Chronic morphine increases hippocampal acetylcholine release: possible relevance in drug dependence.

Previous studies have shown that cocaine and amphetamine stimulate acetylcholine release in the hippocampus via an action of endogenously released dopamine on dopamine D1 and D2 receptors. The present study was aimed at clarifying if the property of stimulating hippocampal acetylcholine 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. twice daily) morphine acquired the ability to stimulate hippocampal acetylcholine 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 development of the stimulant property on acetylcholine release, morphine also acquired that of producing behavioural stimulation and lost that of producing sedation and catalepsy. The morphine-induced increase in acetylcholine output was suppressed by the blockade of dopamine D1 receptors with SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine) (0.1 mg/kg s.c.), which also suppressed the morphine-induced motor stimulation. Moreover, repeated morphine administration markedly potentiated the stimulant effect of the dopamine D1/D2 receptor agonist apomorphine (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 morphine could be related to the development of dopamine receptor supersensitivity. Moreover, increased acetylcholine transmission in the hippocampus may play a role in the 'memory' of the rewarding effects of drugs of abuse.