Selective dopamine D(3) 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 D(3) subtype of the D(2) 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 D(3) 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 D(3) 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 D(3) receptor antagonism is consistent with this receptor mediating an inhibitory action on brain activity following a dopaminergic stimulus.
Schwarz
Adam
A
Department of Neuroimaging, Centre of Excellence for Drug Discovery, Psychiatry, GlaxoSmithKline Medicines Research Centre, 37135 Verona, Italy. adam.j.schwarz@gsk.com
Gozzi
Alessandro
A
Reese
Torsten
T
Bertani
Simone
S
Crestan
Valerio
V
Hagan
Jim
J
Heidbreder
Christian
C
Bifone
Angelo
A
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3; D019966:Substance-Related Disorders / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
D000662:Amphetamines; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D009570:Nitriles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines