Inhibition of phosphodiesterase 2 ameliorates post-traumatic stress-induced alcohol intake disorder by regulating cAMP/cGMP signaling

Background: Post-traumatic stress disorder (PTSD) is the prevalent psychiatric disorders that induces alcohol use disorders (AUD) such as abnormal alcohol intake and anxiety. However, little is known about whether phosphodiesterase 2 (PDE2)-cAMP/cGMP signaling is involved in PTSD induced AUD.

Methods: The present study used single-prolonged stress (SPS) to mimic PTSD that induced increases in ethanol intake and preference (two-bottle choice test) and anxiety-like behavior (elevated-plus maze test and novelty suppressed feeding test). PDE2 Inhibitor Bay 60-7550 was administered to the mice and PKA Inhibitor H89 and PKG inhibitor KT5823 were micro-injected into dorsolateral striatum (DLS) and central amygdala (CA) of mice to determine whether the effects of Bay 60-7550 on anxiety-like behavior in SPS mice are brain region dependent.

Results: PDE2 Inhibitor Bay 60-7550 rescued SPS induced decreases in open arm entries and open arm time exposure in elevated-plus maze test and reversed increased latency to feed in the novelty suppressed feeding test. Moreover, SPS-induced ethanol use disorder was reversed by Bay 60-7550 as evidenced by decreased ethanol intake and preference without changing total fluid intake in the SPS mice after treatment with Bay 60-7550. However, Bay 60-7550 did not change the ethanol metabolism, the sucrose or quinine intake and preference. The locomotor activity was not affected after treatment with Bay 60-7550. Interestingly, Microinjection of PKA or PKG inhibitor H89 or KT5823 into DLS prevented the effects of Bay 60-7550 on alcohol intake and preference and cAMP-response element binding proteins phosphorylation (pCREB) and brain derived neurotrophic factor (BDNF) expression in DLS but not on the anxiety-like behavior in SPS mice; while Microinjection of these inhibitors into CA prevented Bay 60-7550-induced anxiolytic-like effects and pCREB and BDNF levels in CA but did not affect ethanol intake in SPS mice, indicating that the effects of Bay 60-7550 on different behavior are brain region-dependent.

Conclusions: These findings support the hypothesis that PDE2-cAMP/cGMP signaling may differentially mediate PTSD-induced AUD and anxiety-like behavior.