Nicotine and bupropion share a similar discriminative stimulus effect

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Abstract

Bupropion is a weakly potent central nervous system (CNS) stimulant that is marketed both as an antidepressant and as an anti-smoking aid. The mechanism(s) by which it produces its effects is not well understood. In the present study, the effect of bupropion was examined in rats trained to discriminate the stimulus effect of 0.60 mg/kg of (−)-nicotine from saline in a two-lever drug discrimination task. In tests of stimulus generalization (substitution), the nicotine (ED50=0.17 mg/kg) stimulus completely generalized to bupropion (ED50=5.50 mg/kg). In addition, interaction studies were conducted that evaluated the effect of 3.0 mg/kg of bupropion, a dose that when given alone produced saline-appropriate responding, in combination with various doses of nicotine. This application resulted in an enhancement of the potency of nicotine (ED50=0.05 mg/kg), as indicated by a leftward shift of the nicotine dose–effect function. In tests of stimulus antagonism, various doses of bupropion were administered prior to the training dose of nicotine and were found to be ineffective as antagonists of the nicotine stimulus. In contrast, the nicotinic acetylcholine receptor (nicotine receptor) antagonist mecamylamine (AD50=0.40 mg/kg) completely blocked the stimulus effect of nicotine. Mecamylamine did not attenuate the stimulus generalization of bupropion. The results demonstrated that bupropion can produce a nicotine-like response in nicotine-trained animals, but it does so via a mechanism of action that is unlike that of nicotine. It is speculated that bupropion may be somewhat effective as an anti-smoking treatment in people who are motivated to quit smoking because low doses of bupropion produce a nicotine-like effect(s) that serve as a suitable substitute for nicotine.

Introduction

Nicotine is the principal constituent of tobacco (Nicotiana tabacum) and appears to be responsible for the maintenance of tobacco consumption by smokers. Typically, nicotine is absorbed in small amounts from inhaled smoke and quickly distributed throughout the body, where it exerts potent effects on both the peripheral and central nervous systems. In fact, the mechanism responsible for the continuation of smoking behavior appears to involve the interaction of nicotine at central nicotinic acetylcholine receptors and eventual increases in dopamine activity in the nucleus accumbens, an area of the brain thought to be important to drugs of abuse (e.g., Corrigall et al., 1994, Di Chiara and Imperato, 1988).

Tobacco smoking is a major health concern and many people have stopped smoking or attempted to quit smoking. Most smokers find it difficult to quit and, as might be expected, various products have been marketed as aids for smoking cessation. These include nicotine-replacement therapies in combination with counseling/behavioral modification programs. This approach provides the user with nicotine through gum, patches, nasal spray, or oral inhaler. The strategy is to replace the nicotine that is no longer being absorbed through inhaled smoke and to gradually diminish the body's urge for nicotine (for review, see Raw et al., 1998). Psychological counseling is considered to be an essential feature of the therapy. These delivery systems are thought to be equally effective, with about 20% of those that received therapy not smoking at 1 year and up to 10% remaining non-smokers if treatment is continued (e.g., Britton and Jarvis, 2000, Raw et al., 1998).

Recently, bupropion, a weakly potent central nervous system (CNS) stimulant that is marketed as an antidepressant agent, was approved to be marketed as an aid to smoking cessation. Clinical studies have shown that the administration of bupropion, in combination with counseling, produces comparable efficacy to nicotine replacement therapies at the 1-year benchmark for smoking cessation Britton and Jarvis, 2000, Harrison, 2001, Hurt et al., 1997, Jorenby et al., 1999. However, the mechanism by which it facilitates smoking cessation is not well understood. Early studies of bupropion for its antidepressant indication suggested that it functioned as a weak dopamine and/or norepinephrine agonist through inhibition of catecholamine reuptake (e.g., Butz et al., 1982, Dufrensne et al., 1984, Dufrensne et al., 1985, Ferris et al., 1982). More recent studies have indicated that bupropion blocked the effect of nicotine in a number of behavioral assays in mice Fryer and Lukas, 1999, Slemmer et al., 2000. The fact that bupropion appears to be the first non-nicotine compound shown to be somewhat effective in smoking cessation has led to renewed interest in its actions.

