What is the mechanism of action (MOA) of Bupropion?

Mechanism of Action of Bupropion

Bupropion works primarily through inhibition of norepinephrine and dopamine reuptake, though the FDA acknowledges the precise mechanism remains unknown, and it also activates anorexigenic neurons in the hypothalamus contributing to its weight-neutral profile. 1

Primary Neurochemical Mechanisms

Monoamine Reuptake Inhibition

• Bupropion is a relatively weak inhibitor of neuronal uptake of norepinephrine and dopamine, distinguishing it from other antidepressants by having no serotonergic activity. 1
• The drug does not inhibit monoamine oxidase or serotonin reuptake, making it unique among antidepressants. 1
• Research demonstrates that sustained bupropion administration decreases norepinephrine neuron firing through enhanced norepinephrine release rather than simple reuptake blockade, as evidenced by increased activation of inhibitory alpha-2 adrenoceptors. 2

Central Neurotransmitter Release

• The American College of Cardiology notes that bupropion activates the central nervous system to release norepinephrine, dopamine, and other neurotransmitters. 3
• This release mechanism may be more clinically relevant than the weak reuptake inhibition properties. 2

Active Metabolites and Their Contribution

Hydroxybupropion

• Bupropion is extensively metabolized via CYP2B6 to hydroxybupropion, which reaches peak plasma concentrations approximately 7 hours after administration and achieves levels 7 times higher than the parent compound. 1
• At steady state, hydroxybupropion's area under the curve is approximately 13 times that of bupropion, with an elimination half-life of 20 hours. 1
• Hydroxybupropion demonstrates half the potency of bupropion in antidepressant screening tests but contributes significantly to clinical efficacy due to its high plasma concentrations. 1, 4

Additional Metabolites

• Threohydrobupropion and erythrohydrobupropion are formed via reduction of the carbonyl group and are 5-fold less potent than bupropion, though their plasma concentrations remain as high or higher than the parent drug. 1

Hypothalamic and Weight Effects

• Bupropion activates anorexigenic (appetite-suppressing) neurons in the hypothalamus, contributing to its weight-neutral or weight-loss promoting profile. 3, 5
• This hypothalamic effect is weaker than traditional stimulants, and extended-release formulations further moderate any stimulant-like effects through gradual drug delivery. 5

Serotonergic Modulation (Indirect)

• Despite having no direct serotonergic activity, sustained bupropion treatment increases serotonin neuron firing rate by 100% through a norepinephrine-dependent mechanism. 2
• This effect is abolished in norepinephrine-lesioned rats, confirming the indirect nature of serotonergic modulation. 2

Clinical Caveats

• The dopaminergic activity of bupropion does not alter the firing rate of dopamine neurons in the ventral tegmental area, suggesting its dopaminergic effects occur through different mechanisms than direct neuronal firing modulation. 2
• The L-arginine-nitric oxide-cyclic GMP signaling pathway may also contribute to bupropion's antidepressant effects, as demonstrated by the ability of L-arginine to prevent and nitric oxide synthase inhibitors to potentiate its effects. 6