PubMed1990
Agonist interactions with release processes do not validate autoreceptor operation. Instead, the data suggests that autoreceptors function as homoreceptors. Declining efficacy of agonist inhibition of transmitter release with increasing stimulation "intensity" is not assignable to competition with endogenous transmitter for a finite population of receptors. Heteroreceptor activation also reveals a pattern of declining efficacy with increasing intensity. Inhibition of stimulation-induced release by agonists also does not correlate inversely with that of antagonist effectiveness, as it should if both effects are linked to biophase levels of transmitter. Further, per pulse release of transmitter, in the absence of drugs, does not comply with expectations for autoinhibition. Experiments with tetrodotoxin, and study of the magnitudes of agonist and antagonist effects suggest that in the periphery putative autoreceptors may actually be homoreceptors, e.g., sympathetic nerve terminal receptors responsive to circulating catecholamines. In the central nervous system the paracrine secretion of transmitter may invoke homoreceptor activation rather than autoreceptors. Such activation may include, for example, the release of adrenaline from one set of fibers in the hypothalamus to act on dopaminergic or noradrenergic fibers or the release of noradrenaline from the terminals of some noradrenergic fibers in the cortex to activate alpha2 receptors on other cortical noradrenergic fibers, the latter with a somewhat different function in the same brain region. The action of antagonist drugs to enhance transmitter release may be direct on nerve membranes in particular on sodium channels, and often unrelated to feedback regulation. This possibility is discussed by me elsewhere in this volume. It is shown that yohimbine and a low concentration of veratridine have similar and nonadditive effects on transmitter release.