An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials

Abstract

Posttraumatic stress disorder manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Preclinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory that have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for posttraumatic stress disorder that have been developed via a bench to bedside translational model.

Keywords: Antidepressant; Cannabinoid; D-Cycloserine; Exposure; Extinction; Fear; Glucocorticoid; Hydrocortisone; Morphine; Opioid; Propranolol.

Figure 1. Overview of translationally informed treatments for PTSD and mechanism of action

The development of PTSD can be organized into a framework of pre- and post-trauma risk factors and pathological learning, each of which can be uniquely targeted by therapeutics. Hydrocortisone and morphine have been shown to interrupt primary consolidation of conditioned fear and trauma across species. While evidence is inconsistent, propranolol has been suggested to block reconsolidation, a process which renders previously consolidated memories labile, and thus vulnerable to interference. Exposure therapy, the recommended first line treatment for PTSD, is facilitated by D-cycloserine, yohimbine, hydrocortisone, and deep brain stimulation. Furthermore, nabilone and THC (Cnr1 agonists) and SSRIs have been shown to reduce expression of fear with chronic administration. The color red indicates that a specific drug blocks the indicated process, while green indicates a facilitating effect.