title: Therapeutic doses of buspirone block D3 receptors in the living primate brain.
abstract: Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward. Here we used PET with [11C]PHNO (D3R-preferring radioligand), [11C]raclopride (D2R/D3R radioligand) and [11C]NNC-112 (D1R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both [11C]PHNO and [11C]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 [11C]PHNO binding in D3-rich regions (globus pallidum and midbrain) at 3 h, but had minimal effects on [11C]raclopride binding (28-37% at 1 h and 10% at 3 h). Buspirone did not block [11C]NNC-112. Our findings provide evidence that i.m. buspirone blocks D3R and D2R, whereas oral buspirone is more selective towards D3R 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 D3R 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.
authors.affiliation: Laboratory of Neuroimaging,National Institute on Alcohol Abuse and Alcoholism,Upton, NY,USA.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.affiliation: National Institute on Drug Abuse,Bethesda, MD,USA.
authors.forename: Phil
authors.initials: P
authors.lastname: Skolnick
authors.affiliation: Laboratory of Neuroimaging,National Institute on Alcohol Abuse and Alcoholism,Upton, NY,USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: Yeona
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: Dohyun
authors.initials: D
authors.lastname: Kim
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: Payton
authors.initials: P
authors.lastname: King
authors.affiliation: Biosciences Department,Brookhaven National Laboratory,Upton, NY,USA.
authors.forename: David
authors.initials: D
authors.lastname: Alexoff
authors.affiliation: Laboratory of Neuroimaging,National Institute on Alcohol Abuse and Alcoholism,Upton, NY,USA.
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D001552:Benzazepines; D001572:Benzofurans; D002065:Buspirone / Q000008:administration & dosage* / Q000494:pharmacology*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects*; D065127:Dopamine D2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D059907:Functional Neuroimaging; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000187:drug effects*; D007273:Injections, Intramuscular; D008636:Mesencephalon / Q000000981:diagnostic imaging / Q000187:drug effects*; D010078:Oxazines; D048530:Papio anubis; D049268:Positron-Emission Tomography; D020891:Raclopride; D011869:Radioligand Assay; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*
chemical_list: D014151:Anti-Anxiety Agents; D001552:Benzazepines; D001572:Benzofurans; D065127:Dopamine D2 Receptor Antagonists; D010078:Oxazines; D050637:Receptors, Dopamine D3; C077123:NNC 112; C042631:naxagolide; D020891:Raclopride; D002065:Buspirone