Targeting neuronal nitric oxide synthase and the nitrergic system in post-traumatic stress disorder

Rationale Current pharmacological approaches to treatment of post-traumatic stress disorder (PTSD) lack adequate effectiveness. As a result, identifying new molecular targets for drug development is necessary. Furthermore, fear learning and memory in PTSD can undergo different phases, such as fear acquisition, consolidation, and extinction. Each phase may involve different cellular pathways and brain regions. As a result, effective management of PTSD requires mindfulness of the timing of drug administration. One of the molecular targets currently under intense investigation is the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR). However, despite the therapeutic efficacy of drugs targeting NMDAR, their translation into clinical use has been challenging due to their various side effects. One possible solution to this problem is to target signaling proteins downstream to NMDAR to improve targeting specificity. One of these proteins is the neuronal nitric oxide synthase (nNOS), which is activated following calcium influx through the NMDAR. Objective In this paper, we review the literature on the pharmacological modulation of nNOS in animal models of PTSD to evaluate its therapeutic potential. Furthermore, we attempt to decipher the inconsistencies observed between the findings of these studies based on the specific phase of fear learning which they had targeted. Results Inhibition of nNOS may inhibit fear acquisition and recall, while not having a significant effect on fear consolidation and extinction. However, it may improve extinction consolidation or reconsolidation blockade. Conclusions Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting.

Automated summary

Current pharmacological approaches for PTSD lack effectiveness, so new molecular targets are needed. Fear learning and memory in PTSD occur in different stages, involving different cellular pathways and brain regions. Targeting the NMDAR receptor has side effects, so targeting downstream signaling proteins like nNOS may be a solution. Modulating nNOS shows therapeutic potential for PTSD.