Intranigral GR-113808, a selective 5-HT4 receptor antagonist, attenuates morphine-stimulated dopamine release in the rat striatum.
GR-113808, a potent and selective 5-HT4 receptor antagonist, was infused through a microdialysis probe into the striatum and nucleus accumbens of awake rats, and basal and morphine-stimulated extracellular concentrations of dopamine (DA) were measured in these regions. At 1 and 10 microM GR-113808 did not affect the extracellular concentrations of DA in either region and 100 microM significantly reduced dialysate DA only in the striatum. A subcutaneous dose of 5 mg/kg morphine significantly raised extracellular concentrations of DA in the striatum and nucleus accumbens from 60 to 120 min after injection and the effect was not modified by 10 microM GR-113808 infused through the probe 20 min before and for 60 min after morphine. Bilateral injections of GR-113808 (1, 2.5 and 10 micrograms/0.5 microliter) in the substantia nigra pars compacta did not affect dialysate DA in the striatum, except for a significant increase 120 min after the injection of 10 micrograms but the highest dose of GR-113808 prevented the increase of striatal DA caused by 5 mg/kg morphine s.c. The results suggest that 5-HT4 receptors in the substantia nigra modulate the activity of the dopaminergic nigrostriatal system only when the neurons are activated.
Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.
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D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007267:Injections; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013378:Substantia Nigra / Q000502:physiology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
D007211:Indoles; D012702:Serotonin Antagonists; D013449:Sulfonamides; D009020:Morphine; D004298:Dopamine; C082871:GR 113808