Articles
Blockade of Nicotine Self-Administration with Nicotinic Antagonists in Rats

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Abstract

The reinforcing properties of a variety of drugs abused by humans have been investigated using the technique of intravenous self-administration in the rat. To examine the effect of nicotine dose on nicotine self-administration, Wistar rats were allowed to self-administer various doses of nicotine using a within-subjects Latin square design. An inverted U-shaped dose–response curve was obtained, with the highest rates of responding at the 0.03 mg/kg/inf dose. With 1-h daily nicotine self-administration sessions, rats did not appear dependent on nicotine 24 h later, as indicated by the absence of somatic signs of withdrawal after subcutaneous injection of a nicotinic acetylcholine receptor antagonist, mecamylamine (0.57 mg/kg). In another set of studies, pretreatment with subcutaneous mecamylamine or dihydro-β-erythroidine, two nicotinic acetylcholine receptor antagonists, resulted in significant dose-dependent reductions in nicotine self-administration, at two nicotine doses (0.03 and 0.06 mg/kg/inf). These results indicate that nicotine is an effective reinforcer in Wistar rats under the present parameters, and that these reinforcing effects are mediated by activation of nicotinic acetylcholine receptors.

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Subjects

Male Wistar rats from Charles River, Kingston, NY, were used in Experiments 1 and 2. In Experiment 3, male Wistar rats bred at the Beckman Laboratories of The Scripps Research Institute from a Wistar stock originally obtained from Charles River, NY, were used. At Beckman Laboratories, rats are bred using a circular-pair random system of breeding to maintain genetic heterogeneity. New breeders are obtained from Charles River as determined by our internal Genetics Advisory Board. Animals were

Experiment 1: Nicotine Dose–Response Curve

Acquisition of stable nicotine self-administration at the training dose (0.03 mg/kg/inf) required approximately 10 days with 82% of subjects (i.e., 18 of 22 subjects) meeting criterion for acquisition of the behavior (less than 20% deviation from the mean number of injections earned in three consecutive sessions with a minimum criterion of five infusions per hour). An ANOVA (n = 7) revealed a significant main effect of nicotine dose on the number of nicotine injections earned during 3-h

Discussion

Development of animal models of intravenous nicotine self-administration is critical to the continued investigation of the neurobiological substrates of nicotine reinforcement. The first experiment demonstrated that nicotine is self-administered by rats across a range of doses, with the highest number of infusions earned at the 0.03 mg/kg/inf dose. All doses of nicotine tested maintained significantly higher levels of responding than did saline. Further, while the nicotine unit doses were not

Acknowledgements

This is publication number 11696-NP from The Scripps Research Institute. This research was supported by a Tobacco-Related Disease Research Program grant 7RT-0004 (AM) and a NIDA grant DA04398 (GFK). S.S.W. and M.P.E.-J. were supported by NIDA Individual National Research Service Awards DA05898 (S.W.) and DA05723 (M.E.J.). A.M. was supported by a NIDA Research Scientist Award (DA00213). The authors wish to acknowledge the expert technical assistance of Robert Lintz, and the excellent assistance

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    Current address: Glaxo Wellcome Experimental Research S.A., Institut de Biologie Cellulaire et de Morphologie (IBCM), Universite de Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland

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