QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.068957v1 310/3/1281    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nally, R. E. Articles by Waddington, J. L. Search for Related Content PubMed PubMed Citation Articles by Nally, R. E. Articles by Waddington, J. L.

BEHAVIORAL PHARMACOLOGY

Ethologically Based Resolution of D₂-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

Departments of Clinical Pharmacology (R.E.N., J.L.W.) and Biochemistry (O.T., D.T.C.), and Institute of Biopharmaceutical Sciences (R.E.N., J.L.W., O.T., D.T.C.), Royal College of Surgeons in Ireland, Dublin, Ireland; School of Mathematics, Dublin Institute of Technology, Dublin, Ireland (A.K.); and Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York (A.A.F., P.G.)

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.

Address correspondence to: Dr. John L. Waddington, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland. E-mail: jwadding{at}rcsi.ie