Biomedical subjects

Anthony S Rauhut

Publications and source records attributed to Anthony S Rauhut.

5 recordsLinked to original sources

PubMed2005

Tolerance does not develop to the decrease in nicotine self-administration produced by repeated bupropion administration.

The atypical antidepressant bupropion has been shown to be an efficacious smoking cessation agent; however, its therapeutic mechanism of action is unknown. To further understand the mechanism by which bupropion reduces smoking, the present study determined the effect of repeated bupropion pretreatment on nicotine self-administration or sucrose-maintained responding. Rats were trained to self-administer intravenous nicotine (0.02 mg/kg/infusion; Experiment 1) or to respond for sucrose pellets (45 mg each; Experiment 2) on a fixed-ratio 5 schedule. Once rats reached stable responding, bupropion (70 mg/kg, subcutaneously) or vehicle was injected 15 min before the session for 14 consecutive sessions. Bupropion acutely decreased both nicotine self-administration and sucrose-maintained responding by approximately 60%-70%. With repeated bupropion pretreatment, however, responding for nicotine decreased completely. In contrast, the bupropion-induced decrease in responding for sucrose following acute administration did not change significantly with repeated bupropion administration. These results suggest that bupropion acquired some specificity with repeated use, decreasing the intake of nicotine and producing an extinction-like pattern in nicotine self-administration. Thus the present results parallel human clinical studies with bupropion demonstrating its smoking cessation properties following repeated treatment. These results indicate that the rat nicotine self-administration paradigm is a useful animal model for assessing smoking cessation pharmacotherapies.

Analysis of Variance↗

PubMed2003

Effect of bupropion on nicotine self-administration in rats.

RATIONALE AND OBJECTIVE: The mechanisms underlying the therapeutic efficacy of bupropion as a smoking cessation agent are unknown. Bupropion inhibits monoamine uptake as well as neuronal nicotinic receptor (nAChR) function. The present study compared effects of bupropion on nicotine self-administration to those of other stimulant drugs (methamphetamine and apomorphine) that lack nAChR activity in order to determine its mechanism of action. To determine the specificity of bupropion-induced changes in nicotine self-administration, the ability of bupropion to alter sucrose-maintained responding or amphetamine self-administration was determined. METHODS: In nicotine and amphetamine self-administration and sucrose-maintained responding experiments, rats responded for nicotine (0.01 or 0.02 mg/kg per infusion, IV), amphetamine (0.2 mg/kg per infusion, IV) and sucrose pellets (45 mg), respectively, on a fixed ratio 5 schedule. Once responding stabilized, rats were pretreated 15 min before the session with bupropion (1-78 mg/kg) or vehicle. The ability of methamphetamine (0.3-3 mg/kg) or apomorphine (0.01-0.2 mg/kg) to alter responding for nicotine (0.02 mg/kg per infusion, IV) was determined. RESULTS: Bupropion produced a biphasic dose-response pattern at both nicotine infusion doses, increasing infusions at low bupropion doses and decreasing infusions at high bupropion doses. Methamphetamine produced a similar biphasic pattern, whereas apomorphine only decreased nicotine infusions at high doses. Bupropion dose-dependently decreased responding for sucrose and amphetamine. CONCLUSIONS: These results suggest that high bupropion doses decrease responding nonspecifically; whereas low bupropion doses selectively increase responding for nicotine. The increase in nicotine self-administration is likely due to inhibition of dopamine and norepinephrine transporters, combined with inhibition of nAChRs.

Animals↗

PubMed2002

Effects of opioid antagonists on unconditioned and conditioned hyperactivity to morphine.

In a series of experiments, the ability of selective mu- (beta-funaltrexamine, beta-FNA), delta- (naltrindole, nalt) and kappa- (nor-binaltorphimine, nor-BNI) opioid receptor antagonists to attenuate the unconditioned and conditioned hyperactive effects of morphine was examined. For comparison, the nonselective opioid receptor antagonist naloxone (nalx) was also examined. Locomotor activity served as the behavioral measure. Experiment 1 found that doses of 1 and 4, but not 16 mg/kg, of morphine effectively produced conditioned hyperactivity (CH). Experiments 2a-d found that beta-FNA, nalt, nor-BNI and nalx, respectively, attenuated unconditioned morphine-induced hyperactivity. Experiments 3a-c, however, found that none of the selective antagonists, given individually, attenuated CH. In contrast, nalx did attenuate CH (Experiment 3d). Collectively results suggest that the unconditioned and conditioned hyperactive responses to morphine are mediated by different receptor systems and that activation of multiple opioid-receptor subtypes mediate expression of CH.

