RT Journal Article
SR Electronic
T1 Ethologically Based Resolution of D<sub>2</sub>-Like Dopamine Receptor Agonist-versus Antagonist-Induced Behavioral Topography in Dopamine- and Adenosine 3′,5′-Monophosphate-Regulated Phosphoprotein of 32 kDa “Knockout” Mutants Congenic on the C57BL/6 Genetic Background
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1281
OP 1287
DO 10.1124/jpet.104.068957
VO 310
IS 3
A1 Nally, Rachel E.
A1 Kinsella, Anthony
A1 Tighe, Orna
A1 Croke, David T.
A1 Fienberg, Allen A.
A1 Greengard, Paul
A1 Waddington, John L.
YR 2004
UL http://jpet.aspetjournals.org/content/310/3/1281.abstract
AB Given the critical role of dopamine- and adenosine 3′,5′-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32) in the regulation of dopaminergic function, DARPP-32-null mutant mice congenic on the inbred C57BL/6 strain for 10 generations were examined phenotypically for their ethogram of responsivity to the selective D2-like receptor agonist RU 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine) and the selective D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide), using procedures that resolve all topographies of behavior in the natural repertoire. After vehicle challenge, levels of sniffing and rearing seated were reduced in DARPP-32 mutants; the injection procedure seems to constitute a “stressor” that reveals phenotypic effects of DARPP-32 deletion not apparent under natural conditions. Topographical effects of 0.3 to 10.0 mg/kg RU 24213, primarily induction of sniffing and ponderous locomotion with accompanying reductions in rearing, grooming, sifting and chewing, were not altered to any material extent in DARPP-32-null mice. However, topographical effects of 0.005 to 0.625 mg/kg YM 09151-2, namely, reduction in sniffing, locomotion, rearing, grooming, and chewing but not sifting, were essentially absent in DARPP-32 mutants. Thus, the D2-like receptor agonist-mediated ethogram was essentially conserved, whereas major elements of the corresponding D2-like receptor antagonist-mediated ethogram were essentially absent in DARPP-32-null mice. This suggests some relationship between 1) extent of tonic dopaminergic activation of DARPP-32 mechanisms and 2) compensatory mechanisms consequent to the developmental absence of DARPP-32, which may emerge to act differentially on individual elements of the DARPP-32 system. Critically, the present data indicate that phenotypic effects of a given gene deletion using an agonist acting on the system disrupted cannot be generalized to a corresponding antagonist, and vice versa. The American Society for Pharmacology and Experimental Therapeutics