Joyce J N, Gibbs R B, Cotman C W, Marshall J F
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104.
J Neurosci. 1989 Aug;9(8):2776-91. doi: 10.1523/JNEUROSCI.09-08-02776.1989.
The regulation of hippocampal muscarinic M1 and M2 receptors was studied by autoradiographic methods following cholinergic denervation and reinnervation from embryonic septal transplant. In young adult male rats the density of M1 sites, labeled either with 3H-pirenzepine (PZ) or 3H-N-methylscopolamine (NMS, in the presence of excess carbachol), exceeded by 4- to 5-fold the density of M2 sites, labeled with 3H-NMS in the presence of excess PZ. Both receptors appeared to be densest in hippocampal regions lowest in acetylcholinesterase or 3H-hemicholinium-3 binding. The distribution of M1 receptors did differ from the distribution of M2 receptors within subregions of the hippocampus. Along the mediolateral axis from the subiculum to the lateral CA 1, the density of M1 receptors is uniform, but the density of M2 receptors decreases. Also apparent is the relatively small difference in density between the CA1 and dentate gyrus for M1 receptors but a significantly greater difference for M2 receptors. However, the response of M1 and M2 receptors to long-term cholinergic denervation following fimbriafornix transection of the septal cholinergic input and to cholinergic innervation by embryonic septal transplants was similar. Long-term denervation (40-60 d) resulted in a 30-60% increase in both M1 and M2 receptors within regions of the hippocampal formation. Receptor levels were reduced to normal in regions innervated by septal transplants. For both receptors, the changes in the density of sites were due to alterations in the Bmax and not the Kd for the radioligands. The specificity of this regulation is supported by the evidence that (1) the degree and topography of the normalization of muscarinic receptor density was entirely dependent on the degree and pattern of cholinergic reinnervation by the fibers of the septal transplant, (2) cholinergic fiber reinnervation by embryonic striatal grafts also down-regulated the density of M1 and M2 receptors, and (3) successfully surviving transplants (e.g., cerebellar and striatal) that did not provide innervation to the hippocampus did not induce down-regulation of muscarinic receptors. Changes in the density of sites were not related to changes in the width of the hippocampus following denervation and reinnervation. The data support the view that the majority of M1 and M2 receptors are located postsynaptically on neurons within the hippocampus and not presynaptically on cholinergic fibers.
采用放射自显影法，研究了胆碱能去神经支配及胚胎隔区移植再支配后海马毒蕈碱M1和M2受体的调节情况。在成年雄性幼鼠中，用3H-哌仑西平（PZ）或3H-N-甲基东莨菪碱（NMS，在过量卡巴胆碱存在下）标记的M1位点密度，比在过量PZ存在下用3H-NMS标记的M2位点密度高4至5倍。两种受体在乙酰胆碱酯酶或3H-半胆碱-3结合最低的海马区域似乎密度最高。海马各亚区内M1受体的分布与M2受体的分布不同。沿着从海马下托到外侧CA1的内外侧轴，M1受体密度均匀，但M2受体密度降低。同样明显的是，CA1和齿状回之间M1受体密度差异相对较小，而M2受体密度差异则显著较大。然而，M1和M2受体对海马隔区胆碱能输入的穹窿海马伞横断后的长期胆碱能去神经支配以及胚胎隔区移植的胆碱能再支配的反应相似。长期去神经支配（40 - 60天）导致海马结构区域内M1和M2受体均增加30 - 60%。隔区移植支配区域的受体水平恢复正常。对于两种受体，位点密度的变化是由于Bmax的改变，而不是放射性配体的Kd的改变。这种调节的特异性得到以下证据的支持：（1）毒蕈碱受体密度正常化的程度和拓扑结构完全取决于隔区移植纤维胆碱能再支配的程度和模式；（2）胚胎纹状体移植的胆碱能纤维再支配也下调了M1和M2受体的密度；（3）成功存活但未向海马提供支配的移植（如小脑和纹状体）未诱导毒蕈碱受体下调。去神经支配和再支配后位点密度的变化与海马宽度的变化无关。数据支持这样的观点，即大多数M1和M2受体位于海马内神经元的突触后，而非胆碱能纤维的突触前。
