Abstract
361
Objectives We previously presented on the excitatory effects of dopamine (DA) D1-like receptors using simultaneous PET/fMRI with D1 agonist and antagonist drugs. As expected, the agonist resulted in strong excitatory effects, measured by fMRI as increases in cerebral blood volume (CBV), even at low receptor occupancies (R-occ) measured by PET. Unexpectedly, the antagonists also elicited excitatory responses, calling into question their true pharmacological properties; D1 antagonists should bind to D1 without direct response, but will block access of DA to D1 thus attenuating endogenous excitation for an overall inhibitory effect and indirect reduction in CBV. The goal of this work was to explore the properties of two antagonists (NNC112, SCH23390) under conditions when DA residence at the D1 receptor site will have maximum effects, i.e. when DA levels are high.
Methods Two rhesus macaques underwent a total of 13 scans on a simultaneous PET/MR (Siemens Trio with BrainPET insert). Contrast-enhanced fMRI was used to assess the D1 receptor response from antagonists at baseline (b-DA) and high DA (h-DA) levels using amphetamine (AMP) to increase DA. b-DA scans included bolus administration of antagonist (25 μg/kg NNC112 or SCH23390). In h-DA scans, either NNC or SCH was given 40 min after AMP injection (~0.5 mg/kg). In both animals, an AMP-only scan was acquired for comparison with h-DA scans having antagonist challenge.
Results Under b-DA conditions, both antagonists produced moderate increases in CBV (5% at peak for NNC, 6% for SCH) at high peak R-occ (NNC: 85%; SCH: 79%). Under h-DA conditions, both antagonists decreased CBV (NNC: -15%; SCH: -10%) after normalizing against the AMP-only response.
Conclusions These results imply that NNC112 and SCH23390 are D1 partial agonists as previously suggested (Sugamori-1998), not antagonists as widely assumed. The partial agonist properties of SCH23390 redefine the prototypical ‘D1 antagonist’ and casts new light on the potential of D1 as a therapeutic target.
Research Support R01MH100350, R21NS072148, T32EB013180