Rapid, agonist‐induced desensitization of α2‐autoreceptors modulating transmitter release

Abstract

1 The release of previously incorporated [3H]‐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 10 μmol l−1 of the uptake inhibitor, cocaine, or the selective α2‐adrenoceptor agonist, 5‐bromo‐N‐(4,5‐dihydro‐1H‐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 α2‐adrenoceptor‐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 μmol l−1) was present for 2, 8, or 16 min, respectively. Likewise, UK 14,304 (1 μmol l−1) present for these periods of time reduced 3H overflow to 35%, 51%, and 53% of control, respectively. Addition of 1 nmol l−1 to 10 μmol l−1 UK 14,304 for either 2 or 16 min did not produce significantly different IC50 values, but the inhibitory effects were smaller with 16 min as compared to 2 min exposure at concentrations ≥ 10 nmol l−1. 3 In rat sympathetic neurones, noradrenaline (100 nmol l−1) 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 μmol l−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 IC50 values, but the inhibition induced by 16 min as compared to 2 min exposure was smaller at concentrations ≥ 10 nmol l−1. 4 In cerebrocortical slices from either neonatal or adult rats, exposure to 0.1 to 1.0 μmol l−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 α2‐adrenoceptors which regulate noradrenaline release from sympathetic neurones undergo agonist‐induced desensitization within minutes. Such rapid desensitization of α2‐autoreceptors was not detected in brain slice preparations. 1995 British Pharmacological Society