A tobacco extract containing alkaloids induces distinct effects compared to pure nicotine on dopamine release in the rat
Introduction
Tobacco use remains a major public health concern for many countries due to its high prevalence in nicotine addiction and associated diseases. The psychoactive properties of tobacco have been attributed to nicotine, the main alkaloid fund in the tobacco plant [14], [25]. A growing body of preclinical and clinical studies has demonstrated the existence of numerous compounds contained in the plant that could enhance the psychoactive properties of nicotine.
Nicotiana plants are rich in minor alkaloids (cotinine, anabasine, nornicotine, tabagisine, moysmine) in addition to the nicotine that represents 95–97% of total alkaloids. These minor tobacco alkaloids exhibit a similar structure to nicotine and have pharmacological activity, although they are generally less potent than nicotine [26]. Nornicotine and cotinine also play a role as major metabolites of nicotine [5]. It has been reported that the intravenous infusion of nicotine combined with five minor alkaloids found in tobacco smoke (anabasine, nornicotine, anatabine, cotinine and myosmine) increased locomotor activity and behavioral sensitization following self-administration [2]. These results suggest that the minor tobacco alkaloids, particularly anatabine, cotinine and myosmine, could increase the desire for nicotine and thus facilitate smoking behavior.
From a neurochemical point of view, these effects could be associated with an increase in central dopamine (DA) transmission. Indeed, it is widely accepted that the addictive properties of drugs of abuse, such as psychostimulants, opiates and possibly nicotine, are associated with an increase in mesolimbic DA transmission. One symptom of increased DA levels that has been reported in rodents is locomotor hyperactivity [7]. However, the locomotor hyperactivity induced by nicotine is not strictly dependent on the DA tone in the nucleus accumbens [1], [28] and it has been proposed recently that DA in the dorsal striatum could also be involved [10].
Instead of a cocktail of nicotine supplemented with minor alkaloids, tobacco extracts provide a preparation to investigate the role of minor alkaloids with the relative concentration of the alkaloids representative of those contained in the plant. Previous data have reported that such an extract could induce effects distinct to those of pure nicotine [16], [27], and we have postulated that the tobacco extract should enhance central DA transmission. This study compares the effect of pure nicotine with that of a tobacco extract containing alkaloids on DA release using intracerebral microdialysis in the striatum and the nucleus accumbens of freely moving rats.
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Animals
Male Sprague-Dawley rats (Charles River, Lyon, France), weighing 300–350 g were used. Animals, housed in individual plastic cages, were kept at constant room temperature (21 ± 2 °C) and relative humidity (60%) with a 12 h light/dark cycle (dark from 7 P.M.) and had free access to water and food. All animals use procedures conformed to International European Ethical Standards (86/609-EEC) and the French National Committee (décret 87/848) for the care and use of laboratory animals. All efforts were
Results
All measurements were carried out 120 min after the beginning of the perfusion, by which time a steady state was achieved. Absolute basal levels of DA in dialysate did not differ between the different experimental groups throughout the course of the study and were (mean ± S.E.M., without adjusting for probe recovery): 2.4 ± 0.4 (n = 22) and 7 ± 1.2 pg/10 μl (n = 16) rats for the nucleus accumbens and the striatum respectively.
Discussion
In the present study the effect of nicotine alone or combined with minor alkaloids extracted from the tobacco plant on extracellular levels of DA in both the striatum and nucleus accumbens was examined. The results add further support to the growing evidence that minor alkaloids play a role in the psychoactive properties of the tobacco plant.
In agreement with several studies [7], [8], [18], [19], [24], we report that nicotine (0.5 mg/kg) enhanced accumbal and striatal dopamine extracellular
Acknowledgements
This study was supported by the exchange grants of the GDRI N198 (CNRS and INSERM, France and CNRST, Morocco) and NEUROMED. The study received also support from “Centre National de la Recherche Scientifique”, the University of Bordeaux and the Conseil Régional d’Aquitaine. We would like to thank Dr Martin Guthrie for the reading of the manuscript.
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