Dopamine antagonist modulation of amphetamine response as detected using pharmacological MRI

Functional magnetic resonance imaging (fMRI), employing BOLD-contrast, was used to measure changes in regional brain activation following amphetamine administration, either alone or after pre-treatment with the dopamine D1 receptor antagonist SCH23390, or the dopamine D2 receptor antagonist, sulpiride, in anaesthetised rat. After obtaining baseline data, rats (n=8) were given amphetamine (3 g/kg i.v) and volume data sets collected for 90 mins. Acute amphetamine challenge caused widespread increases in BOLD signal intensity in many subcortical structures with rich dopaminergic innervation, with decreases in BOLD contrast observed in the superficial layers of the cortex. Pretreatment with SCH23390 (n=8, 0.5 mg/kg, i.v) substantially attenuated the increases in BOLD activity in response to amphetamine, with lesser effects on the amphetamine-evoked decreases in BOLD signal. In contrast, sulpiride (n=8, 50 mg/kg, i.v) predominantly blocked the decrease in BOLD signal, having a smaller effect on the increases in BOLD signal. In summary, these data are supportive of the notion that different dopamine receptor types are responsible for separate components of the full amphetamine response. Furthermore the utility of BOLD contrast fMRI as a means of characterising the mechanisms of drug action in the whole brain has been demonstrated. Such studies may be of particular use for investigation of localised action and interaction of different dopaminergic agents.