Received for publication April 20, 2004.
Revised July 15, 2004.
Accepted for publication July 15, 2004.

The NR2B-selective NMDA receptor antagonist Ro 25-6981 potentiates the effect of nicotine on locomotor activity and dopamine release in the nucleus accumbens

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 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 minutes 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 non-competitive NMDA receptor antagonist MK-801 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 (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 suggests that, compared to other subunits of the NMDA receptor, the NR2B subunit might play a different role in the reinforcing effects of nicotine.

Key words: MK-801, NMDA, glutamate, subthreshold, subunit, systemic