Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP/PAC1 receptor pathway has a role in human psychological stress responses, such as posttraumatic stress disorder (PTSD). In heavily traumatized subjects, we find a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females (N=64, replication N=74, p<0.005). Using a tag-SNP genetic approach (44 single nucleotide polymorphisms, SNPs) spanning the PACAP (ADCYAP1) and PAC1 (ADCYAP1R1) genes, we find a sex-specific association with PTSD. rs2267735, a SNP in a putative estrogen response element within ADCYAP1R1, predicts PTSD diagnosis and symptoms in females only (combined initial and replication samples: N=1237; p<2x10−5). This SNP also associates with fear discrimination and with ADCYAP1R1 mRNA expression. Methylation of ADCYAP1R1 is also associated with PTSD (p < 0.001). Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or estrogen replacement in rodent models. These data suggest that perturbations in the PACAP/PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via estrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
BACKGROUND The symptoms of PTSD can be explained, at least in part, as an inability to inhibit learned fear during conditions of safety. Our group has shown that fear inhibition is impaired in both combat and civilian PTSD populations. Based on our earlier findings, we employed an established fear extinction paradigm to further explore fear dysregulation in a civilian traumatized population. METHODS Fear-potentiated startle was examined in 127 trauma-exposed individuals with and without PTSD. We used a protocol in which conditioned fear was first acquired through the presentation of one colored shape (reinforced conditioned stimulus, CS+) that was paired with an aversive airblast to the larynx (unconditioned stimulus, US) and a different colored shape that was not paired to the airblast (nonreinforced condition stimulus, CS−). Fear was extinguished 10 minutes later through repeated presentations of the CSs without reinforcement. RESULTS Both groups demonstrated successful fear conditioning based on startle and US-expectancy ratings, however, participants with PTSD displayed greater fear-potentiated startle responses to the CS+ and CS− compared to the group without PTSD. During fear extinction, the PTSD group showed elevated fear-potentiated startle responses to the previously reinforced CS+ during the early and middle stages of extinction. During the acquisition and extinction phases, PTSD participants with higher levels of re-experiencing symptoms exhibited greater potentiated startle responses to the CS+ compared to PTSD participants with lower re-experiencing symptoms. CONCLUSIONS These results suggest that PTSD is associated with enhanced fear learning and a greater “fear load” to extinguish after conditioned fear is acquired.
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