NMDA receptor inhibition prevents tolerance to cocaine.
Male rats were treated with cocaine by utilizing two different experimental paradigms. One group of animals received a low dose (10 mg/kg, IP) of cocaine for 7 days. A second group received 40 mg/kg IP of cocaine for 3 days. In both experimental groups, half the animals were concomitantly treated with 0.25 mg/kg IP (+)-5methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10- imine maleate (MK-801), a noncompetitive NMDA receptor antagonist. Rats treated with the low dose of cocaine after 7 days developed tolerance to the stimulation of locomotor activity induced by cocaine and by the dopamine D2 agonist quinpirole. Rats treated with 40 mg/kg of cocaine showed a marked behavioral sensitization. Both these effects, tolerance and sensitization, were prevented by coadministration of MK-801, thus suggesting these two phenomena are different aspects of a common neuronal response in which NMDA transmission plays a crucial role.
Institute of Pharmacology, University of Siena, Italy.
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De Montis
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Devoto
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D
Meloni
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Gambarana
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Giorgi
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Tagliamonte
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D004361:Drug Tolerance; D004873:Ergolines / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019257:Quinpirole; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013239:Stereotyped Behavior / Q000187:drug effects
D015259:Dopamine Agents; D004873:Ergolines; D016194:Receptors, N-Methyl-D-Aspartate; D019257:Quinpirole; D016291:Dizocilpine Maleate; D003042:Cocaine