The BDNF Val66Met polymorphism moderates the relationship between Posttraumatic Stress Disorder and fear extinction learning

The low expression Met allele of the BDNF Val66Met polymorphism is associated with impaired fear extinction in healthy controls, and poorer response to exposure therapy in patients with Posttraumatic Stress Disorder (PTSD). Given that fear extinction underlies exposure therapy, this raises the question of the impact of BDNFVal66Met polymorphism on fear extinction in PTSD, yet this question has not yet been examined. One hundred and six participants (22 PTSD, 46 trauma-exposed controls (TC) and 38 non-trauma exposed controls (NTC)) completed a fear conditioning and extinction task and saliva samples were taken for DNA extraction and genotyped for the BDNF Val66Met polymorphism. Moderation analyses using PROCESS examined whether BDNF genotype (Val–Val vs Met carriers) moderated the relationship between PTSD symptom severity (and diagnostic status) and skin conductance response (SCR) amplitude during fear extinction. The PTSD group displayed significantly slower fear extinction learning compared to TC and NTC in the early extinction phase. The BDNF Val66Met polymorphism moderated the relationship between PTSD and fear extinction learning, such that poorer fear extinction learning was associated with greater PTSD symptom severity (and PTSD diagnostic status) in individuals with the low-expression Met allele, but no relationship was demonstrated in individuals with the Val–Val allele. This study reveals that impaired fear extinction learning is particularly evident in individuals with PTSD who carry the low-expression BDNF Met Val–Val allele and importantly not in those with the allele. This provides novel evidence of a link between BDNF and impaired fear extinction learning in PTSD, which may contribute to poorer response to exposure therapy

The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management and metabolic diseases. However, around 2007 the tide began to turn when several cannabinoid receptor type 1 (CB1) antagonists/inverse agonists failed as therapeutics against overweight and its complications. More recently, the development of FAAH (Fatty Acid Amide Hydrolase) inhibitors against pain has also faced serious setbacks. In retrospect the much greater complexity of the ECS than originally assumed has played a fundamental role in these difficulties. Although there is no doubt that endocannabinoids and their receptors are of great (patho-)physiological relevance, it has become clear that the ECS is intimately intertwined with other biological systems. Endocannabinoids exist in equilibrium with fatty acids and their metabolic derivatives, including eicosanoids and prostamides. Furthermore, there are several biologically active analogues of endocannabinoids, in particular fatty acid amides, with metabolic pathways overlapping those of the ECS. Finally, endocannabinoids per se and their congeners show “promiscuous” behaviour going beyond interactions with CB1 and CB2 receptors. It has become clear that the complexity of what may be called the “endocannabinoidome” demands for pharmacological approaches that take into account these dynamics. Targeting the “endocannabinoidome” continues to offer opportunities for prevention and therapy, in particular for chronic diseases. However, chances for success are more likely to come from “multiple-target” than from “single-target” approaches