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 disorder 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 (2-bottle choice test) and anxiety-like behavior (elevated-plus maze test and novelty suppressed feeding test). PDE2 inhibitor Bay 60-7550 (Bay) was administered to the mice and protein kinase A (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 on anxiety-like behavior in SPS mice are brain region dependent. RESULTS: PDE2 inhibitor Bay 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 as evidenced by decreased ethanol intake and preference without changing total fluid intake in the SPS mice after treatment with Bay. However, Bay did not change the ethanol metabolism or sucrose or quinine intake and preference. The locomotor activity was not affected after treatment with Bay. Interestingly, microinjection of PKA or PKG inhibitor H89 or KT5823 into DLS prevented the effects of Bay on alcohol intake and preference and cAMP-response element binding proteins phosphorylation and brain derived neurotrophic factor expression in DLS but not on the anxiety-like behavior in SPS mice. Microinjection of these inhibitors into CA prevented Bay-induced anxiolytic-like effects and cAMP-response element binding proteins phosphorylation and brain derived neurotrophic factor levels in CA but did not affect ethanol intake in SPS mice, indicating that the effects of Bay on different behaviors 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.