Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
Delta Phenomics BV, Utrecht, The Netherlands.
Neuropsychopharmacology. 2014 Apr;39(5):1115-24. doi: 10.1038/npp.2013.311. Epub 2013 Nov 6.
High rates of comorbidity between alcohol use disorder (AUD) and major depressive disorder (MDD) are reported. Preclinical models examining effects of primary depression on secondary AUD are currently absent, preventing adequate testing of drug treatment. Here, we combined social defeat-induced persistent stress (SDPS) and operant alcohol self-administration (SA) paradigms to assess causality between these two neuropsychiatric disorders. We then exploited guanfacine, an FDA-approved adrenergic agent reported to reduce drug craving in humans, against SDPS-induced modulation of operant alcohol SA. Wistar rats were socially defeated and isolated for a period of ≥9 weeks, during which depression-like symptomatology (cognitive and social behavioral symptoms) was assessed. Subsequently, animals were subjected to a 5-month operant alcohol SA paradigm, examining acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking. The effects of guanfacine on motivation and relapse were measured at >6 months following defeat. SDPS rats exhibited significant disruption of social and cognitive behavior, including short-term spatial and long-term social memory, several months following defeat. Notably, SDPS increased motivation to obtain alcohol, and cue-induced relapse vulnerability. Guanfacine reversed the SDPS-induced effects on motivation and relapse. Together, our model mimics core symptomatology of a sustained depressive-like state and a subsequent vulnerability to alcohol abuse. We show that SDPS is strongly associated with an enhanced motivation for alcohol intake and relapse. Finally, we show that the clinically employed drug guanfacine has potential as a novel treatment option in comorbid patients, as it effectively reduced the enhanced sensitivity to alcohol and alcohol-associated stimuli.
大量研究报告指出，酒精使用障碍（AUD）和重度抑郁症（MDD）之间存在高共病率。目前缺乏研究原发性抑郁对继发性 AUD 影响的临床前模型，这阻碍了对药物治疗的充分测试。在这里，我们将社会挫败引起的持续压力（SDPS）和操作性酒精自我给药（SA）范式相结合，以评估这两种神经精神疾病之间的因果关系。然后，我们利用胍法辛（一种已被 FDA 批准的肾上腺素能药物，据报道可减少人类对药物的渴望）来对抗 SDPS 对操作性酒精 SA 的调制。Wistar 大鼠接受社会挫败和隔离≥9 周，在此期间评估抑郁样症状（认知和社会行为症状）。随后，动物接受为期 5 个月的操作性酒精 SA 范式，评估获取、动机、消退和线索诱导的复吸。在挫败后>6 个月测量胍法辛对动机和复发的影响。SDPS 大鼠表现出明显的社交和认知行为障碍，包括短期空间和长期社会记忆，在挫败后几个月。值得注意的是，SDPS 增加了获得酒精的动机，并增加了线索诱导的复吸易感性。胍法辛逆转了 SDPS 对动机和复发的影响。总之，我们的模型模拟了持续抑郁样状态的核心症状和随后对酒精滥用的易感性。我们表明，SDPS 与增强的酒精摄入动机和复发密切相关。最后，我们表明，临床使用的药物胍法辛作为一种新的治疗选择，具有潜力，因为它有效地降低了对酒精和酒精相关刺激的敏感性。
