3 weeks following cessation of intermittent morphine administration (10 mg/kg, s.c., once daily for 14 days), [3H]dopamine and [14C]acetylcholine release induced by 10 microM N-methyl-D-aspartate (NMDA) from superfused rat striatal slices appeared to be significantly higher than the release from striatal slices from saline-treated rats. A similar adaptive increase of the NMDA-evoked release of these neurotransmitters was observed in slices of the nucleus accumbens, whereas that of [3H]noradrenaline from hippocampal slices remained unchanged. Blockade of dopamine D2 receptors by 10 microM (--)-sulpiride enhanced NMDA-induced [3H]dopamine and [14C]acetylcholine release from striatal slices from saline-treated animals, but was found to be ineffective in this respect following intermittent morphine treatment. Moreover, morphine administration appeared to cause a profound decrease in the apparent affinity of the full dopamine D2 receptor agonist LY171555 (quinpirole) for these release-inhibitory dopamine D2 receptors, indicating the occurrence of dopamine D2 receptor desensitization. It is suggested that such a desensitization of dopamine D2 receptors on dopaminergic nerve terminals as well as on cholinergic interneurons may play a pivotal role in the long-lasting nature of behavioural sensitization upon cessation of treatment with morphine and possibly other drugs of abuse.