Bupropion and its main metabolite reverse nicotine chronic tolerance in the mouse.

INTRODUCTION: Although the antidepressant bupropion is prescribed to aid in smoking cessation, little is known concerning its mechanisms of action in this regard. One factor that might influence quit success is nicotine tolerance, which could promote high levels of nicotine intake in order to maintain nicotine's subjective effects (thereby making attempts to reduce smoking more difficult). METHODS: To explore whether bupropion and its active hydroxymetabolite modulate nicotine tolerance, mice were injected for 14 days with saline or nicotine. On Day 14, animals received saline, (2S,3S)-hydroxybupropion, or bupropion at different doses. On Day 15, mice were assayed on test day for nicotine-induced analgesia and hypothermia. RESULTS: Animals chronically injected with saline + nicotine developed tolerance to nicotine's effects in both assays. Administration of bupropion and (2S,3S)-hydroxybupropion dose-dependently reversed chronic nicotine tolerance. CONCLUSIONS: These results indicate that bupropion's ability to promote smoking cessation may be partly due to its attenuation of nicotine tolerance since both measured responses of nicotine (antinociception and hypothermia) are mediated to a large extent by neuronal α4ß2* nicotine receptors.

Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice.

Bupropion is an atypical antidepressant that also has utility as a smoking cessation aid. Hydroxybupropions are major metabolites of bupropion and are believed to contribute to antidepressant and perhaps smoking cessation activities. Because bupropion metabolism is more similar in humans and mice than in humans and rats, the present study investigated effects of hydroxybupropion enantiomers in mouse behavioral models measuring various aspects of nicotine dependence. Bupropion and (2S,3S)-hydroxybupropion, but not (2R,3R)-hydroxybupropion, significantly decreased the development of nicotine reward as measured in the conditioned place preference and withdrawal paradigm in mice. Bupropion and both of its metabolites reversed affective and somatic withdrawal signs in nicotine-dependent mice, but the (2S,3S)-hydroxymetabolite had higher potency. Bupropion and (2S,3S)-, but not (2R,3R)-hydroxybupropion, produced partial substitution for nicotine in drug discrimination tests. Our findings support the hypothesis that the effects of bupropion on measures of nicotine dependence reflect actions of bupropion itself, its hydroxymetabolites, or a combination and suggest that the (2S,3S)-hydroxy isomer is the most active principle, making it a potentially better drug candidate for smoking cessation than bupropion.

Nicotine place preference in the mouse: influences of prior handling, dose and strain and attenuation by nicotinic receptor antagonists.

RATIONALE: Although conditioned place preferences (CPPs) are seen with most abused drugs, nicotine does not always produce a preference in this design. OBJECTIVES: The goals of the present experiment were to (1) examine various factors that could contribute to these inconsistent results and (2) begin to evaluate the specific nicotinic receptors involved in the nicotine CPP. METHODS: The influences of prior handling, environmental habituation, and injection habituation on a nicotine CPP were first evaluated in ICR mice. Subsequently, various nicotine doses were assessed for their abilities to produce a CPP, and the effectiveness of nicotinic receptor antagonists in attenuating this preference was examined. Finally, nicotine CPPs were assessed in C57BL/6J and DBA/2J mice to examine the influence of strain in this design. RESULTS: Nicotine CPPs were seen in handled/environmentally habituated, but not in unhandled, ICR mice. Habituation to the injection techniques failed to strengthen the preference. In ICR mice, a CPP was seen with one intermediate dose of nicotine. This CPP was attenuated by mecamylamine and dihydro-beta-erythroidine (DHbetaE). A nicotine CPP was also seen in C57BL/6J, but not in DBA/2J, mice. CONCLUSION: Earlier handling experience and strain are important factors when evaluating a nicotine CPP in the mouse. In addition, certain nicotinic receptors underlie the nicotine CPP, indicating that this model can elucidate underlying mediators of nicotine reward.

Nicotine physical dependence in the mouse: involvement of the alpha7 nicotinic receptor subtype.

