Abstract
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*)-α-(4-hydroxyphenyl)-β-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, pretreatment with the competitive NMDA receptor antagonist CGP39551 [(E)-(±)-2-amino-4-methyl-5-phosphono-3-pentenoic 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.
Footnotes
-
This study was supported by the Swedish Research Council Project 7688, Sigurd and Elsa Golje's Minne Foundation for Medical Research, the Swedish Match Foundation for Nicotine Research, and by funds from Karolinska Institutet.
-
doi:10.1124/jpet.104.070235.
-
ABBREVIATIONS: DA, dopamine; VTA, ventral tegmental area; NAcc, nucleus accumbens; NMDA, N-methyl-d-aspartate; CGS19755, cis-4-phosphonomethyl-2-piperidine carboxylic acid; CGP39551, (E)-(±)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester; LMA, locomotor activity; MK-801, dizocilpine maleate; Ro 25-6981, (±)-(R*,S*)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol; HPLC, high-performance liquid chromatography; ANOVA, analysis of variance.
- Received April 20, 2004.
- Accepted July 15, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|