Frontiers in pharmacology · 2025
The regulation and mechanism of the cAMP-PKA pathway on PTSD-like behaviors exacerbated by alcohol exposure.
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Zhao Shuang, Zhao Wei, Wang Ziqi, Chen Xiaofei, Zong Fangjiao, Zhang Hanting
Аннотация
BACKGROUND: Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) exhibit a significant degree of comorbidity. Nevertheless, the specific effects and underlying mechanisms by which alcohol, as a risk factor, contributes to the development of PTSD-ike phenotypes remain poorly understood. Both chronic alcohol consumption and exposure to traumatic stress can lead to synaptic damage in the hippocampus, potentially serving as a neurobiological basis for the exacerbation of PTSD induced by alcohol.
METHODS: In this study, an animal model was established by allowing mice to voluntarily consume alcohol for 2 weeks, followed by exposure to a single prolonged stress combined with foot shock (SPS&FS). Subsequently, the mice received an intraperitoneal injection of rolipram (1 mg/kg), and behavioral, biochemical, and morphological analyses were performed.
RESULTS: The findings revealed that individuals with early alcohol exposure exhibited more pronounced deficits in fear extinction during the fear extinction task (FET) and displayed higher levels of anxiety-like behavior in both the open field test (OFT) and the elevated plus maze test (EPM). Activation of cAMP-PKA signaling enhanced the downregulation of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), upregulated the expression of PSD95, synaptophysin, AMPA, and NMDA receptor subtypes, and reversed the impairment of CA1 synaptic function and dendritic structure in the hippocampus.
CONCLUSION: Activation of the cAMP-PKA pathway facilitated fear extinction in PTSD mice with early alcohol exposure, alleviated anxiety-like behavior, attenuated symptoms of AUD following ethanol relapses. These findings suggest that modulating hippocampal synaptic plasticity by activating the cAMP-PKA pathway may represent a promising therapeutic approach for attenuating alcohol-exacerbated PTSD-like behaviors.
METHODS: In this study, an animal model was established by allowing mice to voluntarily consume alcohol for 2 weeks, followed by exposure to a single prolonged stress combined with foot shock (SPS&FS). Subsequently, the mice received an intraperitoneal injection of rolipram (1 mg/kg), and behavioral, biochemical, and morphological analyses were performed.
RESULTS: The findings revealed that individuals with early alcohol exposure exhibited more pronounced deficits in fear extinction during the fear extinction task (FET) and displayed higher levels of anxiety-like behavior in both the open field test (OFT) and the elevated plus maze test (EPM). Activation of cAMP-PKA signaling enhanced the downregulation of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), upregulated the expression of PSD95, synaptophysin, AMPA, and NMDA receptor subtypes, and reversed the impairment of CA1 synaptic function and dendritic structure in the hippocampus.
CONCLUSION: Activation of the cAMP-PKA pathway facilitated fear extinction in PTSD mice with early alcohol exposure, alleviated anxiety-like behavior, attenuated symptoms of AUD following ethanol relapses. These findings suggest that modulating hippocampal synaptic plasticity by activating the cAMP-PKA pathway may represent a promising therapeutic approach for attenuating alcohol-exacerbated PTSD-like behaviors.