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The effect of nicotine in combination with various dopaminergic drugs on nigrostriatal dopamine in rats

  • Sanna Janhunen
  • Paula Mielikäinen
  • Päivi Paldánius
  • Raimo K. Tuominen
  • Liisa AhteeEmail author
  • Seppo Kaakkola
Original Article

Abstract

It is well established that nicotine activates brain dopaminergic systems and in addition has neuroprotective actions. Thus, nicotinic acetylcholine receptor (nAChR) agonists might be beneficial in the treatment of Parkinson’s disease, and it is important to study the interactions of nicotine with drugs affecting the nigrostriatal dopaminergic pathway. We used brain microdialysis to study the effects of nicotine on extracellular levels of dopamine (DA) and its metabolites in the rat dorsal striatum in combination with drugs inhibiting either DA uptake (nomifensine), catechol-O-methyltransferase (COMT; tolcapone), monoamine oxidase B (MAO-B; selegiline) or DA receptors (haloperidol). Nicotine (0.5 mg/kg, s.c.) modestly increased DA output, and this effect was antagonised by mecamylamine but not by hexamethonium. Nomifensine (3 mg/kg, i.p.) substantially further enhanced the nicotine-induced increase in DA output and nomifensine+nicotine also evoked a strong mecamylamine-sensitive ipsilateral rotational behaviour in 6-hydroxydopamine lesioned rats. Tolcapone (10 mg/kg, i.p.) did not alter DA output, but markedly decreased homovanillic acid (HVA) and increased 3,4-dihydroxyphenylacetic acid (DOPAC). Selegiline pretreatment (5×1 mg/kg, i.p.) significantly increased extracellular DA and decreased DOPAC and HVA. Haloperidol (0.1 mg/kg, s.c.) slightly increased DA output and more clearly DOPAC and HVA. Tolcapone, selegiline or haloperidol did not enhance the nicotine-induced DA output. These results indicate that the activation of nigrostriatal nAChRs induces a significant DA release in the striatum, which is potentiated by DA uptake inhibition but not by COMT, MAO-B or presynaptic DA receptor inhibition. Our findings therefore agree with the notion that the termination of the effect of DA in the synapse mainly occurs via neuronal reuptake. Thus, selective nAChR agonists, possibly in combination with a DA uptake inhibitor, might improve dopaminergic transmission in Parkinson’s disease.

Keywords

Nicotine Nomifensine Tolcapone Selegiline Haloperidol Extracellular dopamine Rotational behaviour 

Notes

Acknowledgements

This study was supported by grants from the Helsinki University Central Hospital, the Sigrid Jusélius Foundation and the University of Helsinki’s Research Funds. The excellent technical assistance of Ms. Marjo Vaha is gratefully acknowledged.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Sanna Janhunen
    • 1
  • Paula Mielikäinen
    • 1
  • Päivi Paldánius
    • 1
  • Raimo K. Tuominen
    • 1
  • Liisa Ahtee
    • 1
    Email author
  • Seppo Kaakkola
    • 2
  1. 1.Division of Pharmacology and Toxicology, Faculty of PharmacyUniversity of HelsinkiHelsinkiFinland
  2. 2.Department of NeurologyUniversity of HelsinkiHelsinkiFinland

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