Corticotropin releasing hormone and serotonin-the neuropsychopharmacology of fear learning deficit from rodents to humans

Introduction: From an evolutionary perspective, the acquisition of fear responses enables organisms to respond appropriately to predictors of aversive events. Our previous work has demonstrated that failure to condition to a specific threat cue results in an increase in conditioned fear to the context because the threat remains unpredictable [1]. This mechanism may model a pathway to chronic states of anxiety [2]. Recent preclinical data from collaborators suggests that the interplay between brain serotonin (5-HT) and corticotropin releasing hormone (CRH) systems is crucial in successful fear acquisition [3]. Methods: To translate these preclinical findings, we recruited 150 healthy human subjects that underwent a cue and context fear conditioning procedure in a virtual environment. All participants were genotyped for common polymorphisms within regulatory regions of the serotonin transporter (5-HTTLPR) and the CRH receptor 1 (CRHR1). These polymorphisms have previously been linked to panic disorder (CRHR1 [rs878886] G-allele) and anxious symptomology and personality (5-HTTLPR short allele), respectively. As in the rodent experiment, the fear potentiated startle was recorded to assess fear conditioned responses to the threat cue and threat context. Results: Uninstructed fear acquisition to the threat cue was significantly affected by CRHR1 genotype: G-allele carriers of rs878886 failed to discriminate between the threat cue and context. Moreover, subjects carrying the risk-alleles of both genotypes (CRHR1 and 5-HTTLPR) displayed increased contextual conditioned responses. Conclusion: Hence, genetic variation in these transmitter systems may confer a risk for maladaptive acquisition of fear associations, which may constitute a pathway to pathological fear.