A particularly useful procedure for examining the central effects of chemical agents is drug discrimination. In this assay, for example, human or non-human animals can be trained to perform a response (e.g., right-side lever-press) after a particular dose of nicotine has been administered and to complete a different response (left-side lever-press) after saline vehicle has been delivered. The nicotine or non-drug treatment is used to inform the animal to make the appropriate response in order to gain a reinforcer. In order to establish the discrimination, nicotine must be given repeatedly to subjects—a requirement that makes the paradigm somewhat analogous to the human smoker (for review, see Rosecrans, 1989). Once acquired, stimulus generalization (substitution) and antagonism tests can be performed to determine if a test compound can mimic or block the effect of the training drug. Such tests have indicated that nicotine exerts its stimulus effect, at least in part, through an interaction at nicotine receptors; in particular, at a subtype of nicotine receptors termed α4β2 receptors (e.g., Stolerman et al., 1997). This conclusion is based on the fact that the stimulus effect of nicotine is blocked by mecamylamine, a nonselective receptor antagonist of nicotine receptors antagonist, and dihydro-β-erythrodine, a nicotine receptor antagonist that shows high affinity for the α4β2 subunit (e.g., Hirschhorn and Rosecrans, 1974, Kumar et al., 1987, Rose et al., 1989, Shoaib et al., 2000). Although nicotine has been the subject of numerous discrimination studies, bupropion has received limited attention as a training drug Blitzer and Becker, 1985, Jones et al., 1980, Terry and Katz, 1997. In these latter studies, bupropion stimulus generalization occurred to several CNS stimulants and catecholamine uptake inhibitors. The compounds included (+)-amphetamine, caffeine, cocaine, methylphenidate, mazindol, nomifensine, and GBR 12909 (1-(2-(bis-(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine). On the other hand, dopamine receptor antagonists have been shown to have no effect (Blitzer and Becker, 1985) or block (Terry and Katz, 1997) the stimulus effect of bupropion; inconsistent data that hinder the establishment of a definitive bupropion–catecholamine interaction. To date, a detailed evaluation of the stimulus properties of nicotine and bupropion has not been reported. A review of the drug discrimination literature revealed an abstract by Cohen et al. (1999) that indicated partial generalization (63–75%) of bupropion in rats trained to discriminate nicotine from saline. Unfortunately, a full report of the study's methodology and results has not yet appeared in the literature. Thus, the present investigation was undertaken to establish a more detailed description and comparison of the stimulus activities of these two agents. Specifically, animals were trained to discriminate the stimulus effect of 0.60 mg/kg of nicotine from saline vehicle. Once achieved, tests of stimulus generalization were conducted with bupropion. In addition, a number of interaction studies were performed that evaluated the effect of various doses of bupropion in combination with various doses of nicotine. In a final series of comparative tests, the nicotine receptor antagonist mecamylamine was evaluated in combination with nicotine and bupropion.

Section snippets

Animals

The animals were eight male Sprague–Dawley rats (Charles River Laboratories) weighing 300–350 g at the beginning of the study. The animals were housed individually and, prior to the start of the study, their body weights were reduced to approximately 80% of their free-feeding weight. During the entire course of the study, the animals' body weights were maintained at this reduced level by partial food restriction; in their home cages, the animals were allowed drinking water ad lib. This study

Results

Eight rats were trained to discriminate 0.60 mg/kg of (−)-nicotine from saline vehicle. Once trained, the animals made ≥95% of their responses on the (−)-nicotine-appropriate lever when administered training drug, and ≤10% of their responses on the same lever following administration of saline. Response rates (mean responses/min) were not noticeably different after nicotine (11.9±3.1 responses/min) training dose and saline (13.7±2.6 responses/min) treatments. Administration of doses of

Discussion

The results indicate that (−)-nicotine and bupropion share a discriminative stimulus effect. This is based on the dose-dependent substitution of bupropion in rats trained to discriminate the stimulus effect of 0.60 mg/kg of (−)-nicotine from saline vehicle (Fig. 1). A comparison of ED50 values revealed that nicotine (ED50=0.17 mg/kg) is over 30 times more potent than bupropion (ED50=5.50 mg/kg). This result appears to be in apparent conflict with a previous finding that indicated only partial

Acknowledgments

This work was supported in part by NIDA grant DA 05274. Our thanks to Robert Vann and Tatiana Bondareva for technical assistance.

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