The effect of nicotine in combination with various dopaminergic drugs on nigrostriatal dopamine in rats
- 171 Downloads
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.
KeywordsNicotine Nomifensine Tolcapone Selegiline Haloperidol Extracellular dopamine Rotational behaviour
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.
- Brazell MP, Mitchell SN, Joseph MH, Gray JA (1990) Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate-putamen. Neuropharmacology 29:1177–1185PubMedGoogle Scholar
- Court J, Clementi F (1995) Distribution of nicotinic subtypes in human brain. Alzheimer Dis Assoc Disord 9 [Suppl 2]:6–14Google Scholar
- Haikala H (1987) Use of a novel type of rotating disc electrode and a flow cell with laminar flow pattern for the electrochemical detection of biogenic monoamines and their metabolites after Sephadex gel chromatographic purification and high-performance liquid chromatographic isolation from rat brain. J Neurochem 49:1033–1041PubMedGoogle Scholar
- Janhunen S, Kaakkola S, Tuominen RK, Ahtee L (2001) Nicotine induces rotation in combination with nomifensine in unilaterally 6-hydroxydopamine lesioned rats. Parkinsonism Relat Disord 7 [Suppl 1]:559Google Scholar
- Kaakkola S (1980) Contralateral circling behaviour induced by intranigral injection of morphine and enkephalin analogue FK 33-824 in rats. Acta Pharmacol Toxicol 47:385–393Google Scholar
- Kaakkola SK, Tuominen RK, Mielikäinen P, Paldanius P, Ahtee L (2000) Effects of nomifensine and tolcapone on nicotine-induced dopamine release in rat striatum. Soc Neurosci Abstr 26:900Google Scholar
- Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, vol 2. Academic, New YorkGoogle Scholar
- Villafane G, Degos J-D, Lagrue G, Cesaro P (2001) Long-term nicotine treatment in Parkinson’s disease: report of a case. Parkinsonism Relat Disord 7 [Suppl 1]:S73Google Scholar