Postnatal development of presynaptic receptors that modulate noradrenaline release in mice

The objective of the study was to clarify the postnatal development of the following transmitter release-modulating receptors of noradrenergic neurons in mice: alpha2-adrenoceptors, muscarinic, opioid and cannabinoid receptors (inhibitory), beta-adrenoceptors and receptors for angiotensin II and bradykinin (facilitatory). Wildtype (NMRI) and in some cases alpha2A/D-adrenoceptor-deficient mice aged 1 day (P1) or 8-16 weeks (adults) were used. Hippocampal and occipito-parietal cortex slices and sympathetically innervated tissues (atria and vas deferens) were preincubated with [3H]-noradrenaline and then superfused and stimulated electrically. Stimulation led to distinct increases in tritium efflux which were abolished by tetrodotoxin or removal of calcium. Concentration-response curves of appropriate agonists and in the case of alpha2-autoreceptors antagonists were determined. For beta-adrenoceptors and angiotensin receptors, the interaction of agonists with antagonists was also examined. Results demonstrate that alpha2A/D-autoreceptors operate already at P1 whereas nonalpha2A/D-autoreceptors, presumably alpha2C, develop later. Of the various heteroreceptors, those of brain noradrenergic neurons (OP3 and ORL1) modulate the release of [3H]-noradrenaline at least as effectively at P1 as in adults. Those of peripheral sympathetic neurons (muscarinic, probably mainly M2, OP1, OP2, OP3, CB1, AT1 and B1), in contrast, operate less effectively or not at all at P1, with one exception: beta2-adrenoceptors increase the release of [3H]-noradrenaline (atria) to the same extent, irrespective of age. Overall, results indicate that brain and peripheral noradrenergic neurons release their transmitter already shortly after birth. Presynaptic receptor mechanisms mature differentially in the brain and the periphery. Moreover, the various presynaptic receptors differ in their postnatal development and may play differential roles at different ages.