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Pathway Description
Bupropion Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2022-04-01
Last Updated: 2023-10-25
Bupropion, known as the brand name Wellbutrin, is a norepinephrine/dopamine reuptake inhibitor (NDRI) used most commonly as a treatment for major depressive disorder (MDD), and seasonal affective disorder (SAD). It can also be used as a treatment for smoking cessation. Unlike most other drugs used to treat MDD, bupropion has been found to have no interaction with serotonin transporters. Bupropion works with other drugs to help with other neurological disorders such as seizures, and ADHD with bipolar comorbidity.
Bupropion works by weakly inhibiting dopamine and norepinephrine transporters in presynaptic neurons. Dopamine is synthesized from tyrosine which is catalyzed by Tyrosine 3-monooxygenase into L-dopa which is catalyzed by Aromatic-L-amino-acid decarboxylase into dopamine. This mainly occurs in the substantia nigra, ventral tegmental area, and hypothalamus which are all parts of the limbic system where bupropion has the most effect in regulating MDD. Dopamine is released into the synapse where it is much more difficult for it to re-enter the presynaptic neuron due to bupropion inhibiting the sodium-dependent dopamine receptor. This causes dopamine to accumulate in higher concentrations in the synapse. The high concentration of dopamine activates dopamine receptors prolongs the duration of action on dopamine receptors. The D1 dopamine receptor is the receptor found to receptor most associated with MDD. There is also evidence that the D1-D2 heteromer is implicated in MDD, but that has not been studied enough to understand its effects. The D1 dopamine receptor activates Gs coupled protein which with GTP activates adenylate cyclase. Adenylate cyclase catalyzes ATP into cAMP which activates PKA which causes neuronal excitability. This helps regulate mood and behaviour in the brain as well as activating the reward system.
Norepinephrine's effects on MDD is less studied and less understood than dopamine. Norepinephrine is synthesized in the locus ceruleus from dopamine which is catalyzed by Dopamine beta-hydroxylase into norepinephrine. Norepinephrine is released into the synapse where it accumulates because bupropion is weakly inhibiting the sodium-dependent noradrenaline receptor which prevents norepinephrine from re-entering the presynaptic neuron. This higher concentration of norepinephrine prolongs the duration of action on adrenergic receptors. Depressed patients have drastically low levels of norepinephrine, but a defeciency in the adrenergic receptors themselves seems to be implicated in MDD as well. Norepinephrine activates Alpha-1A adrenergic receptors in the brain, which are desensitized in the brains of depressed patients and implicated in the limbic system for regulating behaviour and mood. Activation of Alpha-1A receptors activates the Gq signalling cascade which has a variety of excitatory effects on neurons in the brain, especially in the limbic system. The exact effects of norepinephrine in the brain, especially in the brain of patients with MDD is still being researched, and therefore is still not entirely understood. Depression does seem to cause problems with the activation of the receptors which means more norepinephrine is required to see the same effects as in people without MDD. Bupropion does this at least for alpha-1A adregnergic receptors in the limbic system. Alpha-2 adrenergic receptors have been found to have a higher density in the brain of depressed patients, and seem to cause symptoms of depression. Beta adrenergic receptors have also been observed to be highly activated in patients with depression.
References
Bupropion Pathway References
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