Psychopharmacology

, Volume 175, Issue 1, pp 114–123 | Cite as

Nicotine-induced dopamine release in the nucleus accumbens is inhibited by the novel AMPA antagonist ZK200775 and the NMDA antagonist CGP39551

  • Alexander R. Kosowski
  • Gvido Cebers
  • Aleta Cebere
  • Ann-Charlott Swanhagen
  • Sture Liljequist
Original Investigation
First Online:
Received:
Accepted:

Abstract

Rationale

Accumulated data suggest that N-methyl-d-aspartate (NMDA) receptors are involved in the reinforcing properties of nicotine. However, less is known about the role of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors in this context.

Objectives

To study the effect of the novel systemically administered AMPA receptor antagonist ZK200775 ([1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(fluoromethyl) quinoxalin-1-yl] methylphosphonate) on nicotine-induced dopamine (DA) release in the nucleus accumbens (NAcc) and nicotine-stimulated locomotor activity (LMA) and particularly the relative role of NMDA and AMPA receptors in nicotine-stimulated DA release and LMA.

Methods

Male Wistar rats were administered ZK200775, CGP39551 or NBQX 30 min prior to nicotine and DA release and LMA was measured using in vivo microdialysis or photocell equipped activity boxes. Glutamate-produced neurotoxicity in cultured brain cells and binding assays were performed to determine the glutamate receptor subtype selectivity and affinity to nicotine receptors of ZK200775, respectively.

Results

ZK200775 (3.0 but not 1.5 or 6.0 mg/kg) significantly decreased the nicotine-induced (0.6 mg/kg) DA release in the NAcc and nicotine-stimulated LMA. ZK200775 (1.5, 3.0, 6.0 mg/kg) alone influenced neither DA release nor LMA. ZK200775 showed 34-fold selectivity for AMPA receptors compared to NMDA receptors and no affinity to nicotine receptors. The NMDA receptor antagonist CGP39551 (10 mg/kg) significantly decreased both the nicotine-induced DA release and nicotine-stimulated LMA whereas the AMPA receptor antagonist NBQX (10 mg/kg) had no effect. Notably, CGP39551 and ZK200775 (3.0 mg/kg) displayed a different pattern in inhibition of nicotine-induced DA release.

Conclusions

Both NMDA- and AMPA receptors are involved in nicotine’s dependence-producing properties, although in a spatiotemporally differential manner.

Keywords

NBQX Locomotor activity Microdialysis Cerebellar granule cells Glutamate receptor subtype selectivity Systemic administration Affinity 
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Notes

Acknowledgements

This study was supported by the Swedish Medical Research Council (project no. 7688), Sigurd and Elsa Golje’s Minne Foundation for Medical Research, Swedish Match Foundation for Nicotine Research, and funds from the Karolinska Institutet.

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Alexander R. Kosowski
    • 1
  • Gvido Cebers
    • 1
  • Aleta Cebere
    • 1
  • Ann-Charlott Swanhagen
    • 1
  • Sture Liljequist
    • 1
  1. 1.Department of Clinical Neuroscience, Division of Drug Dependence ResearchKarolinska InstitutetStockholmSweden

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