Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction.
The poor long‐term success of fear extinction‐based exposure therapy for post‐traumatic stress disorder (PTSD) is often caused by the relapse of previously extinguished fear. We have previously observed that activation of substantia nigra (SN) dopamine (DA) neurons during fear extinction enhances extinction memory and reduces renewal. Although the specific targets mediating the effects of SN DA on extinction are unknown, their identification could pave the way for the development of novel strategies to reduce fear relapse in PTSD patients. A primary target of SN DA is the dorsal striatum, which consists of two regions: The dorsomedial striatum (DMS), responsible for goal directed learning, and the dorsolateral striatum (DLS), concerning more inflexible, habitual behaviors. The goal of these experiments was to begin to investigate the roles of the DMS and DLS in fear extinction and relapse in adult, male Long Evans rats. Inactivation of the DLS during auditory fear extinction with a Muscimol/Baclofen cocktail (0.03/0.3 nmol/uL) enhanced fear extinction memory but had no effect on fear renewal, while inactivation of the DMS prevented renewal, but had no effect on extinction memory in the extinction context. To investigate the involvement of DA, D1 receptor signaling was blocked in either the DMS or DLS during fear extinction. D1 blockade in the DMS impaired extinction retrieval in the extinction context, but the extinction memory remained susceptible to renewal. D1 blockade in the DLS had no effect on extinction memory or renewal. Despite this, optogenetic stimulation of SN terminals in the DLS during fear extinction reduced fear renewal without impacting extinction memory in the extinction context. These results suggest that the DMS and DLS play different roles in fear extinction and relapse. The DMS supports context‐specific fear extinction through a mechanism involving D1 receptor signaling. Although the contribution of the DLS to normal fear extinction is minimal, fear extinction memory can be rendered resistant to renewal by manipulations that increase the role of the DLS in extinction (DMS inactivation, optogenetic stimulation). Manipulations that increase the involvement of the DLS in fear extinction, such as exercise, could therefore represent effective augmentation strategies for fear extinction in order to reduce relapse.Support or Funding InformationNIH grant 068283 NIH grant 2 T34 GM096958‐06This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exercise has beneficial effects on cognition and mental health, such as enhancing the extinction of a traumatic memory. Rats allowed to run in a wheel for a single, two‐hour session immediately following fear extinction training show enhanced fear extinction memory. The mechanisms by which exercise augments fear extinction are unknown. The mammalian target of rapamycin (mTOR) is a translation regulator involved in synaptic plasticity, and is a target of cellular signals sensitive to exercise. Chronic exercise increases mTOR signaling in brain regions involved in extinction learning, but whether a single bout of exercise capable of enhancing fear extinction increases mTOR is also unknown. The goal of this study was to determine if a single session of wheel running increases mTOR signaling and, if so, whether mTOR signaling contributes to the exercise‐augmentation of fear extinction. Adult, male Long Evans rats exposed to auditory fear conditioning received intracerebral‐ventricular injections of the mTOR inhibitor rapamycin prior to fear extinction training. Immediately after fear extinction training, rats were placed in locked or mobile running wheel for two hours. Post‐extinction exercise enhanced fear extinction memory retrieval the following day, and this effect was blocked by rapamycin.Moreover, an acute bout of exercise increased mTOR signaling in several regions involved in memory and fear extinction. The increase in mTOR signaling produced by exercise was also blocked by rapamycin. These data suggest that acute exercise enhances fear extinction through a mechanism involving mTOR signaling.Support or Funding InformationSupported by the Undergraduate Research Opportunity Program, 2 T34 GM096958‐06, and NIH MH114992This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.