title: Bupropion inhibits the cellular effects of nicotine in the ventral tegmental area.
abstract: Each year, tobacco use causes over 4 million deaths worldwide and billions of dollars are spent on treatment for tobacco-related illness. Bupropion, an atypical antidepressant, improves the rates of successful smoking cessation, however, the mechanisms by which bupropion reduces cigarette smoking and depression are unknown. Here we show that clinical concentrations of bupropion inhibit nicotine's stimulatory effects on brain reward areas. Many drugs of abuse, including nicotine, stimulate dopamine (DA) release in the mesoaccumbens reward system. Nicotinic acetylcholine receptors in the ventral tegmental area (VTA) mediate nicotine's stimulation of DA release, as well as its rewarding effects. Nicotinic receptors are expressed by excitatory and inhibitory neurons that control DA neuron excitability, and by the DA neurons themselves. Bupropion is a broad-spectrum non-competitive nicotinic receptor antagonist. Here we report that pre-treatment of brain slices with a clinically relevant concentration of bupropion dramatically reduces the effects of nicotine on DA neuron excitability. Nicotinic receptors on VTA DA neurons and their synaptic inputs are inhibited by 75 - 95% after bupropion treatment. We also find that bupropion alone reduces GABAergic transmission to DA neurons, thereby diminishing tonic inhibition of these neurons. This increases DA neuron excitability during bupropion treatment in the absence of nicotine, and may contribute to bupropion's antidepressant actions.
authors.affiliation: Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Huibert D
authors.initials: HD
authors.lastname: Mansvelder
authors.forename: Zara M
authors.initials: ZM
authors.lastname: Fagen
authors.forename: Ben
authors.initials: B
authors.lastname: Chang
authors.forename: Robert
authors.initials: R
authors.lastname: Mitchum
authors.forename: Daniel S
authors.initials: DS
authors.lastname: McGehee
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016642:Bupropion / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018733:Nicotinic Antagonists; D016642:Bupropion; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid