Abstract
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.
Footnotes
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This work was supported by Science Foundation Ireland-Enterprise Ireland, the Stanley Medical Research Institute, and a Galen Fellowship from the Irish Brain Research Foundation, in the Institute of Biopharmaceutical Sciences under the Higher Education Authority's Programme for Research in Third Level Institutions (to J.L.W.) and by the Peter Jay Sharp Foundation Grants MH 40899, DA 10044, and MH 39327 (to P.G.).
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doi:10.1124/jpet.104.068957.
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ABBREVIATIONS: DARPP-32, dopamine- and adenosine 3′,5′-monophosphate-regulated phosphoprotein of 32 kDa; PP-1, protein phosphatase-1; PKA, protein kinase A; RU 24213, N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine; YM 09151-2, cis-N-[1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide.
- Received March 26, 2004.
- Accepted May 12, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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