Rapid, agonist-induced desensitization of α2-autoreceptors modulating transmitter release (original) (raw)

1995, British Journal of Pharmacology

The release of previously incorporated [3HJ-noradrenaline was investigated in cultures of dissociated chick or rat sympathetic neurones and in cerebrocortical slices from neonatal or adult rats. Noradrenaline, in the presence of gmol I`of the uptake inhibitor, cocaine, or the selective M2adrenoceptor agonist, 5-bromo-N-(4,5-dihydro-IH-imidazol-2-yl)-6-quinoxalinamine (UK 14,304), was applied for different periods of time in order to detect a possible time-dependence of the a2adrenoceptor-mediated inhibition of electrically evoked tritium outflow. 2 In chick sympathetic neurones, stimulation-evoked overflow was reduced to 30%, 42%, or 56% of control when noradrenaline (1 Lmol I-) was present for 2, 8, or 16 min, respectively. Likewise, UK 14,304 (1 jimol 1') present for these periods of time reduced 3H overflow to 35%, 51%, and 53% of control, respectively. Addition of 1 nmolI 1 to ;mol I`UK 14,304 for either 2 or 16 min did not produce significantly different ICs values, but the inhibitory effects were smaller with 16 min as compared to 2 min exposure at concentrations > 10 nmol I-. 3 In rat sympathetic neurones, noradrenaline (100 nmol I') reduced stimulation-evoked overflow to 33%, 56%, or 57% of control, when present for 2, 8, or 16 min, respectively. Addition of UK 14,304 (1 pmol 1-1) for these periods of time caused inhibition to 11%, 41%, and 46% of control. Applying UK 14,304 for either 2 or 16 min did not result in significantly different IC5o values, but the inhibition induced by 16 min as compared to 2 min exposure was smaller at concentrations > 10 nmol 1'. 4 In cerebrocortical slices from either neonatal or adult rats, exposure to 0.1 to 1.0 pmol 1' UK 14,304 for 16 min never caused a smaller inhibition than a corresponding 3 min exposure, although various experimental conditions were investigated. 5 The results demonstrate that a2-adrenoceptors which regulate noradrenaline release from sympathetic neurones undergo agonist-induced desensitization within minutes. Such rapid desensitization of a2autoreceptors was not detected in brain slice preparations.