Mechanism of Action of Buspirone (Buspar)
Buspirone acts primarily as a partial agonist at serotonin 5-HT1A receptors, particularly at presynaptic autoreceptors in the raphe nuclei, which attenuates central serotonergic neurotransmission. 1
Primary Mechanism
- Buspirone has high affinity for serotonin 5-HT1A receptors, where it functions as a partial agonist, particularly at presynaptic sites in the dorsal raphe nuclei 1, 2
- This action inhibits the synthesis and release of serotonin and decreases the firing rate of serotonin-containing neurons 3
- The FDA label explicitly states that buspirone differs fundamentally from benzodiazepines in that it has no significant affinity for benzodiazepine receptors and does not affect GABA binding 1
Secondary Receptor Interactions
- Buspirone displays moderate affinity for dopamine D2 receptors, where it acts as an antagonist, though this effect is likely not responsible for its anxiolytic action 1, 2
- The drug shows some affinity for 5-HT2 receptors, contributing to its complex neuropharmacologic profile 3
- At therapeutic doses, buspirone enhances noradrenergic neuron firing rates, which correlates with dopaminergic stimulation rather than serotonergic inhibition 4
Clinical Pharmacologic Distinctions
Buspirone lacks anticonvulsant, muscle relaxant, and prominent sedative effects that characterize benzodiazepine anxiolytics, earning it the designation as "anxioselective" 1, 5
Key Pharmacologic Features:
- Undergoes extensive first-pass metabolism, with unchanged buspirone accounting for only about 1% of plasma radioactivity 1
- Metabolized primarily by CYP3A4 through oxidation pathways 1
- Produces an active metabolite (1-pyrimidinylpiperazine) with approximately one-quarter the activity of the parent compound, though human blood levels remain clinically insignificant 1
- Elimination half-life of 2-3 hours after single doses 1
Important Clinical Caveat
Buspirone requires 2-4 weeks of regular administration to achieve full therapeutic anxiolytic effect, unlike benzodiazepines which provide immediate relief 6, 7. This delayed onset necessitates explicit patient education to set appropriate expectations and avoid premature discontinuation 7.