Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Few treatments exist to reduce comorbid PTSD/AUD. Elucidating the mechanisms underlying their comorbidity could reveal new avenues for therapy. Here, we employed a model of comorbid PTSD/AUD, in which rats were subjected to a stressful shock in a familiar context followed by alcohol drinking. We then examined fear overgeneralization and irritability in these rats. Familiar context stress elevated drinking, increased fear overgeneralization, increased alcohol-related aggressive signs, and elevated peripheral stress hormones. We then examined transcripts of stress- and fear-relevant genes in the central amygdala (CeA), a locus that regulates stress-mediated alcohol drinking. Compared with unstressed rats, stressed rats exhibited increases in CeA transcripts for Crh and Fkbp5 and decreases in transcripts for Bdnf and Il18. Levels of Nr3c1 mRNA, which encodes the glucocorticoid receptor, increased in stressed males but decreased in stressed females. Transcripts of Il18 binding protein (Il18bp), Glp-1r, and genes associated with calcitonin gene-related peptide signaling (Calca, Ramp1, Crlr-1, and Iapp) were unaltered. Crh, but not Crhr1, mRNA was increased by stress; thus, we tested whether inhibiting CeA neurons that express corticotropin-releasing factor (CRF) suppress PTSD/AUD-like behaviors. We used Crh-Cre rats that had received a Cre-dependent vector encoding hM4D(Gi), an inhibitory Designer Receptors Exclusively Activated by Designer Drugs. Chemogenetic inhibition of CeA CRF neurons reduced alcohol intake but not fear overgeneralization or irritability-like behaviors. Our findings suggest that CeA CRF modulates PTSD/AUD comorbidity, and inhibiting CRF neural activity is primarily associated with reducing alcohol drinking but not trauma-related behaviors that are associated with PTSD/AUD.

创伤后应激障碍（PTSD）和酒精使用障碍（AUD）通常是共病的。很少有治疗方法可以减少共病 PTSD/AUD。阐明其合并症的机制可能会揭示新的治疗途径。在这里，我们采用了一种共病 PTSD/AUD 模型，其中大鼠在熟悉的环境中受到应激性休克，然后饮酒。然后我们检查了这些老鼠的恐惧过度概括和易怒性。熟悉的环境压力增加饮酒，增加恐惧过度概括，增加与酒精相关的攻击性迹象，以及升高的外周应激激素。然后，我们检查了中央杏仁核（CeA）中与压力和恐惧相关的基因的转录本，CeA 是调节压力介导的饮酒的位点。与未受应激的大鼠相比，应激大鼠表现出Crh和Fkbp5的 CeA 转录本增加，而Bdnf和Il18的转录本减少。编码糖皮质激素受体的Nr3c1 mRNA水平在受到压力的男性中增加，但在压力的女性中降低。 Il18结合蛋白 ( Il18bp )、Glp-1r和与降钙素基因相关肽信号转导相关的基因 ( Calca、Ramp1、Crlr-1和Iapp )的转录本未改变。Crh mRNA 因应激而增加，但Crhr1则不然；因此，我们测试了抑制表达促肾上腺皮质激素释放因子（CRF）的 CeA 神经元是否会抑制 PTSD/AUD 样行为。我们使用的Crh- Cre 大鼠接受了编码 hM4D(Gi) 的 Cre 依赖性载体，hM4D(Gi) 是一种由设计药物独家激活的抑制性设计受体。 CeA CRF 神经元的化学遗传学抑制减少了酒精摄入量，但不会担心过度概括或易激惹的行为。我们的研究结果表明，CeA CRF 调节 PTSD/AUD 合并症，抑制 CRF 神经活动主要与减少饮酒有关，但与减少与 PTSD/AUD 相关的创伤相关行为无关。