INTERMITTENT MORPHINE TREATMENT CAUSES LONG-TERM DESENSITIZATION OF FUNCTIONAL DOPAMINE D-2 RECEPTORS IN RAT STRIATUM

3 weeks following cessation of intermittent morphine administration (1 0 mg/kg, s.c., once daily for 14 days), [H-3]dopamine and [C-14]acetyl choline release induced by 10 mu M N-methyl-D-aspartate (NMDA) from su perfused rat striatal slices appeared to be significantly higher than the release from striatal slices from saline-treated rats. A similar a daptive increase of the NMDA-evoked release of these neurotransmitters was observed in slices of the nucleus accumbens, whereas that of [H-3 ]noradrenaline from hippocampal slices remained unchanged. Blockade of dopamine D-2 receptors by 10 mu M (-)-sulpiride enhanced NMDA-induced [H-3]dopamine and [C-14]acetylcholine release from striatal slices fr om saline-treated animals, but was found to be ineffective in this res pect following intermittent morphine treatment. Moreover, morphine adm inistration appeared to cause a profound decrease in the apparent affi nity of the full dopamine D-2 receptor agonist LY171555 (quinpirole) f or these release-inhibitory dopamine D-2 receptors, indicating the occ urrence of dopamine D-2 receptor desensitization. It is suggested that such a desensitization of dopamine D-2 receptors on dopaminergic nerv e terminals as well as on cholinergic interneurons may play a pivotal role in the long-lasting nature of behavioural sensitization upon cess ation of treatment with morphine and possibly other drugs of abuse.