ACUTE AND CHRONIC EFFECTS OF CHOLINESTERASE-INHIBITORS AND PILOCARPINE ON THE DENSITY AND SENSITIVITY OF CENTRAL AND PERIPHERAL ALPHA-2-ADRENOCEPTORS

The specific binding of the agonists [H-3]clonidine and [H-3]UK 14304 (bromoxidine) and of the antagonist [H-3]RX 821002 (2-metoxy idazoxan) to rat brain membranes, as well as clonidine-induced mydriasis, cloni dine-induced inhibition of brain (3,4-dihydroxyphenylalaninme) DOPA sy nthesis and clonidine-induced inhibition of twitch responses in the va s deferens, was used to evaluate the density and sensitivity of centra l and peripheral alpha2-adrenoceptors after prolonged activation of th e cholinergic system. Acute (12 h), short-term (4 days) or chronic (7- 18 days) treatment with the cholinesterase inhibitors neostigmine (0.1 mg/kg), physostigmine (0.1 mg/kg) and diisopropylfluorophosphate (2 m g/kg) and with the muscarinic receptor agonist pilocarpine (10 mg/kg) did not alter the density of brain alpha2-adrenoceptors. In contrast, various functional responses mediated by central and peripheral alpha2 -adrenoceptors were potentiated after the repeated treatments. Thus, t he inhibitory alpha2-autoreceptor that modulates the synthesis of brai n noradrenaline and the central postsynaptic inhibitory alpha2-adrenoc eptor that induces mydriasis displayed greater responses in vivo after chronic treatment with neostigmine or pilocarpine. These treatments a lso increased the sensitivity of peripheral presynaptic alpha2-adrenoc eptors in the vas deferens. The results indicate that prolonged activa tion of central and peripheral cholinergic pathways results in up-regu lation of alpha2-adrenoceptor function without apparent increases in r eceptor density.