The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs' amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs' function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics.

译文

腹侧被盖区 (VTA) 在促进吸毒成瘾发展的奖励和动机过程中起着重要作用。突触前 α1-AR活化调节谷氨酸和 γ-氨基丁酸 (GABA) 的释放。这项工作阐明了VTA突触前 α1-ARs的作用及其对可卡因敏化过程中谷氨酸能和gaba能神经传递的调节。通过全细胞电压钳测量的兴奋性和抑制性电流 (epsc和IPSCs) 表明,在可卡因治疗1天后,但在可卡因注射5天后,α1-ARs激活会增加epsc的幅度。对 α1-ARs激动剂没有药理反应,这凸显了反复服用可卡因后受体的脱敏。在7天的停药期后,α1-ARs的脱敏作用持续存在。相反,ipscs振幅降低显示的 α1-ARs对GABA神经传递的调节不受急性或慢性可卡因注射的影响。总之,这些数据表明,即使在缺乏 α1-ARs对谷氨酸释放和蛋白的功能的情况下,反复服用可卡因后,α1-ARs也可以通过减少GABA对VTA多巴胺 (DA) 神经元的抑制作用来增强DA神经元的兴奋性。激酶C (PKC) 激活。可卡因敏化中的 α1-AR调节变化增加了我们对去甲肾上腺素能系统在可卡因成瘾中的作用的了解,并可能为治疗提供可能的途径。

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