Buspirone's Effect on Dopamine D2 Receptors
Buspirone has moderate affinity for dopamine D2 receptors and functions as an antagonist at these receptors, though this is not its primary mechanism of action. 1
Primary Mechanism and D2 Receptor Interaction
Buspirone's main pharmacological activity is mediated through serotonin 5-HT1A receptors as a partial agonist, with D2 receptor antagonism being a secondary effect. 1, 2
The FDA label explicitly states that buspirone has "moderate affinity for brain D2-dopamine receptors," distinguishing it from typical anxiolytics that lack dopaminergic activity. 1
At therapeutic anxiolytic doses, buspirone demonstrates low affinity and acts as an antagonist specifically at presynaptic D2 autoreceptors in the nigrostriatal pathway. 2, 3
Dose-Dependent D2 Receptor Effects
Low to Moderate Doses (Therapeutic Range)
At doses of 1.25-5 mg/kg, buspirone selectively blocks presynaptic nigrostriatal D2 dopamine autoreceptors without affecting postsynaptic striatal D2 or D1 receptors. 3
This selective presynaptic blockade increases dopamine synthesis and availability, which explains why buspirone potentiates dexamphetamine-induced stereotypy and antagonizes haloperidol-induced catalepsy at these doses. 3
Therapeutic doses do not induce catalepsy or extrapyramidal symptoms, confirming minimal postsynaptic D2 receptor blockade. 3, 4
High Doses (Supratherapeutic)
At doses of 10-40 mg/kg, buspirone blocks both postsynaptic striatal D2 and D1 dopamine receptors, inducing catalepsy and antagonizing dopamine agonist effects. 3
In humans, even high acute doses (60-120 mg) achieve only modest D2 receptor occupancy of approximately 25%, with no significant occupancy at 30 mg doses. 5
Chronic Administration Effects
Chronic buspirone administration (up to 3 months) does not alter dopamine autoreceptor sensitivity or postsynaptic D2 receptor sensitivity, unlike typical neuroleptics. 4
Repeated dosing with buspirone (twice daily for 7 days) produces a 55% upregulation in D2 receptor density in the striatum without changes in receptor affinity (Kd values), suggesting compensatory receptor changes. 6
Continuous infusion at 1.0 mg/kg/day for 2 weeks produces only minimal subsensitivity to acute dopaminergic challenges, contrasting sharply with haloperidol which causes marked subsensitivity. 4
Three months of buspirone treatment reverses neuroleptic-induced increases in striatal D2 receptor binding (45% increase from trifluoperazine), indicating a modulatory effect on the extrapyramidal system. 4
Clinical Implications
The moderate D2 affinity and selective presynaptic action at therapeutic doses explain why buspirone lacks the extrapyramidal side effects characteristic of typical D2 antagonists. 4
Plasma prolactin levels (a D2 receptor blockade marker) correlate with D2 receptor occupancy after buspirone administration, though the occupancy remains modest even at high doses. 5
The lack of significant postsynaptic D2 blockade at therapeutic doses differentiates buspirone from antipsychotics, which require 60-80% D2 occupancy for efficacy but carry substantial extrapyramidal risks. 4, 5