Imperato A, Scrocco M G, Ghirardi O, Ramacci M T, Angelucci L
Istituto di Farmacologia Medica 2nda Cattedra, Università La Sapienza, Rome, Italy.
Ann N Y Acad Sci. 1991;621:90-7. doi: 10.1111/j.1749-6632.1991.tb16971.x.
The regulation of acetylcholine (ACh) release by the different subtypes of muscarinic (M) receptors in the hippocampus of freely-moving Fischer and Sprague-Dawley rats, was investigated. Atropine (10 mumol/kg i.p.) induced a pronounced increase of ACh release (+400% over basal values) in the hippocampus of young rats (3 months) while the effect was drastically reduced (+100% over basal values) in old rats (24 months). The preferential M2 antagonist AF-DX 116 (50 mumol/kg i.p.) showed similar effects in young and old rats being, furthermore, 10 times less potent than atropine. The preferential M1 antagonist pirenzepine (50 mumol/kg i.p.) was even less potent than AF-DX 116 in enhancing ACh release in young rats, while the effect was more pronounced in the old ones. Therefore, the effect of the preferential M3 antagonist 4-DAMP was studied. 4-DAMP 10(-6) M, dissolved in the Ringer solution perfusing the hippocampus, induced an enhancement of ACh release (+200% and +70% over basal values, in young and old rats, respectively) which was comparable to that obtained after atropine at the same concentration. AF-DX 116 and pirenzepine, on the other hand, were by far less potent. Six months' pretreatment with acetyl-l-carnitine (ALCAR) reduced the significant differences between young and old rats in the release response after M1 and M3 receptor antagonists. Taken all together, these findings indicate that the regulation of ACh release, at least in the hippocampus, is mainly through the M3 receptors subtype of muscarinic receptors and that this subtype is the most involved in the aging process. Moreover, the ability of ALCAR to preserve the receptor-mediated functional ACh release response with respect to old animals suggests that ALCAR could be utilized in the amelioration of receptor functionality in the aging brain.
研究了自由活动的Fischer大鼠和Sprague-Dawley大鼠海马中不同亚型的毒蕈碱（M）受体对乙酰胆碱（ACh）释放的调节作用。阿托品（10 μmol/kg腹腔注射）可使幼鼠（3个月）海马中的ACh释放显著增加（比基础值增加400%），而在老年大鼠（24个月）中，该效应则大幅降低（比基础值增加100%）。选择性M2拮抗剂AF-DX 116（50 μmol/kg腹腔注射）在幼鼠和老年大鼠中显示出类似的效应，此外，其效力比阿托品低10倍。选择性M1拮抗剂哌仑西平（50 μmol/kg腹腔注射）在增强幼鼠ACh释放方面的效力甚至比AF-DX 116更低，而在老年大鼠中效应更明显。因此，研究了选择性M3拮抗剂4-DAMP的作用。溶解于灌注海马的林格溶液中的4-DAMP 10⁻⁶ M可使ACh释放增加（幼鼠和老年大鼠分别比基础值增加200%和70%），这与相同浓度阿托品作用后的增加幅度相当。另一方面，AF-DX 116和哌仑西平的效力要低得多。用乙酰左旋肉碱（ALCAR）进行6个月的预处理可减少幼鼠和老年大鼠在M1和M3受体拮抗剂作用后释放反应的显著差异。综上所述，这些发现表明，至少在海马中，ACh释放的调节主要通过毒蕈碱受体的M3受体亚型，且该亚型在衰老过程中最为相关。此外，ALCAR能够在老年动物中维持受体介导的功能性ACh释放反应，这表明ALCAR可用于改善衰老大脑中的受体功能。
