Trigo José Manuel, Renoir Thibault, Lanfumey Laurence, Hamon Michel, Lesch Klaus-Peter, Robledo Patricia, Maldonado Rafael
Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Biol Psychiatry. 2007 Sep 15;62(6):669-79. doi: 10.1016/j.biopsych.2006.11.005. Epub 2007 Feb 16.
The neurobiological mechanism underlying the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA) remains unclear. The aim of the present study was to determine the contribution of the serotonin transporter (SERT) in MDMA self-administration behavior by using knockout (KO) mice deficient in SERT.
Knockout mice and wild-type (WT) littermates were trained to acquire intravenous self-administration of MDMA (0, .03, .06, .125, and .25 mg/kg/infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. Additional groups of mice were trained to obtain food and water to rule out operant responding impairments. Microdialysis studies were performed to evaluate dopamine (DA) and serotonin (5-HT) extracellular levels in the nucleus accumbens (NAC) and prefrontal cortex (PFC), respectively, after acute MDMA (10 mg/kg).
None of the MDMA doses tested maintained intravenous self-administration in KO animals, whereas WT mice acquired responding for MDMA. Acquisition of operant responding for food and water was delayed in KO mice, but no differences between genotypes were observed on the last day of training. MDMA increased DA extracellular levels to a similar extent in the NAC of WT and KO mice. Conversely, extracellular concentrations of 5-HT in the PFC were increased following MDMA only in WT mice.
These findings provide evidence for the specific involvement of SERT in MDMA reinforcing properties.
3,4-亚甲基二氧甲基苯丙胺（摇头丸）强化作用的神经生物学机制尚不清楚。本研究的目的是通过使用血清素转运体（SERT）缺陷的基因敲除（KO）小鼠来确定SERT在摇头丸自我给药行为中的作用。
对基因敲除小鼠和野生型（WT）同窝小鼠进行训练，使其在固定比率1（FR1）强化程序下静脉内自我给药摇头丸（0、0.03、0.06、0.125和0.25 mg/kg/输注）。另外几组小鼠接受获取食物和水的训练，以排除操作反应障碍。在急性给予摇头丸（10 mg/kg）后，分别进行微透析研究，以评估伏隔核（NAC）和前额叶皮质（PFC）中多巴胺（DA）和血清素（5-HT）的细胞外水平。
所测试的任何剂量的摇头丸都不能使基因敲除动物维持静脉内自我给药，而野生型小鼠获得了对摇头丸的反应。基因敲除小鼠获取食物和水的操作反应延迟，但在训练的最后一天未观察到基因型之间的差异。摇头丸使野生型和基因敲除小鼠伏隔核中多巴胺细胞外水平升高的程度相似。相反，仅在野生型小鼠中，摇头丸后前额叶皮质中5-HT的细胞外浓度升高。
这些发现为SERT特异性参与摇头丸的强化特性提供了证据。
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