Earley B, Glennon M, Leonard B E, Junien J L
Department of Pharmacology, University College, Galway, Ireland.
Neurochem Int. 1995 Jun;26(6):559-70. doi: 10.1016/0197-0186(95)00004-r.
The distribution patterns of M1 and M2 muscarinic receptor subtypes following TMT and JO 1784 administration in the male Sprague-Dawley rat were investigated. In the present study, JO 1784 was injected in doses of 1, 4 and 16 mg/kg i.p. for one week prior to the single injection of TMT (8 mg/kg i.p.) and subsequently for 33 days. The effects of JO 1784 on the density of muscarinic receptor sub-types (M1 and M2) in the control and trimethyltin (TMT) treated rats were then evaluated. The topographic distribution and changes in muscarinic (M1 and M2) receptor densities were determined by means of autoradiography using [3H]quinuclidinylbenzilate (QNB). Both sub-types of muscarinic receptors contributed to the observed decrease in total muscarinic receptor binding in TMT-treated rats. In control rats, JO 1784 alone decreased M1 receptor density in the amygdaloid nuclei, basal ganglia, cortex and hippocampus and decreased M2 receptor density in the amygdaloid nuclei, basal ganglia, cortex, hippocampus, hypothalamus and septal regions. In TMT treated rats, chronic JO 1784 administration has a "neuroprotective effect" on both M1 and M2 receptors subtypes. Thus, following chronic administration of JO 1784 to TMT treated rats, both increases and decreases in M1 receptor density were observed relative to TMT animals. A significant increase in M1 receptor density was found in the cortex, olfactory regions, septum, thalamus and basal forebrain nuclei. In the hippocampus (CA2 and CA3), a significant decrease in M1 receptor density was observed. In TMT-treated rats, JO 1784 produced a significant increase in M2, receptor density in several brain regions with the most marked effects occurring in the amygdaloid nuclei, basal ganglia, cortex, hippocampus and hypothalamus. The ability of the selective sigma ligand, JO 1784, to attenuate the loss of muscarinic receptors in TMT treated rats could be of importance in the development of novel neuroprotective drugs.
研究了在雄性Sprague-Dawley大鼠中给予TMT和JO 1784后M1和M2毒蕈碱受体亚型的分布模式。在本研究中，在单次注射TMT（腹腔注射8mg/kg）前一周，以1、4和16mg/kg的剂量腹腔注射JO 1784，持续一周，随后持续33天。然后评估JO 1784对对照大鼠和三甲基锡（TMT）处理大鼠中毒蕈碱受体亚型（M1和M2）密度的影响。使用[3H]喹核酯（QNB）通过放射自显影法确定毒蕈碱（M1和M2）受体密度的地形图分布和变化。两种毒蕈碱受体亚型都导致了TMT处理大鼠中总毒蕈碱受体结合的观察到的减少。在对照大鼠中，单独的JO 1784降低了杏仁核、基底神经节、皮质和海马中的M1受体密度，并降低了杏仁核、基底神经节、皮质、海马、下丘脑和隔区中的M2受体密度。在TMT处理的大鼠中，长期给予JO 1784对M1和M2受体亚型都有“神经保护作用”。因此，在对TMT处理的大鼠长期给予JO 1784后，相对于TMT动物，观察到M1受体密度既有增加也有减少。在皮质、嗅觉区域、隔区、丘脑和基底前脑核中发现M1受体密度显著增加。在海马体（CA2和CA3）中，观察到M1受体密度显著降低。在TMT处理的大鼠中，JO 1784在几个脑区中使M2受体密度显著增加，最显著的影响发生在杏仁核、基底神经节、皮质、海马体和下丘脑。选择性σ配体JO 1784减轻TMT处理大鼠中毒蕈碱受体损失的能力在新型神经保护药物的开发中可能具有重要意义。
