Acute and chronic effects of reserpine on biochemical and functional parameters of central and peripheral α2-adrenoceptors

Abstract

The specific binding of the agonist, [ 3H]UK 14304, and of the antagonist, [ 3H]RX 821002, to rat brain membranes, as well as clonidine-induced mydriasis, clonidine-induced inhibition and idazoxan-induced stimulation of brain 3,4-dihydroxyphenylalanine (DOPA) synthesis, and clonidine and UK 14304-induced inhibition of twitch responses in the vas deferens were used to evaluate the affinity and sensitivity of central and peripheral α 2-adrenoceptors after various treatments with reserpine. Treatment with reserpine (0.25 mg/kg s.c., every 48 h) for 4, 11 and 18 days induced consistent and significant increases in the affinity (K D values) of [ 3H]UK 14304 for the cortical α 2-adrenoceptor with no change in receptor density. Chronic treatment with reserpine also resulted in a greater affinity of (-)-adrenaline for the high-affinity state of the α 2-adrenoceptor when the catecholamine competed with the binding of [ 3H]RX 821002 to cortical membranes. In line with these radioligand binding data, various functional responses mediated by central and peripheral α 2-adrenoceptors were found to be potentiated after repeated treatment with reserpine. Thus, the inhibitory α 2-autoreceptor that modulates the synthesis of brain noradrenaline and the central postsynaptic inhibitory α 2-adrenoceptor that induces mydriasis displayed greater responses in vivo after chronic treatment with reserpine. Short-term and chronic treatments with reserpine also increased the sensitivity of peripheral presynaptic α 2-adrenoceptors in the vas deferens. The results indicated that chronic treatment with a low dose of reserpine, which results in prolonged noradrenaline depletion (greater than 85%), induces biochemical (increased affinity of agonists for the high-affinity state of the receptor) and in vivo functional supersensitivity of pre- and postsynaptic α 2-adrenoceptors in the rat brain.