Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, Team Physiopathology of Addiction and Relapse, Université Pierre et Marie Curie, Paris, France.
Biol Psychiatry. 2013 Jul 15;74(2):90-8. doi: 10.1016/j.biopsych.2012.11.029. Epub 2013 Jan 17.
In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists months after the last administration. It has been shown that behavioral sensitization to amphetamine develops parallel to an increased release of norepinephrine (NE) in the prefrontal cortex (PFC).
Rats and mice were repeatedly treated with amphetamine (1 or 2 mg/kg intraperitoneally, respectively) to obtain sensitized animals. The NE release in the PFC was measured by microdialysis in freely moving mice (n = 55). Activity of locus coeruleus (LC) noradrenergic neurons was determined in anaesthetized rats (n = 15) by in vivo extracellular electrophysiology. The α2A-adrenergic autoreceptor (α2A-AR) expression was assessed by autoradiography on brain slices, and Gαi proteins expression was measured by western blot analysis of LC punches.
In sensitized rats LC neurons had a higher spontaneous firing rate, and clonidine-an α2A-adrenergic agonist-inhibited LC neuronal firing less efficiently than in control animals. Clonidine also induced lower levels of NE release in the PFC of sensitized mice. This desensitization was maintained by a lower density of Gαi1 and Gαi2 proteins in the LC of sensitized mice rather than weaker α2A-AR expression. Behavioral sensitization was facilitated by α2A-AR antagonist, efaroxan, during amphetamine injections and abolished by clonidine treatment.
Our data indicate that noradrenergic inhibitory feedback is impaired for at least 1 month in rats and mice repeatedly treated with amphetamine. This work highlights the key role of noradrenergic autoreceptor signaling in the persistent modifications induced by repeated amphetamine administration.
在啮齿类动物中，滥用药物会引起运动过度活跃，重复注射会增强这种反应。这种效应被称为行为敏感化，在最后一次给药后数月仍持续存在。已经表明，对安非他命的行为敏感化与前额叶皮层（PFC）中去甲肾上腺素（NE）释放增加平行发展。
通过对大鼠和小鼠进行反复腹腔注射安非他命（分别为 1 或 2mg/kg）来获得敏化动物。通过自由活动小鼠的微透析（n = 55）测量 PFC 中的 NE 释放。通过体内细胞外电生理学在麻醉大鼠（n = 15）中测定蓝斑核（LC）去甲肾上腺素能神经元的活性。通过脑片放射自显影评估α2A-肾上腺素能自身受体（α2A-AR）表达，并通过 LC 打孔的 Western blot 分析测量 Gαi 蛋白表达。
在敏化大鼠中，LC 神经元的自发放电率更高，而可乐定（一种α2A-肾上腺素能激动剂）对 LC 神经元放电的抑制作用不如对照动物那么有效。可乐定也诱导敏化小鼠 PFC 中 NE 释放水平降低。这种脱敏作用是由于敏化小鼠 LC 中 Gαi1 和 Gαi2 蛋白密度较低，而不是α2A-AR 表达较弱所致。在安非他命注射期间，α2A-AR 拮抗剂依氟烷促进了行为敏感化，而氯丙嗪治疗则消除了行为敏感化。
我们的数据表明，在反复给予安非他命治疗的大鼠和小鼠中，至少在 1 个月内，去甲肾上腺素能抑制性反馈受损。这项工作强调了去甲肾上腺素能自身受体信号在反复给予安非他命引起的持久改变中的关键作用。
