Effects Of Cholinergic Afferent Innervations Into Cerebellar Cortex On Cardiovascular Modulation And The Aging Changes

The cerebellar cholinergic system belongs to the third type of the afferent nerve fiber system(after the climbing and mossy fibers),and has important modulatory effects on cerebellar circuits and cerebellar-mediated functions.However,the role of acetylcholine(ACh)in cerebellar regulation of blood pressure(BP)has not been examined.In this study,the arterial pressure was measured in rats after cholinergic reagents were microinjected into the cerebellar cortex,in order to explore how the cholinergic modulation on BP and the underlying receptor mechanism.We have obtained the following results:1,After microinjection of ACh(30,100,and 300 mM)into cerebellar cortex of the young(2 mo)rats,the BP showed a concentration-dependent decrease,indicating that cerebellar cholinergic afferents exerts depressor effects on BP regulation.2,After microinjection of ACh nonselective mAChR agonist(oxotremorine M,OXO)and ACh mixed with nonselective mAChR antagonist atropine into the cerebellar cortex,the results showed that OXO dose-dependently decreased the BP,which displayed a homodromous effect of ACh-mediated depressor response;meanwhile,atropine effectively blocked the effect of ACh on the BP down-regulation,indicating mACh receptors in cerebellar cortex participate in ACh-mediated depressor response.3,After microinjection of a selective M2 receptor agonist(arecaidine but-2-ynyl ester tosylate,ABET)and OXO mixed with a selective M2 receptor antagonist(methoctramine hydrate,MCT)into the cerebellar cortex,the results demonstrated that ABET dose-dependently decreased the BP and heart rate,and MCT dose-dependently blocked the OXO-mediated cardiovascular depressor response,suggesting that M2 receptors in the cerebellar cortex are involved in cardiovascular regulation,activation of which evokes significant depressor and bradycardic responses.4,After microinjection of ACh(30,100,and 300 mM)into cerebellar cortex of the old(16-20 mo)rats,the BP also showed a concentration-dependent decrease,however,responses in the old animals were significantly attenuated compared to the young,indicating that cerebellar cholinergic effects undergo retrogression with aging.These results clarify the modulatory effects,the receptor mechanisms of cholinergic afferents on cerebellum-mediated cardiovascular activities,as well as the aging changes,which refurbishes our understandings on cerebellar cholinergic function and provides valuable references to optimize therapeutic regimen on certain clinical practice(such as hypertension)in future.