CHRONIC MORPHINE INCREASES HIPPOCAMPAL ACETYLCHOLINE-RELEASE - POSSIBLE RELEVANCE IN DRUG-DEPENDENCE

Previous studies have shown that cocaine and amphetamine stimulate ace tylcholine release in the hippocampus via an action of endogenously re leased dopamine on dopamine D-1 and D-2 receptors. The present study w as aimed at clarifying if the property of stimulating hippocampal acet ylcholine release was shared by morphine. The acute administration of morphine (10 mg/kg i.p.) failed to modify acetylcholine release in the hippocampus. However, after repeated administration(10 mg/kg i.p., tw ice daily) morphine acquired the ability to stimulate hippocampal acet ylcholine release. Thus, at days 5 and 7 of chronic morphine treatment , a challenge dose of morphine (10 mg/kg i.p.) increased acetylcholine release by 50 and 100%, respectively. Concomitantly with the developm ent of the stimulant property on acetylcholine release, morphine also acquired that of producing behavioural stimulation and lost that of pr oducing sedation and catalepsy. The morphine-induced increase in acety lcholine output was suppressed by the blockade of dopamine D-1 recepto rs with SCH 23390 thyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) ( 0.1 mg/kg s.c.), which also suppressed the morphine-induced motor stim ulation. Moreover, repeated morphine administration markedly potentiat ed the stimulant effect of the dopamine D-1/D-2 receptor agonist apomo rphine (R(-)-10,11-dihydroxyaporphine) (0.1 or 0.5 mg/kg s.c.) both on hippocampal acetylcholine release and on behaviour. These results may suggest that the enhancement of hippocampal acetylcholine release as well as the development of behavioural sensitisation after chronic mor phine could be related to the development of dopamine receptor superse nsitivity. Moreover, increased acetylcholine transmission in the hippo campus may play a role in the 'memory' of the rewarding effects of dru gs of abuse.