Araujo D M, Lapchak P A, Meaney M J, Collier B, Quirion R
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
J Neurosci. 1990 Sep;10(9):3069-78. doi: 10.1523/JNEUROSCI.10-09-03069.1990.
The main objective of the present work was to determine whether the regulation of ACh release by nicotinic and muscarinic autoreceptors is compromised in the aged rat brain. For this, the effects of the nicotinic agonist N-methylcarbamylcholine (MCC) and the muscarinic-M2 antagonist AF-DX 116 on ACh release from brain slices of young (3-month-old), adult (9-month-old), and aged (27-month-old) rats were tested. The ability of MCC to enhance spontaneous ACh release in hippocampal, cerebral cortical, and cerebellar slices was only modestly altered with age. In contrast, the sensitivity of muscarinic autoreceptors in the aged hippocampus and cerebral cortex, but not the striatum, to blockade by the muscarinic-M2 antagonist AF-DX 116 was severely attenuated. To assess whether the age-related changes in cholinergic autoreceptor function may be due to deficits in presynaptic cholinergic markers, we tested whether choline acetyltransferase (ChAT) activity, basal and evoked ACh release, and nicotinic and muscarinic binding sites are altered in the aged rats. ChAT activity in forebrain regions was decreased in the aged compared to the young and mature adult rats. Furthermore, the potassium-evoked, but not the spontaneous, release of ACh was markedly depressed in striatal, hippocampal, and cortical slices of aged rats. The densities of nicotinic and muscarinic-M2 binding sites, assessed using 3H-MCC and 3H-AF-DX 116 as selective ligands, respectively, were markedly reduced in homogenates of the striatum, hippocampus, cerebral cortex, and thalamus of aged rats. In contrast, muscarinic-M1 sites, selectively labeled with 3H-pirenzepine, were not affected. Therefore, it appears that age-related decrements in ChAT activity and in muscarinic-M2, but not nicotinic, binding sites in the rat brain are reflected in a decreased function of muscarinic-M2 autoreceptors. However, the positive correlation between loss of ChAT activity, decreased muscarinic-M2 binding sites, and impaired muscarinic autoreceptor function is clearly tissue dependent.
本研究的主要目的是确定在老年大鼠脑中，烟碱型和毒蕈碱型自身受体对乙酰胆碱（ACh）释放的调节是否受损。为此，测试了烟碱型激动剂N-甲基氨甲酰胆碱（MCC）和毒蕈碱-M2拮抗剂AF-DX 116对年轻（3个月大）、成年（9个月大）和老年（27个月大）大鼠脑片ACh释放的影响。MCC增强海马、大脑皮层和小脑切片中自发ACh释放的能力仅随年龄有适度改变。相反，老年海马和大脑皮层而非纹状体中毒蕈碱型自身受体对毒蕈碱-M2拮抗剂AF-DX 116阻断的敏感性严重减弱。为评估胆碱能自身受体功能的年龄相关变化是否可能归因于突触前胆碱能标志物的缺陷，我们测试了老年大鼠中胆碱乙酰转移酶（ChAT）活性、基础和诱发的ACh释放以及烟碱型和毒蕈碱型结合位点是否改变。与年轻和成年大鼠相比，老年大鼠前脑区域的ChAT活性降低。此外，老年大鼠纹状体、海马和皮层切片中钾诱发而非自发的ACh释放明显降低。分别使用3H-MCC和3H-AF-DX 116作为选择性配体评估的烟碱型和毒蕈碱-M2结合位点的密度在老年大鼠的纹状体、海马、大脑皮层和丘脑匀浆中明显降低。相反，用3H-哌仑西平选择性标记的毒蕈碱-M1位点未受影响。因此，似乎大鼠脑中ChAT活性以及毒蕈碱-M2而非烟碱型结合位点的年龄相关减少反映在毒蕈碱-M2自身受体功能降低上。然而，ChAT活性丧失、毒蕈碱-M2结合位点减少和毒蕈碱型自身受体功能受损之间的正相关显然依赖于组织。
