Alteba Shirley, Portugalov Anna, Hillard Cecilia J, Akirav Irit
School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa 3498838, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa 3498838, Israel.
Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee 53226, USA.
Neuroscience. 2021 Feb 10;455:89-106. doi: 10.1016/j.neuroscience.2020.12.022. Epub 2020 Dec 25.
Early-life stress (ELS) is associated with later onset of depression. Early cannabis use may be a risk factor that interacts with environmental factors to increase the risk of psychopathologies. We aimed to examine the long-term effects of ELS on depression- and anxiety-like behavior, and examine whether chronic fatty acid amide hydrolase (FAAH) inhibition during mid-adolescence could ameliorate or exacerbate ELS effects on behavior. Male and female rats were exposed to ELS during post-natal days (P) 7-14, injected with the FAAH inhibitor URB597 (0.4 mg/kg, i.p.) or vehicle for 2 weeks during mid-adolescence (P30-45) or late-adolescence (P45-60). Rats were tested in adulthood for behavior and alterations in CB1 receptors (CB1r) and glucocorticoid receptors (GRs) in the brains' stress circuit. ELS produced decreased social preference, impaired social recognition, increased learned helplessness and anxiety-like behavior. Administering URB597 during mid-adolescence did not prevent the deleterious long-term effects of ELS on behavior in males and females. When URB597 was administered during late-adolescence, it ameliorated ELS-induced depression- and anxiety-like behavior. Moreover, in males, ELS and URB597 decreased CB1r levels in the prefrontal cortex (PFC) and CA1 and GRs in the PFC and basolateral amygdala (BLA). In females, ELS and URB decreased CB1r in the BLA and GRs in the CA1 and BLA. The findings suggest that mid-adolescence, as opposed to late-adolescence, may not be a potential developmental period for chronic treatment with FAAH inhibitors and that sex-dependent alterations in CB1r and GRs expression in the BLA-PFC-CA1 circuit may contribute to the depressive behavioral phenotype.
早年生活应激（ELS）与后期抑郁症的发病有关。早年使用大麻可能是一种风险因素，它与环境因素相互作用，增加精神病理学风险。我们旨在研究ELS对抑郁样和焦虑样行为的长期影响，并研究青春期中期慢性脂肪酸酰胺水解酶（FAAH）抑制是否会改善或加剧ELS对行为的影响。雄性和雌性大鼠在出生后第7 - 14天暴露于ELS，在青春期中期（P30 - 45）或青春期后期（P45 - 60）注射FAAH抑制剂URB597（0.4 mg/kg，腹腔注射）或溶剂，持续2周。成年大鼠接受行为测试以及大脑应激回路中CB1受体（CB1r）和糖皮质激素受体（GRs）的变化测试。ELS导致社交偏好降低、社交识别受损、习得性无助增加和焦虑样行为。青春期中期给予URB597并不能预防ELS对雄性和雌性行为的有害长期影响。青春期后期给予URB597时，它改善了ELS诱导的抑郁样和焦虑样行为。此外，在雄性中，ELS和URB597降低了前额叶皮质（PFC）和CA1中的CB1r水平以及PFC和基底外侧杏仁核（BLA）中的GRs水平。在雌性中，ELS和URB降低了BLA中的CB1r以及CA1和BLA中的GRs。研究结果表明，与青春期后期相比，青春期中期可能不是FAAH抑制剂慢性治疗的潜在发育时期，并且BLA - PFC - CA1回路中CB1r和GRs表达的性别依赖性改变可能导致抑郁行为表型。
