Conditioned fear response is modulated by a combined action of the hypothalamic–pituitary–adrenal axis and dopamine activity in the basolateral amygdala

The present study sought to determine the extent to which the combined activity of the hypothalamic–pituitary–adrenal (HPA) axis and dopaminergic systems is important for the expression of conditioned fear responses. The first experiment examined changes in plasma corticosterone concentration and the conditioned freezing response in rats treated with the dopamine D2 receptor agonist quinpirole (0.25 mg/kg), the dopamine D2 receptor antagonist sulpiride (40 mg/kg), corticosterone (3 or 6 mg/kg), or the corticosterone synthesis blocker metyrapone (30 mg/kg) and subjected to a conditioned fear test. A second experiment assessed the effects of corticosterone (3 or 6 mg/kg) and metyrapone (30 or 60 mg/kg) on fear-potentiated startle. A third experiment assessed the HPA axis modulation of conditioned fear using in vivo microdialysis targeted at dopaminergic neurotransmission in the basolateral amygdala (BLA). Quinpirole and sulpiride decreased conditioned freezing but did not affect plasma corticosterone concentration. Corticosterone and metyrapone did not affect fear-potentiated startle, but metyrapone attenuated conditioned freezing, suggesting that the expression of conditioned freezing requires HPA axis activation. Metyrapone inhibited the increase in dopamine levels in the BLA in response to the conditioned stimulus, whereas corticosterone had no significant effect. These results suggest that HPA axis activation is an initial step in an integrated neuroendocrine–neurochemical–behavioral response when the organism evaluates a threat associated with an environmental stimulus and triggers defense reactions to cope with this situation.