What is the mechanism of action of Wellbutrin (bupropion)?

Mechanism of Action of Wellbutrin (Bupropion)

Bupropion works primarily as a norepinephrine and dopamine reuptake inhibitor while also blocking nicotinic acetylcholine receptors, making it uniquely effective for depression and smoking cessation without the sexual dysfunction and weight gain common to other antidepressants. 1

Primary Mechanisms

Norepinephrine and Dopamine Reuptake Inhibition:

• Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and this action is presumed to mediate its antidepressant effects. 2
• The drug does not inhibit monoamine oxidase or the reuptake of serotonin, distinguishing it from SSRIs and MAOIs. 2
• Bupropion enhances the release of norepinephrine and dopamine in reward centers of the brain, contributing to its therapeutic effects. 3

Nicotinic Acetylcholine Receptor Antagonism:

• Bupropion acts as a noncompetitive antagonist of several nicotinic acetylcholine receptors (nAChRs), particularly α4β2 and α3β4* subtypes. 4, 3
• This receptor blockade contributes significantly to its smoking cessation efficacy by decreasing nicotine reward and withdrawal symptoms. 1, 3
• The drug binds to nAChRs in the resting state, decreasing the probability of ion channel opening and accelerating the desensitization process. 4

Active Metabolite Contribution

Hydroxybupropion:

• Bupropion is extensively metabolized to three active metabolites, with hydroxybupropion being the most clinically significant. 2
• Hydroxybupropion is formed via hydroxylation of the tert-butyl group through the cytochrome P450 enzyme CYP2B6. 2
• At steady state, peak plasma concentration of hydroxybupropion is approximately 7 times the peak level of the parent drug, with an AUC about 13 times that of bupropion. 2
• This metabolite contributes to both antidepressant and smoking cessation efficacy, though it is approximately one-half as potent as bupropion in antidepressant screening tests. 2, 3

Additional Mechanisms

Serotonergic Effects:

• Sustained bupropion administration increases the firing rate of serotonin neurons by 100% through a norepinephrine-dependent mechanism, not through direct serotonin reuptake inhibition. 5
• Bupropion acts as a negative allosteric modulator of serotonin type 3A receptors (5-HT3ARs), with hydroxybupropion achieving inhibitory concentrations within therapeutically-relevant ranges. 6

Noradrenergic Modulation:

• Sustained treatment produces a dose-dependent attenuation of norepinephrine neuron firing (up to 80% at 30 mg/kg per day) due to increased activation of inhibitory somatodendritic α2-adrenoceptors. 5
• This effect is attributable mainly to enhanced norepinephrine release rather than reuptake inhibition alone. 5

Clinical Implications

Unique Pharmacological Profile:

• The combination of dopamine/norepinephrine reuptake inhibition and nicotinic receptor antagonism explains bupropion's dual efficacy in depression and smoking cessation. 1, 3
• Unlike dopamine reuptake blockers, bupropion does not alter the firing rate of dopamine neurons in the ventral tegmental area at therapeutic doses. 5
• The drug's activity on vesicular monoamine transporter-2 (VMAT-2), which pumps dopamine, norepinephrine, and serotonin into presynaptic vesicles, may be an additional component of its mechanism. 7