Manasa Enja, M.D., Suneela Cherlopalle, M.D., Murali K. Kolikonda, M.D., Steven Lippmann, M.D.

Introduction
People with posttraumatic stress disorder (PTSD) repeatedly re-experience the agony of past emotionally upsetting circumstances. PTSD is characterized by hypervigilance, intrusive thoughts, sleep disturbance, and avoidance behavior towards reminders of past trauma. These symptoms often lead to social, occupational, and/or interpersonal dysfunction.

Catecholamines in PTSD
Epinephrine and norepinephrine are the primary catecholamines secreted in response to stress.The majority of epinephrine comes from the adrenal cortex and norepinephrine is predominantly produced in the locus coeruleus, located beneath the floor of fourth ventricle (1). Neuronal projections from locus coeruleus into the amygdala, hypothalamus, thalamus, median prefrontal cortex, and hippocampus are implicated in the pathophysiology of PTSD (1).

After an acute psychologically stressful event, there is excessive secretion of norepinephrine in the brain and that plays a critical role in the pathogenesis of PTSD (1). The noradrenergic activation of the amygdala facilitates the consolidation of these emotionally significant experiences (2).

Memory Consolidation
Short-term memories involve release of neurotransmitters. Long-term memory is a complex process involving synthesis of new proteins necessary for memory consolidation (3,4). Each time an event is recalled, it alters the stored memory, rendering it temporarily unstable and modifiable (4). Therefore, there is the potential to alter the memory each time something is recalled. Reconsolidation is necessary for recalled memories to regain stability (4).

Propranolol in PTSD
Norepinephrine and epinephrine act on alpha and beta adrenoreceptors. Propranolol, a suggested pharmacotherapy for people with PTSD, is a non-selective beta blocker which can cross the blood-brain barrier and influence noradrenergic receptor sites in the brain (1). Its  mechanism of action in patients with PTSD is through blockage of peripheral noradrenergic effects and central inhibition of the protein synthesis required for memory consolidation (5).

In a study involving 23 subjects presenting to an emergency department following a motor vehicle accident, propranolol was administered in less than 20 hours after the traumatic event (6). Of the 11 patients who received propranolol, only one developed PTSD, while three of the eight who refused propranolol, exhibited  such symptoms. This drug also alleviated some physiologic responses during traumatic memory reactivation in chronic PTSD sufferers (5). Having the patients retrieve their traumatic memories and then administer propranolol before reconsolidation of this memory is documented to be a therapeutic intervention (5). Thus, propranolol appears to block the reconsolidation of traumatic memories through its action on central noradrenergic receptors, which in turn may diminish the severity of PTSD symptoms.

A major limitation for therapeutic propranolol is that it has not been studied in large trials. In combat related PTSD, propranolol administration could be problematic in soldiers with physical trauma and blood loss, due the drug’s potential for decreasing heart rate and blood pressure via its beta blocking activity (1). Dose related adverse effects include weakness, fatigue, nausea/vomiting, light-headedness, hypotension, orthostasis, bradycardia, and congestive heart failure. At the quantities presented in the cited PTSD subjects, no significant side effects were reported other than mild sedation (5). This suggests that propranolol may be an efficacious pharmaceutical for prevention of PTSD acutely and to consider as a therapeutic option after its development.

References
1.    Searcy CP, Bobadilla L, Gordon WA, et al. Pharmacological prevention of combat – related PTSD: A literature review. Military Medicine. 2012; 177: 649-654.
2.    McGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annual Review of Neuroscience. 2004; 27: 1-28.
3.    Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell. 2014; 157: 163-186.
4.    Flaskerud JH. Memory and Memories. Issues in Mental Health Nursing. 2013; 34: 59-61.
5.    de Kleine RA, Rothbaum BO, van Minnen A. Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review. European Journal of Psychotraumotology. 2013; 4: 21626 – http://dx.doi.org/10.3402/ejpt.v4i0.21626.
6.     Vaiva G, Ducrocq F, Jezequel K, et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biological Psychiatry 2003; 54: 947-949.