Mapping and quantification of dopamine D2 receptor activation Kevin J. Black, Tamara Hershey, Jonathan M. Koller, Juanita L. Carl, Joel S. Perlmutter Departments of Psychiatry, Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of Medicine, and School of Engineering, Washington University

Methods 4 normal baboons, 5 study days ventilated with 70% N2O throughout the study U91356a (antiparkinsonian dose ~10-125 mg/kg); Ki’s: D2 = 1.3nM; D3 = 32nM; D4 = 195nM D1 > 1000nM 5HT1A = 58nM PET rCBF scans before, after 1-220 mg/kg iv PET methods validated in baboons (Herscovitch et al., 1983; Raichle et al., 1983; Videen et al., 1987) scans aligned to the b2k atlas (www.purl.org/net/kbmd/b2k) (Black et al 2001) analysis with SPM99 as previously described (Black et al, 2000)

Results 1 relative CBF increases: A single large (20cc) contiguous cluster of voxels with p < 0.001, peak t > 8 (34 d.f.), corrected p « 0.0001. Peaks in cerebellum, temporal poles, amygdala, edge of brain relative CBF decreases: 5 significant clusters Peak t > 7.5 (34 d.f.), corrected p « 0.0001. Peaks in dorsolateral prefrontal cortex, putamen, medial parietal and posterior cingulate cortex, primary sensorimotor cortex, and superior temporal gyrus

Results 2: rCBF decreases (NOTE: significant values imply decreases disproportionate to any global changes)

Results 3: rCBF decreases Time course of DLPFC peak: stable response over 1hr T (mean ± S.D.)

Results 4: whole-brain CBF Average blood flow throughout the brain decreased after U91356a (below left) Thus the “increases” are really areas spared this effect (see graph below right) These results can only be interpreted correctly because we used quantitative methods

U91356a rCBF changes are pharmacologically specific (ROIs centered on L & R GPi, averaged – from Black et al, 1997) D2 antag D1 antag peripheral D2 S2 antag

Conclusions The D2-specific dopamine agonist U91356a decreases whole-brain blood flow by ~30% Even after accounting for this global change, there are statistically very robust regional decreases In approximate descending order of significance these decreases have peak statistical values in: dorsolateral prefrontal cortex, putamen, medial parietal and posterior cingulate cortex, primary sensorimotor cortex, and superior temporal gyrus

Discussion The pattern of blood flow changes after dopamine agonists depends on the drug’s receptor specificity (see next page) These results can help inform pharmacologic challenge neuroimaging results in humans with less specific agonists (see next page) A challenge test such as this one may lend itself to quantifying the brain’s responses to stimulation of receptor-specific neuronal pathways in human disease states

Acknowledgments Funding: NINDS (NS01898 and others), NARSAD Young Investigator Award (K.J.B.), Tourette Syndrome Association, Charles A. Dana Foundation, American Parkinson Disease Association, and McDonnell Center for Higher Brain Function. U91356a was a gift from Upjohn. Technical support: Terry Anderson, Craig Collins, John Hood Jr., Bettina Tobben, Lennis Lich