RAPID, AGONIST-INDUCED DESENSITIZATION OF ALPHA(2)-AUTORECEPTORS MODULATING TRANSMITTER RELEASE

1 The release of previously incorporated [H-3]-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 mu mol l(-1) of the uptake inhibitor, cocaine, or the selective alpha(2)-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 alpha(2)-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 mu mol l(-1)) was present for 2, 8, or 16 min, respectively. Likewise, UK 14,304 (1 mu mol 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 mu mol 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 greater than or equal to 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 mu mol 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 greater than or equal to 10 nmol l(-1). 4 In cerebrocortical slices from either neonatal or adult rats, exposure to 0.1 to 10 mu mol 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 alpha(2)-adrenoceptors which regulate noradrenaline release from sympathetic neurones undergo agonist-induced desensitization within minutes. Such rapid desensitization of alpha(2)-autoreceptors was not detected in brain slice preparations.