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Selective dopamine D3 receptor antagonist SB‐277011‐A potentiates phMRI response to acute amphetamine challenge in the rat brain

Dopamine (DA) receptors are a major target for drugs employed in the treatment of neuropsychiatric disorders such as schizophrenia and drug dependence. The D3 subtype of the D2 DA receptor family presents a particularly focal distribution in limbic brain areas known to be associated with cognitive and emotional functions. This study examined the modulation of brain activation induced by acute administration of amphetamine in the rat by the highly selective DA D3 receptor antagonist SB‐277011‐A using relative cerebral blood volume (rCBV) pharmacological MRI (phMRI). The acute administration of D‐amphetamine (1 mg/kg i.v.) produced a widespread rCBV response that was strongest in cortical regions. SB‐277011‐A (20 mg/kg i.p.) itself did not produce significant changes in rCBV, but potentiated the phMRI response to 1 mg/kg i.v. D‐amphetamine in a regionally specific manner, involving a number of structures outside the focal distribution of the D3 receptor. Potentiated regions included the accumbens, dorsal caudate putamen, islands of Calleja, thalamus, cingulate cortex, ventral tegmental area, dorsal Raphe nucleus, and ventral subiculum. The increased response following D3 receptor antagonism is consistent with this receptor mediating an inhibitory action on brain activity following a dopaminergic stimulus. Synapse 54:1–10, 2004. © 2004 Wiley‐Liss, Inc.