Although chronic nicotine produces dependence in mice, the role of specific nicotinic receptors has not been examined in knockout animals. The present study utilized alpha7 nicotinic receptor knockout mice to explore the role of this receptor subunit in nicotine dependence. Mice were chronically exposed to nicotine (0 or 200 microg/ml) in their drinking water and assayed for somatic withdrawal signs, hyperalgesia (tail-flick and hot-plate) and spontaneous activity following nicotine cessation. Nicotine withdrawal produced increased somatic signs in both strains and hyperalgesia in wild-type, but not in knockout animals. These results indicate that the alpha7 nicotinic receptor subunit may mediate some aspects of nicotine dependence.

Nicotine physical dependence and tolerance in the mouse following chronic oral administration.

RATIONALE: Although nicotine dependence and tolerance develop in rats, few studies have examined these processes in the mouse. Establishing such mouse models would eventually allow for an examination of the role of specific nicotinic receptor subtypes in mediating these processes (i.e. through the use of receptor knockouts). OBJECTIVES: The goals of the present study were to establish mouse models of nicotine dependence and tolerance. METHODS: Mice were chronically exposed to nicotine (0-200 mug/ml) in their drinking solution and assayed for plasma nicotine and cotinine levels, withdrawal signs following nicotine cessation (spontaneous withdrawal) or nicotinic antagonist administration (precipitated withdrawal), or nicotine tolerance. Dependence assays included somatic sign observations (paw tremors, backing and head shakes), tail-flick, plantar stimulation, elevated plus-maze and spontaneous activity. Tolerance was assayed using tail-flick, hot-plate and body temperature tests. RESULTS: Plasma nicotine and cotinine levels were elevated during oral nicotine exposure (15.85 ng/ml and 538.00 ng/ml, respectively) and quickly declined following nicotine cessation (<1 ng/ml and <2 ng/ml, respectively), providing evidence that the oral route was pharmacologically relevant. Nicotine withdrawal increased numbers of somatic signs (spontaneous and mecamylamine-precipitated withdrawal) and/or hyperalgesia (spontaneous withdrawal only). Chronic nicotine exposure also produced tolerance, as indicated by reduced responsivity to acute nicotine in assays of analgesia and hypothermia. CONCLUSIONS: These results indicate that chronic oral nicotine produces dependence and tolerance in the mouse. Further, nicotine dependence may be mediated by multiple nicotinic receptor subtypes, since specific nicotinic receptor antagonists failed to precipitate withdrawal.

Morphine- and cocaine-induced c-Fos levels in Lewis and Fischer rat strains.

Lewis (LEW) and Fischer 344 (F344) rat strains have been reported to differ in their sensitivity to the rewarding and aversive effects of both cocaine and morphine. Specifically, LEW rats self-administer morphine and cocaine to a greater extent than F344 rats, while LEW (compared to F344) rats are more sensitive to the aversive effects of cocaine but less sensitive to the aversive effects of morphine. Consistent with assessments of the rewarding effects of morphine and cocaine in these two strains, LEW rats have lower basal, and generally higher drug-induced, activity in brain regions associated with reward. Although the brain areas that mediate the aversive effects of drugs are becoming better defined, no studies have compared the activation of these areas by aversion-inducing drugs in the LEW and F344 strains. As such, the relationship between the ability of drugs to activate these aversion-associated brain areas and to induce a conditioned taste aversion (CTA) in these strains is unknown. To explore this relationship, LEW and F344 rats were injected with saline or doses of morphine or cocaine (32 mg/kg for both drugs) that have been shown to generate differential taste aversion learning in these strains. All animals were subsequently tested for c-Fos expression in areas of the brain associated with aversion learning (the lateral and medial parabrachial nucleus, intermediate and caudal nucleus tractus solitarius and area postrema), reward (the shell of the nucleus accumbens) and locomotion (the core of the nucleus accumbens and the caudate putamen). The present results indicated that patterns of morphine- and cocaine-induced c-Fos within CTA-associated, but not reward- or locomotor-associated, brain regions paralleled the differential behavioral sensitivities of LEW and F344 rats to these drugs within CTA learning. Analyses with other drugs that do and do not induce aversions differentially would further assess the role of these brain areas in aversion learning, in general, and in strain-dependent differences, in particular.