Axo-axonal interaction in autonomic regulation of the cerebral circulation

Abstract

Noradrenaline (NE) and acetylcholine (ACh) released from the sympathetic and parasympathetic neurones in cerebral blood vessels were suggested initially to be the respective vasoconstricting and dilating transmitters. Both substances, however, are extremely weak post-synaptic transmitters. Compelling evidence indicates that nitric oxide (NO) which is co-released with ACh from same parasympathetic nerves is the major transmitter for cerebral vasodilation, and its release is inhibited by ACh. NE released from the sympathetic nerve, acting on presynaptic β2-adrenoceptors located on the neighbouring parasympathetic nitrergic nerves, however, facilitates NO release with enhanced vasodilation. This axo-axonal interaction mediating NE transmission is supported by close apposition between sympathetic and parasympathetic nerve terminals, and has been shown in vivo at the base of the brain and the cortical cerebral circulation. This result reveals the physiological need for increased regional cerebral blood flow in 'fight-or-flight response' during acute stress. Furthermore, α7- and α3β2-nicotinic ACh receptors (nAChRs) on sympathetic nerve terminals mediate release of NE, leading to cerebral nitrergic vasodilation. α7-nAChR-mediated but not α3β2-nAChR-mediated cerebral nitrergic vasodilation is blocked by β-amyloid peptides (Aβs). This may provide an explanation for cerebral hypoperfusion seen in patients with Alzheimer's disease. α7- and α3β2-nAChR-mediated nitrergic vasodilation is blocked by cholinesterase inhibitors (ChEIs) which are widely used for treating Alzheimer's disease, leading to possible cerebral hypoperfusion. This may contribute to the limitation of clinical use of ChEIs. ChEI blockade of nAChR-mediated dilation like that by Aβs is prevented by statins pretreatment, suggesting that efficacy of ChEIs may be improved by concurrent use of statins.