The involvement of dopamine and D2 receptor-mediated transmission in effects of cotinine in male rats.
The involvement of dopamine and D2 receptor-mediated transmission in effects of cotinine in male rats.
复制标题
多巴胺和 D2 受体介导的传递参与可替宁对雄性大鼠的影响。
DOI：
10.1016/j.neuropharm.2023.109495
复制
发表时间：
2023
影响因子：
4.7
通讯作者：
Ding,Zheng-Ming
中科院分区：
文献类型：
--
作者：
Tan,Xiaoying;Neslund,ElizabethM;Ding,Zheng-Ming
以往的研究表明，尼古丁的主要代谢产物可替宁支持大鼠静脉自我给药，并表现出复发样的觅药行为。随后的研究开始揭示中脑边缘多巴胺系统在可替宁作用中的重要作用。被动给药可替宁升高了丘脑核（NAC）和D1受体拮抗剂SCH 23390中的细胞外多巴胺水平，可替宁自身给药减弱。本研究的目的是进一步研究中脑边缘多巴胺系统在介导可替宁作用中的作用。进行常规微透析以检查主动自我给药期间NAC多巴胺的变化。定量微透析和蛋白质印迹被用来确定可替宁诱导的NAC内的神经适应。进行行为药理学以研究D2样受体在可替宁自我给药和复发样行为中的潜在参与。NAC细胞外多巴胺水平在可替宁和尼古丁主动自我给药期间增加，但在可替宁自我给药期间增加不太稳健。重复皮下注射可替宁降低基础细胞外多巴胺浓度，而不改变NAC中的多巴胺再摄取。慢性自我管理的可替宁导致D2受体的蛋白表达减少的核心内，但不壳次区域的NAC，但没有改变任何D1受体或酪氨酸羟化酶在任何一个分区。另一方面，长期尼古丁自我给药对这些蛋白质中的任何一种都没有显著影响。依替氯必利（一种D2样受体拮抗剂）的全身给药减弱了可替宁自我给药和线索诱导的可替宁寻求恢复。这些结果进一步支持了中脑边缘多巴胺传递在介导可替宁的强化效应中起关键作用的假设。
Previous studies indicated that cotinine, the major metabolite of nicotine, supported intravenous self-administration and exhibited relapse-like drug-seeking behaviors in rats. Subsequent studies started to reveal an important role of the mesolimbic dopamine system in cotinine's effects. Passive administration of cotinine elevated extracellular dopamine levels in the nucleus accumbens (NAC) and the D1 receptor antagonist SCH23390 attenuated cotinine self-administration. The objective of the current study was to further investigate the role of mesolimbic dopamine system in mediating cotinine's effects in male rats. Conventional microdialysis was conducted to examine NAC dopamine changes during active self-administration. Quantitative microdialysis and Western blot were used to determine cotinine-induced neuroadaptations within the NAC. Behavioral pharmacology was performed to investigate potential involvement of D2-like receptors in cotinine self-administration and relapse-like behaviors. NAC extracellular dopamine levels increased during active self-administration of cotinine and nicotine with less robust increase during cotinine self-administration. Repeated subcutaneous injections of cotinine reduced basal extracellular dopamine concentrations without altering dopamine reuptake in the NAC. Chronic self-administration of cotinine led to reduced protein expression of D2 receptors within the core but not shell subregion of the NAC, but did not change either D1 receptors or tyrosine hydroxylase in either subregion. On the other hand, chronic nicotine self-administration had no significant effect on any of these proteins. Systemic administration of eticlopride, a D2-like receptor antagonist attenuated both cotinine self-administration and cue-induced reinstatement of cotinine seeking. These results further support the hypothesis that the mesolimbic dopamine transmission plays a critical role in mediating reinforcing effects of cotinine.