Reboxetine: Functional Inhibition of Monoamine Transporters and Nicotinic Acetylcholine Receptors

Miller, Dennis K.; Wong, Erik H. F.; Chesnut, M. Dathan; Dwoskin, Linda P.

doi:10.1124/jpet.302.2.687

Cited by 57 publications

(43 citation statements)

References 33 publications

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“…7), which confirms findings in rat hypothalamic synaptosomes (Wong et al, 2000) and rat hippocampal synaptosomes (Miller et al, 2002). This reduction is most likely due to an inhibition of the neuronal amine pump (uptake-1 mechanism) because cocaine and desipramine also reduced the uptake (Fig.…”

Section: Discussionsupporting

confidence: 87%

Effects of Reboxetine on Sympathetic Neuroeffector Transmission in Rabbit Carotid Artery

Rasmussen

Nedergaard

2003

J Pharmacol Exp Ther

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Section: Discussionsupporting

confidence: 87%

Effects of Reboxetine on Sympathetic Neuroeffector Transmission in Rabbit Carotid Artery

Rasmussen

Nedergaard

2003

J Pharmacol Exp Ther

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“…Box 1773, HUB Building/College and Louther Streets, Carlisle, PA 17013. ated antidepressant in clinical use in Europe (Berzewdski et al, 1997), and its therapeutic efficacy has been attributed to selective inhibition of the norepinephrine transporter (Montgomery, 1999;Sacchetti et al, 1999;Wong et al, 2000;Miller et al, 2002b). However, recent studies have shown that reboxetine, like other antidepressants, including bupropion (Fryer and Lukas, 1999;Hennings et al, 1999;Slemmer et al, 2000;Miller et al, 2002a), acts as a noncompetitive inhibitor of nAChRs (Miller et al, 2002b).…”

mentioning

confidence: 99%

“…In the present study, the ability of reboxetine and (ϩ)-(S,S)-reboxetine to alter nicotine self-administration was determined. Since reboxetine acts as a noncompetitive inhibitor of nAChRs (Miller et al, 2002b), the ability of reboxetine to alter nicotine self-administration was compared with that of the classic noncompetitive nAChR antagonist, mecamylamine (experiment 1). To assess the specificity of the effects of reboxetine on nicotine self-administration, the ability of reboxetine (racemic) and (ϩ)-(S,S)-reboxetine to alter sucrose-maintained responding also was determined (experiment 2).…”

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confidence: 99%

“…Thus, it seems likely that the reboxetine-induced decrease in nicotine self-administration may be due to an alteration in the activity of the mesolimbic dopamine system. However, it is unlikely that reboxetine modulates mesolimbic dopamine activity via direct inhibition of dopamine transporter function, since reboxetine has a low affinity (IC 50 ϭ 89 M) for dopamine transporters (Miller et al, 2002b). Moreover, after 14 days of once daily administration of reboxetine, the ability of reboxetine to inhibit dopamine transporters is not altered (IC 50 ϭ 100 M; Miller et al, 2002b), further suggesting that inhibition of dopamine transporters was not involved in the reboxetine-induced decrease in nicotine self-administration across 14 sessions in the present study.…”

mentioning

confidence: 99%

“…Reboxetine has been shown to inhibit nicotine-evoked 86 Rb ϩ efflux (IC 50 ϭ 650 nM), indicating functional antagonism of the ␣4␤2* nAChR subtype (Miller et al, 2002b). Several gene-knockout studies have implicated the ␤2-subunit in nicotine self-administration (Picciott et al, 1998;Cordero-Erausquinm et al, 2000).…”

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Reboxetine: Attenuation of Intravenous Nicotine Self-Administration in Rats

Rauhut

Mullins²,

Dwoskin³

et al. 2002

J Pharmacol Exp Ther

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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 selfadminister 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), (ϩ)-(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, (ϩ)-(S,S)-reboxetine, and mecamylamine dose dependently decreased nicotine self-administration by ϳ60%, whereas reboxetine and (ϩ)-(S,S)-reboxetine decreased sucrose-maintained responding to a lesser extent (ϳ20%). 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.Clinical and epidemiological evidence has linked smoking and depression. The incidence of major depression is higher among smokers than nonsmokers (Glassman, 1993;Kendler et al., 1993;Breslau et al., 1998). The likelihood of successful smoking cessation decreases in those individuals with a history of major depression or depressive symptoms at the initiation of smoking cessation (Hall et al., 1991;Glassman, 1993). Furthermore, depressive symptoms associated with nicotine withdrawal are more severe in depressed patients compared with patients without histories or symptoms of depression (Glassman, 1993). The onset of smoking cessation may initiate an acute depressive episode in certain individuals (Stage et al., 1996;Covey et al., 1997). Furthermore, nicotine has been reported to have antidepressant properties in depressed individuals (Glassman, 1993;Salin-Pascual and Drucker-Colin, 1998) and in animal models of depression (Tizabi et al., 1999). Such evidence has led to the self-medication hypothesis of nicotine dependence, such that individuals ma...

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Monoaminergic‐based Pharmacotherapy for Depression

Papakostas¹,

Fava²

2005

Biology of Depression

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Although recent advances in neuropharmacology, neuroendocrinology, molecular biology, and pharmacogenetics have been instrumental in bringing about potential treatments for depression which are fundamentally unrelated to their predecessors, including substance P antagonists, glutaminergic agents, and corticotropinreleasing factor (CRF) antagonists, nevertheless it was agents that influenced the function of monoamine receptors and transporters that were discovered initially by serendipity and then developed as treatments for depression. The development of such compounds also served as a framework for the understanding of depression as a medical illness affecting brain functioning. As a result of these efforts, our field has gained further understanding of the role of monoamines in depression. In previous chapters, the relevance of monoamines in the underlying pathophysiology of depression was reviewed. In the following chapter we will focus on describing the contemporary role of monoaminergic agents in the treatment of depression. 6.

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Reboxetine: Functional Inhibition of Monoamine Transporters and Nicotinic Acetylcholine Receptors

Cited by 57 publications

References 33 publications

Effects of Reboxetine on Sympathetic Neuroeffector Transmission in Rabbit Carotid Artery

Effects of Reboxetine on Sympathetic Neuroeffector Transmission in Rabbit Carotid Artery

Reboxetine: Attenuation of Intravenous Nicotine Self-Administration in Rats

Monoaminergic‐based Pharmacotherapy for Depression

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