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

摘要

Given the critical role of dopamine- and adenosine 3',5'-mono-phosphate-regulated phosphoprotein of 32 kDa (DARPP-32) in the regulation of dopaminergic function,DARPP-32-null mutant mice congenic on the inbred C57BL76 strain for 10 generations were examined phenotypically for their ethogram of responsiv-ity to the selective D_2-like receptor agonist RU 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylarnine) and the selective D_2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-meth-ylaminobenzamide),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 D_2-like receptor agonist-mediated ethogram was essentially conserved,whereas major elements of the corresponding D_2-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.