Intermittent morphine treatment causes long-term desensitization of functional dopamine D2 receptors in rat striatum.
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.
Nestby
P
P
Department of Pharmacology, Graduate School Neurosciences Amsterdam, Research Institute Neurosciences Vrije Universiteit, Netherlands.
Tjon
G H
GH
Visser
D T
DT
Drukarch
B
B
Leysen
J E
JE
Mulder
A H
AH
Schoffelmeer
A N
AN
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013469:Sulpiride / Q000494:pharmacology
D009294:Narcotics; D017448:Receptors, Dopamine D2; D016202:N-Methylaspartate; D009020:Morphine; D013469:Sulpiride; D000109:Acetylcholine; D004298:Dopamine