Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion

Cessation of drug use in chronic opiate abusers produces a severe withdrawa l syndrome that is highly aversive, and avoidance of withdrawal or associat ed stimuli is a major factor contributing to opiate abuse(1,2). Increased n oradrenaline in the brain has long been implicated in opiate withdrawal(3), but it has not been clear which noradrenergic systems are invoked. Here we show that microinjection of beta-noradrenergic-receptor antagonists, or of an alpha 2-receptor agonist, into the bed nucleus of the stria terminalis (BNST) in rats markedly attenuates opiate-withdrawal-induced conditioned pl ace aversion, Immunohistochemical studies revealed that numerous BNST-proje cting cells in the A1 and A2 noradrenergic cell groups of the caudal medull a were activated during withdrawal Lesion of these ascending medullary proj ections also greatly reduced opiate-withdrawal-induced place aversion. wher eas lesion of locus coeruleus noradrenergic projections had no effect on op iate-withdrawal behaviour. We conclude that noradrenergic inputs to the BNS T from the caudal medulla are critically involved in the aversiveness of op iate withdrawal.