Mice lacking adenylyl cyclase-5 cope badly with repeated restraint stress

Physiological responses to acute stress proceed with the activation of the hypothalamus-pituitary-adrenal gland (HPA) system. Many brain regions are known to modulate the HPA axis activation in stress responses, but the detailed neural circuits and signaling system in the upstream of the HPA axis have to be explored further. Type 5 adenylyl cyclase (AC5) is highly concentrated in the dorsal striatum and nucleus accumbens, which are implicated in reward and stress-related behavior. AC5^-/- mice exposed to daily 2-hr restraint stress for only 3-5 days showed poor stress-coping responses, including severe body weight loss, poor coat condition, respiratory difficulties, and freezing behavior. Plasma corticosterone levels during 2-hr stress sessions increased in AC5^-/- mice compared with those of AC5^+/+ mice. However, neither the corticosterone receptor antagonist RU486 nor the CRH receptor antagonist NBI27914 blocked their poor stress coping, whereas the administration of the GABA_A receptor allosteric modulator diazepam or the D1 dopamine receptor antagonist SCH23390 prior to restraint stress sessions changed their stress-coping response to the stressed AC5^+/+ mouse level. Stress-triggered c-Fos expression was completely blunted in the dorsal striatum of AC5^-/-. These results suggest that the AC5-associated signal system and neural network are involved in the regulation of anxiety and stress-coping response.