Pauly J R, Marks M J, Robinson S F, van de Kamp J L, Collins A C
Department of Pharmacology, Medical College of Georgia, Augusta, Georgia, USA.
J Pharmacol Exp Ther. 1996 Jul;278(1):361-9.
It has recently been shown using regionally dissected tissue that both chronic mecamylamine treatment and chronic nicotine treatment increase the number of [3H]-nicotine binding sites in mouse brain, and that additive increases in the number of binding sites is observed after cotreatment with the two drugs. The studies reported here extend these findings by using quantitative autoradiographic methods to analyze the brains of chronically treated mice at a finer anatomical level of resolution. DBA/2 mice were chronically infused (i.v.) with saline, 4.0 mg/ kg/hr nicotine, 4.0 mg/kg/hr mecamylamine or both drugs for 7 days. The brains of these mice were subsequently analyzed to determine the effects of chronic drug treatment on [3H]-nicotine binding and on the levels of mRNA encoding the nicotinic receptor subunits, alpha 4 and beta 2. [3H]-Nicotine binding was increased in 37 of 46 brain regions after chronic nicotine treatment (average increase = 66.5%), in 41 of 46 regions after chronic mecamylamine treatment (average increase = 56.5%), and in 45 of 46 brain regions after chronic treatment with both drugs (average increase = 107.1%). The changes in [3H]-nicotine binding produced by the two drugs across brain regions were highly (r = 0.98) and significantly correlated. These results are consistent with the proposal that the same receptors are affected by agonist or antagonist treatment. Chronic treatment had no significant effect on the levels of alpha 4 or beta 2 mRNA as measured by in situ hybridization. Therefore, the increases in [3H]-nicotine binding do not arise from changes in the steady-state levels of either alpha 4 or beta 2 mRNA which are believed to encode the subunits of this nicotinic receptor subtype.
最近利用局部解剖的组织研究表明，慢性给予美加明和慢性给予尼古丁均会增加小鼠脑中[3H] - 尼古丁结合位点的数量，并且两种药物联合处理后，结合位点数量会出现累加性增加。本文报道的研究通过使用定量放射自显影方法，在更高分辨率的精细解剖水平上分析慢性处理小鼠的脑，从而扩展了这些发现。给DBA/2小鼠静脉内长期输注生理盐水、4.0毫克/千克/小时的尼古丁、4.0毫克/千克/小时的美加明或两种药物，持续7天。随后分析这些小鼠的脑，以确定慢性药物处理对[3H] - 尼古丁结合以及对编码烟碱受体亚基α4和β2的mRNA水平的影响。慢性尼古丁处理后，46个脑区中的37个区域[3H] - 尼古丁结合增加（平均增加 = 66.5%），慢性美加明处理后，46个区域中的41个区域增加（平均增加 = 56.5%），两种药物联合慢性处理后，46个脑区中的45个区域增加（平均增加 = 107.1%）。两种药物在不同脑区引起的[3H] - 尼古丁结合变化高度相关（r = 0.98）且具有显著相关性。这些结果与激动剂或拮抗剂处理影响相同受体的观点一致。通过原位杂交测量，慢性处理对α4或β2 mRNA水平没有显著影响。因此，[3H] - 尼古丁结合的增加并非源于α4或β2 mRNA稳态水平的变化，这两种mRNA被认为编码该烟碱受体亚型的亚基。
