Our findings suggest that a FAAH genetic polymorphism modulates PTSD risk in PTBI subjects with intact vmPFC but not in those subjects with vmPFC lesions. Presence of the wild-type allele at this SNP was linked with an increase of recollections of the traumatic event. Lastly, we showed that negative early experiences increased PTSD risk only in those subjects presenting at least one wild-type allele.
To date, the relationship between the presence of the C (that is wild-type allele) and FAAH function is not completely understood. Recent data from an amphetamine challenge study linked a heightened arousability to the C allele; increased arousal has been linked with reduced FAAH activity in animal models thus suggesting possible higher FAAH activity in C allele carriers compared with T allele carriers.6
Published data on FAAH activity showed that FAAH inhibition and thus increase of endocannabinoid levels has been linked with heightened aversive memory extinction and reduced anxiety levels in animal studies.7, 8
Moreover reduction of endocannabinoid activity has been linked with impairments of extinction of aversive memories and increased anxiety levels.8
Our observation of an effect of FAAH only in those subjects with an intact vmPFC seems to be consistent with a role of vmPFC in traumatic events recollection and with our previous observation of a protective effect of vmPFC lesions on PTSD.9
Indeed in neuroimaging studies, recollection of traumatic events in PTSD subjects has been linked with vmPFC functions.19, 20
Moreover aversive memory consolidation and extinction has been linked with prefrontal functions both in animal and human studies,21, 22
thus damage to the neural structures linked with aversive memories extinction would likely overshadow the relatively more modest effects of a single SNP on consolidation and extinction processes. This observation is compatible with our previous report of the need of intact prefrontal structures to allow for genetic influences to modulate aggressive behaviors in PTBI.10
One of the major challenges in the current approach to PTSD is the identification of reliable markers for the factors that lead to an increased risk for developing the disorder (that is vulnerability) and of those that lead to a persistence of the disorder (that is maintenance). Identification of vulnerability markers could be a key factor in the development of primary prevention of PTSD in selected populations. Our data suggest that the FAAH rs2295633 SNP could serve as a possible marker for increased PTSD risk in subjects exposed to brain injury and combat experiences; future studies are warranted to explore the clinical utility of FAAH genotyping to guide primary prevention of PTSD in other at-risk populations. In addition, it would be helpful to understand the epigenetic/environmental factors that might have led those patients with an increased risk not to develop PTSD.
Moreover, our data suggest that PTSD subjects presents different clinical and psychopathological characteristics according to FAAH genotype, with C/- subjects showing more intense recollections of traumatic events and of negative childhood experiences. Given the key role of extinction learning and of early experiences in different psychotherapeutic approaches to PTSD, FAAH genotyping could help to develop individualized therapies based on different genetic characteristics for the more severe and challenging cases of PTSD.
In conclusion, our findings point to FAAH as a contributor to PTSD after PTBI, possibly through the modulation of aversive memories by extinction processes. These data suggest a role for endocannabinoid signaling in the development and maintenance of PTSD and hint at the therapeutic potential of endocannabinoid systems-modulating drugs for PTSD patients.5