Analgesics, Opioid↗

PubMed2002

Reboxetine: attenuation of intravenous nicotine self-administration in rats.

The ability of reboxetine, a selective inhibitor of the norepinephrine transporter and noncompetitive antagonist at neuronal nicotinic receptors, to alter nicotine self-administration in rats was compared with that of mecamylamine, a classical noncompetitive antagonist at nicotinic receptors. The ability of reboxetine to alter sucrose-maintained responding was also examined to assess the specificity of the effect on nicotine self-administration. Rats were trained on a fixed ratio 5 schedule to self-administer nicotine (0.02 mg/kg/infusion i.v.) or to respond for sucrose pellets. Upon reaching a stable baseline, rats were pretreated 15 min before the session with vehicle, reboxetine (racemic), (+)-(S,S)-reboxetine (0.3-30 mg/kg s.c.) or mecamylamine (0.5-4 mg/kg s.c). To assess the effect of repeated administration, reboxetine (5.6 mg/kg) was injected once daily for 14 consecutive sessions before either nicotine self-administration or sucrose-maintained responding. Specificity was further assessed by examining the ability of repeated administration of reboxetine (5.6 mg/kg) to alter nicotine-induced hyperactivity (0.8 mg/kg). Reboxetine, (+)-(S,S)-reboxetine, and mecamylamine dose dependently decreased nicotine self-administration by ~60%, whereas reboxetine and (+)-(S,S)-reboxetine decreased sucrose-maintained responding to a lesser extent (~20%). Repeated administration of reboxetine (5.6 mg/kg) decreased nicotine self-administration and sucrose-maintained responding across the 14 sessions, suggesting that tolerance did not develop to these effects of reboxetine. Additionally, reboxetine did not alter baseline locomotor activity, indicating that the decrease in operant responding for nicotine and sucrose was not the result of a nonspecific decrease in activity. The reboxetine-induced decrease in nicotine self-administration and sucrose-maintained responding may be the result of inhibition of norepinephrine transporters and/or neuronal nicotinic receptor function.

Adrenergic Uptake Inhibitors↗

PubMedDate not supplied

Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent.

Bupropion hydrochloride ((+/-)-2-tert-butylamino)-3'-chloropropiophenone x HCl) is a nonselective inhibitor of the dopamine transporter (DAT) and the norepinephrine transporter (NET) and is also an antagonist at neuronal nicotinic acetylcholine receptors (nAChRs). In animal models used commonly to screen for antidepressant activity, bupropion shows a positive response. Also using animal models, bupropion has been shown to attenuate nicotine-induced unconditioned behaviors, to share or enhance discriminative stimulus properties of nicotine and to have a complex effect on nicotine self-administration, i.e., low doses augmenting nicotine self-administration and high doses attenuating self-administration. Current studies show that bupropion facilitates the acquisition of nicotine conditioned place preference in rats, further suggesting that bupropion enhances the rewarding properties of nicotine. Bupropion has been shown to attenuate the expression of nicotine withdrawal symptoms in both animal models and human subjects. With respect to relapse, current studies show that bupropion attenuates nicotine-induced reinstatement in rats, but large individual differences are apparent. Clinically, bupropion is used as a treatment for two indications, as an antidepressant, the indication for which it was developed, and as a tobacco use cessation agent. In clinical trials, bupropion is being tested as a candidate treatment for psychostimulant drug abuse, attention-deficit hyperactivity disorder (ADHD) and obesity. Bupropion is available in three bioequivalent oral formulations, immediate release (IR), sustained release (SR), and extended release (XL). Extensive hepatic metabolism of bupropion produces three pharmacologically active metabolites, which may contribute to its clinical profile.

Animals↗