Therapeutic doses of buspirone block D3 receptors in the living primate brain

Sung Won Kim, Joanna S. Fowler, Phil Skolnick, Lisa Muench, Yeona Kang, Colleen Shea, Jean Logan, Dohyun Kim, Pauline Carter, Payton King, David Alexoff, Nora D. Volkow
2014 International Journal of Neuropsychopharmacology  
Dopamine D 3 receptor (D 3 R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D 3 R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT 1A partial agonist and used as an anxiolytic, also binds to D 3 R and D 4 R with high affinity, with lower affinity to D 2 R, and interferes with cocaine reward. Here we used PET with [ 11 C]PHNO (D 3 R-preferring radioligand), [ 11 C]raclopride (D 2
more » ... /D 3 R radioligand) and [ 11 C]NNC-112 (D 1 R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both [ 11 C]PHNO and [ 11 C]raclopride binding to striatum, exhibiting high occupancy (50-85%) at 15 min and rapid wash-out over 2-6 h. In contrast, oral buspirone (3 mg/kg) significantly blocked [ 11 C]PHNO binding in D 3 -rich regions (globus pallidum and midbrain) at 3 h, but had minimal effects on [ 11 C]raclopride binding (28-37% at 1 h and 10% at 3 h). Buspirone did not block [ 11 C]NNC-112. Our findings provide evidence that i.m. buspirone blocks D 3 R and D 2 R, whereas oral buspirone is more selective towards D 3 R blockade in vivo, consistent with extensive first pass metabolism and supporting the hypothesis that its metabolites (5-and 6′-hydroxybuspirone) merit evaluation for treating SUDs. They also indicate that for oral buspirone to achieve greater than 80% sustained D 3 R occupancy, as might be needed to treat addiction, higher doses (at least three-fold) than those used to treat anxiety (maximal 60 mg) will be required. Nonetheless, based on previous clinical studies, these doses would be safe and well tolerated.
doi:10.1017/s1461145714000194 pmid:24679922 fatcat:w6n76jmhjvgz7ab7kr7xu7x4pu