Modulation of acetylcholine release by presynaptic muscarinic autoreceptors

The existence of a modulatory system controlling the acetylcholine (ACh) release was first proposed for the nicotinic subtype in 1962. Following the first observation of a possible positive feedback loop activated by the released Ach, many studies were oriented in the investigation of the involved presynaptic autoreceptors. Most of the data have been obtained at the motor end-plate, commonly defined as the simplest model of peripheral synapse. The characterization of the chemical transmission since its first proposal showed a more complex pattern involving both the cholinergic and the adrenergic systems. It is now evident that this regulation is widespread both in the central and in the peripheral nervous system. The evidence that the release of ACh can be up- or down-regulated by the transmitter itself (autoregulation) or other neuromediators (heteroregulation) is now proved. In the last decades the attention was focused to the identification of the receptor subtypes located on the releasing nerve terminal. For the purpose, different techniques were used in the various laboratories. The functional approach was based mainly on the electrophysiological characterization of the events evolved prior, during and after the activation of the motor endplate nicotinic receptor. On the other hand, the overflow studies were carried out using radiolabeled ACh (rACh) obtained treating muscle fibers with radioactive choline (rCh). Many scientific papers proposed common data indicating a clear positive (nicotinic) or negative (muscarinic) modulation of the ACh release. Temporally, the description of the muscarinic regulation followed the discovery of the nicotinic one. However, by a pure pharmacological point of view it represents a challenge due to the more complex organization and function. In the peripheral nervous system, i.e. neuromuscular, the meaning of both the muscarinic and nicotinic modulations may appear as free of function. Conversely, in the central systems some effects, such as antinociception and others, could represent the basis of a functional activity such as proposed by Corrado group. The complete characterization of this phenomenon by a physiological and a pharmacological point of view could represents the goal for future uses and therapeutic potential. The present review illustrates the know how and the efforts in the characterisation of the muscarinic regulation of transmitter release from the beginning of its discovery trying to order the numerous scientific data published in this field. Furthermore, our personal data obtained with the Loose Patch Clamp (LPC) technique will be briefly presented and discussed. Our work was built up using agonists and antagonists of the muscarinic receptor subtype in the aim of better characterize the modulation function of the mediator Ach. We used carbachol (Cch), oxotremorine (Oxo) and dl-muscarine as agonists and 1-hyoscyamine, pirenzepine, ipratropium, 11[[2-1[(diethylamino) methyl-1-piperidinyl]-acetyl]-5, 11-dihydro-6H-pyrido [2,3-b][1,4] benzodiazepine-6-one (AFDX-116), methoctramine and 1,1-dimethyl-4 diphenylacetoxy-N-methylpiperidine (4-DAMP) as antagonists.