of sex and estrous cycle

Abstract Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition that affects men and women equally, but with a sexually dimorphic pattern of development. Reproductive cycle events can influence symptom severity of OCD in females, indicating that ovarian hormones or their interaction with distinct neurotransmitter systems may play a role in OCD pathophysiology. Clinical studies and animal models have confirmed the importance of the serotonergic (5-HT) system in the neurobiology and treatment of OCD. Accordingly, the non-selective 5-HT2c agonist, meta-chlorophenylpiperazine (mCPP), exacerbates symptoms in untreated OCD patients. In rodents, it evokes repetitive behaviors that engage brain areas that are homologous with those found to be dysfunctional in OCD patients. These regions, including the medial prefrontal and anterior cingulate cortices, are also involved in fear inhibition, which is impaired in OCD. Here, we treated rats with mCPP (0.5 and 3.0 mg/kg) to evaluate its influence on self-grooming behavior and assess potential fear extinction retention deficits, taking into account sex differences and females’ estrous cycle. We found that mCPP exacerbated grooming in male and female rats, irrespective of the estrous cycle phase. Fear extinction retention, however, was impaired only in females. Moreover, females undergoing fear extinction training during the metestrus/diestrus phases of the estrous cycle were more sensitive to the impairments induced by mCPP. Our results indicate that mCPP can induce OCD-like symptoms, exacerbating self-grooming and impairing fear extinction. It suggests that changes in 5-HT signaling through 5-HT2c receptors may have an important role in the OCD pathophysiology and that the influence of gonadal hormones in OCD should be further investigated.