Neuropharmacology of nicotine: effects on the autoregulation of acetylcholine release by substance P and methionine enkephalin in rodent cerebral slices and toxicological implications.

1. The neuronal release of acetylcholine (ACh) and its autoregulation by neuromodulators, substance P (SP) and methionine enkephalin (MEK), have been studied using superfused rodent cerebral slices. Nicotine exerts significant effects on autoregulation of ACh release, which may have toxicological implications. 2. Positive and negative feedback systems have been postulated for autoregulation of ACh release. The components of the positive feedback system include a muscarinic (Ms) receptor, SP, and activation of Ca2+ influx. Low levels of ACh in the biophase of the cholinergic synaptic gap may trigger the positive feedback system, and high levels of ACh may trigger the negative feedback system. 3. There are also neuronal pathways for direct reciprocal regulations of SP and MEK. 4. Low concentrations of nicotine triggers the release of ACh followed by MEK and SP. Release of SP causes neurogenic inflammation. 5. Nicotine and its metabolite, cotinine, activate platelet activating factor (PAF)-hydrolase and thereby enhance the turnover rate of PAF. This effect may contribute to tobacco-induced arterial thrombosis in peripheral and central nervous systems.