The CRPP Synapse, Trauma, and Addiction focuses on memory plasticity in the context of stress, trauma spectrum disorders, and substance use disorders. Specifically, we aim to activate drug- and trauma-related memories in animal models and patients, and then weaken them pharmacologically using matrix metalloprotease 9 (MMP-9) inhibitors such as doxycycline or minocycline, which are able to modify synaptic plasticity

Based on theoretical and practical clinical grounds, we propose that post-traumatic stress disorder (PTSD) and substance use disorders (SUD) share key mechanistic similarities in terms of underlying learning and memory mechanisms, so that one disorder could effectively “prime” development of the other, hence making patients in recovery from PTSD more susceptible to SUD and vice versa. We test this hypothesis in animals by examining how prior exposure to SUD or PTSD affects subsequent behavior within the PTSD or SUD models, respectively (Animal Workpackage, WP2). As an outcome in humans and to identify distinct and common memory characteristics in PTSD and SUD, we will track frequency, characteristics, and timing of these memories in patients using a daily diary approach that builds on our successful work looking at the characteristics and daily timing of intrusive memories in PTSD (Human Workpackage, WP1). Subsequently, these data might improve patient outcome by the simple expedient of controlling treatment timing.

Moreover, we propose that minocycline, a potent tetracycline derivative that has emerged from our preclinical studies of PTSD in the first funding period, will be effective to weaken pathognomonic trauma- and drug-related memories both in PTSD and in SUD patient populations. To examine this possibility, we plan a randomized clinical trial. A parallel study will be run in animals, testing not only minocycline, but also drugs that have been used in PTSD and SUD, respectively. The fundamental idea underlying our choice here is that similarities between PTSD and SUD might allow medications use in one disorder to ameliorate treatment of the other.

Finally, using the animal models and technologies we have developed, we will investigate at a synaptic level the specific neural changes wrought by these two disorders. During the first funding period, documenting these changes led to unexpected findings about the role of inhibitory synapse dis-inhibition in PTSD, as well as uncovering specific phosphorylation events affecting PTSD development. It also led to the discovery that sleep deprivation was itself a stress that similarly reorganized synaptic function. Additionally, it uncovered important sex-dimorphic differences in these mechanisms. Using next-generation technologies developed in the first funding period, we propose to extend these discoveries to specific neurons involved in trauma memory and drug craving, as well as to test specific mouse models deficient in the post-translational signaling cascades we have identified.

The consortium’s vision is that our discoveries benefit both patients and the next generation of clinician-scientists that we train.

Workpackage Human