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

1 The release of previously incorporated [H-3]-noradrenaline was inves tigated in cultures of dissociated chick or rat sympathetic neurones a nd in cerebrocortical slices from neonatal or adult rats. Noradrenalin e, 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-dihy dro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304), was applied for d ifferent periods of time in order to detect a possible time-dependence of the alpha(2)-adrenoceptor-mediated inhibition of electrically evok ed tritium outflow. 2 In chick sympathetic neurones, stimulation-evoke d overflow was reduced to 30%, 42%, or 56% of control when noradrenali ne (1 mu mol l(-1)) was present for 2, 8, or 16 min, respectively. Lik ewise, UK 14,304 (1 mu mol l(-1)) present for these periods of time re duced 3H overflow to 35%, 51%, and 53% of control, respectively. Addit ion of 1 nmol l(-1) to 10 mu mol l(-1) UK 14,304 for either 2 or 16 mi n did not produce significantly different IC50 values, but the inhibit ory 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 sympat hetic neurones, noradrenaline (100 nmol l(-1)) reduced stimulation-evo ked 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 thes e periods of time caused inhibition to 11%, 41%, and 46% of control. A pplying UK 14,304 for either 2 or 16 min did not result in significant ly different IC50 values, but the inhibition induced by 16 min as comp ared to 2 min exposure was smaller at concentrations greater than or e qual to 10 nmol l(-1). 4 In cerebrocortical slices from either neonata l or adult rats, exposure to 0.1 to 10 mu mol l(-1) UK 14,304 for 16 m in never caused a smaller inhibition than a corresponding 3 min exposu re, although various experimental conditions were investigated. 5 The results demonstrate that alpha(2)-adrenoceptors which regulate noradre naline release from sympathetic neurones undergo agonist-induced desen sitization within minutes. Such rapid desensitization of alpha(2)-auto receptors was not detected in brain slice preparations.