An Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder

Abstract

Background Obsessive-compulsive disorder (OCD) is treated with exposure with response prevention (ERP) therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from expressing their compulsions. Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions. Patients failing ERP therapy are candidates for deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS), which facilitates patients’ response to ERP therapy. An animal model of ERP would be useful for understanding the neural mechanisms of extinction in OCD. Methods Using a platform-mediated signaled avoidance task, we developed a rodent model of ERP called “extinction with response prevention (“Ext-RP”), in which rats are given extinction trials while blocking access to the avoidance platform. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacological inactivation of lateral orbitofrontal cortex (lOFC) or DBS of the ventral striatum reduced persistent avoidance. Results Following Ext-RP training, most rats showed reduced avoidance at test (Ext-RP success), but a subset persisted in their avoidance (Ext-RP failure). Pharmacological inactivation of lOFC eliminated persistent avoidance, as did DBS applied to the VS during Ext-RP. Conclusions DBS of VS has been previously shown to inhibit lOFC activity. Thus lOFC, which is known to be hyperactive in OCD, may be responsible for impairing patients’ response to ERP therapy.

Alteration of BDNF in the medial prefrontal cortex and the ventral hippocampus impairs extinction of avoidance

“…There is also a correlation between the activation of fearassociated structures and the severity of avoidance symptoms in PTSD [71]. This suggests that elevated fear may promote persistent avoidance, an idea supported by recent studies in rodents [24,26]. Persistent avoidance leads to psychosocial dysfunction and a reduction in the opportunities for spontaneously-occurring extinction of the traumatic memory [15].…”

“…A total of 127 male Sprague-Dawley rats (Harlan Laboratories, Indianapolis, IN) were housed and handled as previously described [25,26]. Briefly, rats were restricted to 18 g/day of standard laboratory rat chow, and trained to press a bar for food on a variable interval schedule of reinforcement (VI-30 s).…”

Active avoidance requires inhibitory signaling in the rodent prelimbic prefrontal cortex

“…were included due to similar functions of Cg1 and PL (Courtin et al, 2014). Following surgical 89 implantation of cannulas, rats were trained in platform-mediated avoidance over 10 days as 90 previously described ( Figure 1B, Bravo-Rivera et al, 2014, Rodriguez-Romaguera et al, 2016. 91…”

“…In some cases, MUS reached the ventral half of cingulate cortex (Cg1), but they 88were included due to similar functions of Cg1 and PL (Courtin et al, 2014). Following surgical 89 implantation of cannulas, rats were trained in platform-mediated avoidance over 10 days as 90 previously described ( Figure 1B, Bravo-Rivera et al, 2014, Rodriguez-Romaguera et al, 2016. 91At Test 1 (Day 11), we infused MUS into PL at the same concentration as our prior studies 92 using fluorescent MUS (Do-Monte et al, 2015b, Rodriguez-Romaguera et al, 2016 and waited 93 45 minutes before commencing a 2-tone test of avoidance expression (without shock).…”

“…Following surgical 89 implantation of cannulas, rats were trained in platform-mediated avoidance over 10 days as 90 previously described ( Figure 1B, Bravo-Rivera et al, 2014, Rodriguez-Romaguera et al, 2016. 91At Test 1 (Day 11), we infused MUS into PL at the same concentration as our prior studies 92 using fluorescent MUS (Do-Monte et al, 2015b, Rodriguez-Romaguera et al, 2016 and waited 93 45 minutes before commencing a 2-tone test of avoidance expression (without shock). Figure 94 1C shows that MUS inactivation significantly reduced the time spent on the platform during the 95 tone, as compared to saline (SAL) infused controls (SAL 92% vs. MUS 57%, unpaired t-test, 96…”