Functional evidence for postsynaptic supersensitivity of central noradrenergic receptors after denervation

Abstract

THE development of postsynaptic or postjunctional supersensitivity in peripheral, noradrenergically innervated tissue after deafferentation has been clearly demonstrated^1–3. In addition there exists considerable functional and biochemical evidence that central dopaminergic receptors in the neostriatum become supersensitive after lesions of the nigro-neostriatal projection^4–8. Neurochemical evidence has been provided which is consistent with the development of postjunctional supersensitivity of central noradrenoceptors after deafferentation. Thus after intraventricular injections of 6-hydroxydopamine (6-OHDA), a neurotoxin for catecholaminergic neurones, noradrenaline (NA) stimulated synthesis of cyclic AMP is potentiated^9–11. Functional evidence for the development of this type of supersensitivity in central NA receptors is, however, lacking. An enhanced response to intracisternally administered α-methylnoradrenaline in 6-OHDA pretreated rats has been reported¹² but such an effect could be mediated by changes in either pre- or postsynaptic mechanisms. Our experiments were designed to provide functional confirmation for the presence of postjunctional supersensitivity in central noradrenoceptors after lesions of central noradrenergic neurones. Clonidine [2-(2,6-dichlorophenylamino)-2-imidazoline] is a directly acting α-NA receptor agonist^13–15 and has been shown to lower body temperature by a central α-noradrenergic mechanism. Thus intraperitoneal, intracisternal or intrahypothalamic injections of clonidine decrease body temperature^16,17. It was hypothesised that if central noradrenoceptive neurones become supersensitive after destruction of noradrenergic afferents by 6-OHDA, then clonidine-induced hypothermia should be potentiated in lesioned animals.