Hesketh Shirley A, Brennan Adrian K, Jessop David S, Finn David P
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
Psychopharmacology (Berl). 2008 May;198(1):29-36. doi: 10.1007/s00213-007-1033-3. Epub 2007 Dec 15.
There is growing interest in investigating the mechanisms of action of selective serotonin reuptake inhibitors (SSRIs), beyond their association with the serotonergic system, due to their wide therapeutic potential for disorders including depression, pain and addiction.
The aim of this study was to investigate whether chronic treatment with the SSRI, citalopram, alters the functional coupling of G(i/o)-associated cannabinoid type 1 (CB(1)) and mu-opioid receptors in selected areas of rat brain implicated in psychiatric disorders and pain.
Using an autoradiographic approach, the effects of the cannabinoid receptor agonist, HU210 (in the presence or absence of the CB(1) receptor antagonist AM251), or the mu-opioid receptor agonist, [D: -Ala(2),N-Me-Phe4,Gly(5)-ol]-enkephalin (DAMGO; in the presence or absence of the mu-opioid receptor antagonist D: -Phe-Cys-Tyr-D: -Trp-Orn-Thr-Pen-Thr-NH(2)), on [(35)S]GTPgammaS binding in discrete brain regions of citalopram-treated (10 mg kg(-1) day(-1) for 14 days by subcutaneous minipump) and control rats were investigated.
The HU210-induced increase in [(35)S]GTPgammaS binding observed in the hypothalamic paraventricular nucleus of control rats was abolished after chronic treatment with citalopram. Reduced response to HU210 in rats receiving chronic treatment with citalopram was also observed in the hippocampus and medial geniculate nucleus. Citalopram had no significant effect on DAMGO-induced [(35)S]GTPgammaS binding in the brain regions investigated, with the exception of the medial geniculate nucleus where a modest impairment was observed.
These data provide evidence for reduced cannabinoid receptor-mediated G-protein coupling in the hypothalamus, hippocampus and medial geniculate nucleus of rats chronically treated with citalopram, effects which may, in part, underlie the mechanism of action of SSRIs.
由于选择性5-羟色胺再摄取抑制剂（SSRI）在包括抑郁症、疼痛和成瘾在内的疾病治疗方面具有广泛的潜力，因此，除了其与血清素能系统的关联外，人们对研究其作用机制的兴趣也与日俱增。
本研究旨在调查SSRI西酞普兰的长期治疗是否会改变与G（i/o）相关的1型大麻素（CB（1））和μ-阿片受体在大鼠大脑中与精神疾病和疼痛相关的特定区域的功能耦合。
采用放射自显影方法，研究了大麻素受体激动剂HU210（存在或不存在CB（1）受体拮抗剂AM251）或μ-阿片受体激动剂[D：-丙氨酸（2），N-甲基苯丙氨酸4，甘氨酸（5）-醇]-脑啡肽（DAMGO；存在或不存在μ-阿片受体拮抗剂D：-苯丙氨酸-半胱氨酸-酪氨酸-D：-色氨酸-鸟氨酸-苏氨酸-青霉胺-苏氨酸-NH（2））对经西酞普兰治疗（通过皮下微型泵以10 mg kg（-1）天（-1）的剂量持续14天）和对照大鼠离散脑区中[（35）S]GTPγS结合的影响。
西酞普兰长期治疗后，对照大鼠下丘脑室旁核中观察到的HU210诱导的[（35）S]GTPγS结合增加被消除。在接受西酞普兰长期治疗的大鼠的海马体和内侧膝状核中也观察到对HU210的反应降低。除内侧膝状核观察到适度损害外，西酞普兰对所研究脑区中DAMGO诱导的[（35）S]GTPγS结合无显著影响。
这些数据为长期接受西酞普兰治疗的大鼠下丘脑、海马体和内侧膝状核中大麻素受体介导的G蛋白偶联减少提供了证据，这些效应可能部分构成了SSRI作用机制的基础。
