The NR2B-Selective N-Methyl-D-aspartate Receptor Antagonist Ro 25-6981 [((+-))-(R~*,S~*)-alpha-(4-Hydroxyphenyl)-j3-methyl-4-(phenylmethyl)-l-piperidine Propanol] Potentiates the Effect of Nicotine on Locomotor Activity and Dopamine Release in the Nu

摘要

It has been proposed that nicotine-stimulated locomotor activity(LMA)and nicotine-induced dopamine(DA)release in the mesocorticolimbic DA system is partly regulated by glutamate receptors,particularly N-methyl-D-aspartate(NMDA)receptors.The functional characteristics of NMDA receptors depend on their subunit composition(NR1 in combination with NR2A-D).In the present study,we investigated the effect of the NR2B-selective NMDA receptor antagonist Ro 25-6981 [((+-))-(R~*,S~*)-alpha-(4-hydroxyphenyl)-]3-methyl-4-(phenylmethyl)-1-piperidine propanol] on nicotine-stimulated LMA and nicotine-induced DA release in the nucleus accumbens(NAcc)in rats.Ro 25-6981(3 and 10 mg/kg i.p.)given 10 min prior to a high dose(0.6 mg/kg s.c.)or a subthreshold dose(0.1 mg/kg s.c.)of nicotine potentiated nicotine-stimulated LMA with no effect when administered alone.Similarly,administration of a low dose(0.05 mg/kg i.p.)of the noncompetitive NMDA receptor antagonist MK-801(dizocilpine maleate)had no effect on LMA by itself but potentiated nicotine-induced(0.1 mg/kg)LMA.However,pretreat-ment with the competitive NMDA receptor antagonist CGP39551 [(E)-((+-))-2-amino-4-methyl-5-phosphono-3-pente-noic acid ethyl ester](10 mg/kg i.p.)did not potentiate the LMA effect of 0.1 mg/kg nicotine as seen with Ro 25-6981.In vivo microdialysis revealed a significant increase of DA release in the NAcc in response to nicotine(0.1 mg/kg s.c.).In analogy to our LMA data,Ro 25-6981(10 mg/kg i.p.)significantly potentiated the nicotine-induced DA release,although it had no effect on DA release when given alone.The data suggest that,compared with other subunits of the NMDA receptor,the NR2B subunit might play a different role in the reinforcing effects of nicotine.