Effect of the selective dopamine D3 receptor antagonist SB-277011-A on regional c-Fos-like expression in rat forebrain.
SB-277011-A is a dopamine D(3) receptor antagonist that exhibits over 100-fold selectivity over dopamine D(2) receptors and a broad spectrum of other receptor, ion channels, and enzymes. We employed c-Fos immunohistochemistry to characterise the functional neuroanatomical effects of acute administration of SB-277011-A and observed a time-dependent increase in the density of c-Fos-like positive nuclei in rat forebrain with maximal effects observed 2 h post-dose. The relative influence of the different brain regions on the overall effect of SB-277011-A was ranked by partial least squares discriminant analysis loadings plot which indicated that sites within the nucleus accumbens exerted the greatest influence on the separation of the vehicle and SB-277011-A treatment groups. At the 2 h time-point, c-Fos-like expression was shown to be significantly elevated (p<0.05) in the core and shell of the nucleus accumbens, at both rostral and caudal levels, and in the lateral septum. No significant changes were detected in the caudate nucleus (lateral or medial) or in the cingulate, infralimbic prefrontal, or somatosensory cortices. The capacity of SB-277011-A to trigger immediate early gene expression in these limbic regions of rat brain adds to a growing consensus of the potential utility of dopamine D(3) receptor antagonism in psychiatric disorders including schizophrenia and drug dependency.
Southam
Eric
E
Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park North, Harlow, Essex, CM19 5AW, UK. eric_2_southam@gsk.com
Lloyd
Andrew
A
Jennings
Carol A
CA
Cluderay
Jane E
JE
Cilia
Jackie
J
Gartlon
Jane E
JE
Jones
Declan N C
DN
D000818:Animals; D007150:Immunohistochemistry; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D013997:Time Factors
D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines