Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity
Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity
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DOI：
10.1038/tp.2013.131
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发表时间：
2014-03-01
影响因子：
6.8
通讯作者：
Moeller, F. G.
中科院分区：
文献类型：
--
作者：
Anastasio, N. C.;Liu, S.;Moeller, F. G.
可卡因依赖仍然是一个具有挑战性的公共卫生问题，复发被认为是其慢性和严重程度的主要决定因素。环境背景和刺激变得可靠地与其使用相关，导致持久的条件反应（“线索反应”），可以预测复发以及治疗成功。线索反应的幅度和对人类和动物行为的影响的个体差异表明，线索反应个体可能处于更大的成瘾和/或复发的风险。在目前的翻译研究中，我们调查的贡献5-羟色胺（5-HT）5-HT 2C受体（5-HT 2CR）系统的变化在人类和啮齿动物的可卡因线索反应的个体差异。我们发现，可卡因依赖的主题携带单核苷酸多态性（SNP）的HTR 2C基因编码的半胱氨酸转换为丝氨酸在密码子23（Ser 23变体）表现出显着更高的注意力偏好可卡因线索在可卡因字Stroop任务比那些携带Cys 23变体。在大鼠可卡因线索反应性的个体差异模型中，我们确定了高可卡因线索反应性测量为食欲接近行为（由离散线索复合物加强的杠杆按压）与内侧前额叶皮层中5-HT 2CR蛋白表达降低和对选择性5-HT 2CR激动剂WAY 163909的抑制作用的敏感性减弱相关。我们的翻译研究结果表明，5-HT 2CR系统的功能状态是可卡因相关线索产生脆弱性的机制因素，这一观察结果为未来开发生物标志物和治疗方法以抑制可卡因依赖复发开辟了新的途径。
Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses ('cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocain-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.