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Fear extinction decreases conditioned fear responses that normally occur when a conditioned stimulus (CS) is repeatedly presented in the absence of an aversive unconditioned stimulus (US), which is the behavioral basis of exposure therapy for posttraumatic stress disorder (PTSD). However, knowledge about the neurobiology of extinction is insufficient. The present study investigated changes in the protein expression of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the dorsal hippocampus (DH)and ventral hippocampus (VH), induced by extinction and return of conditioned fear responses to an auditory signal. Western blot analysis indicated that shock stress enhanced the expression of MRs in only the DH, whereas extinction selectively increased the expression of MRs in the VH. The infusion of MRs antagonist spironolactone in the VH indicated that MRs in the VH did not affect the retrieval of fear and extinction memories, but facilitated the formation of extinction memory. However, no changes in GRs in either the DH or VH were observed in each phase of auditory fear conditioning. These results suggest that MRs in the DH and VH have differential functions in the extinction of auditory fear conditioning. MRs in the DH appear to be related to only stressful experiences, whereas MRs in the VH are involved in extinction formation. The enhancement of MRs in the VH might be necessary to improve PTSD.

Accumulating evidence suggests that stress-dose corticosteroids impair fear memory in animals and humans. Corticosteroid treatment after critical illness is seen as a potential psychotropic medication by which to prevent posttraumatic stress disorder. However, individual difference in the responsiveness to stress (i.e., stress reactivity) is a factor that modulates the efficacy of corticosteroids. To understand the contribution of fear reactivity to the effect of post-stress corticosterone, male Sprague-Dawley rats were subjected to classical tone-cued fear conditioning and separated into high and low reactivity (HR and LR, respectively) responder groups based on their levels of freezing during conditioning. The HR rats showed significantly higher fear responses than the LR rats during conditioning as assessed by freezing behavior. At two intervals, 30 min and 48 hr later, the HR rats still displayed more pronounced conditioned responses to cued stimuli compared with the LR rats. Moreover, in contrast to the LR rats, the enhanced fear response in the HR rats was difficult to attenuate by post-training high-dose corticosterone. These results suggest that fear reactivity results in stronger fear memory, and that it is difficult to disrupt this strong fear memory in the HR phenotype using monotherapy. However, the strong fear memory in the HR rats was impaired by concurrent intramedial prefrontal cortex infusion of a high dose of the dopamine D1 receptor antagonist SCH 23390 and systemic administration of corticosterone. SCH 23390 and corticosterone alone did not decrease freezing levels in the HR rats. The fear impairment induced by SCH 23390 combined with corticosterone was not attributable to the effect of these drugs on locomotor activity. This effect was not found with administration of the D2 antagonist eticlopride combined with corticosterone. Our findings demonstrate that the conditioned fear memory in individuals with high stress reactivity is difficult to disrupt using monotherapy, but that combined pharmacotherapy may be useful for treating intervention-resistant fear.

Fear extinction decreases conditioned fear responses that normally occur when a conditioned stimulus (CS) is repeatedly presented in the absence of an aversive unconditioned stimulus (US), which is the behavioral basis of exposure therapy for posttraumatic stress disorder (PTSD). However, knowledge about the neurobiology of extinction is insufficient. The present study investigated changes in the protein expression of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the dorsal hippocampus (DH)and ventral hippocampus (VH), induced by extinction and return of conditioned fear responses to an auditory signal. Western blot analysis indicated that shock stress enhanced the expression of MRs in only the DH, whereas extinction selectively increased the expression of MRs in the VH. The infusion of MRs antagonist spironolactone in the VH indicated that MRs in the VH did not affect the retrieval of fear and extinction memories, but facilitated the formation of extinction memory. However, no changes in GRs in either the DH or VH were observed in each phase of auditory fear conditioning. These results suggest that MRs in the DH and VH have differential functions in the extinction of auditory fear conditioning. MRs in the DH appear to be related to only stressful experiences, whereas MRs in the VH are involved in extinction formation. The enhancement of MRs in the VH might be necessary to improve PTSD.