Topographical Assessment of Ethological and Dopamine Receptor Agonist-Induced Behavioral Phenotype in Mutants with Congenic DARPP-32 ‘Knockout’

Abstract

Congenic (10 backcrosses into C57BL/6J) mutants with targeted gene deletion of DARPP-32, a neuronal phosphoprotein regarded as an essential mediator of the biological effects of dopamine (DA), were assessed phenotypically using an ethologically based approach that resolves all topographies of behavior in the mouse repertoire. Over initial exploration, female, but not male, DARPP-32 mutants evidenced increased locomotion and decreased grooming, while a decrease in rearing seated was evident in mutants of both genders; continuing assessment over several hours did not reveal additional phenotypic effects. Following challenge with the nonselective DA receptor agonist apomorphine, low doses were associated with reduced levels of sniffing, grooming, total rearing, and rearing seated in DARPP-32 mutants relative to wildtypes; this would suggest some role for DARPP-32 in mediating the biological effects of presynaptic D 2 -like autoreceptor or inhibitory postsynaptic D 2 -like receptor activation. Following challenge with higher doses, while stereotyped sniffing and locomotion with chewing was largely unaltered, the additional murine response of Straub tail was essentially abolished in DARPP-32 mutants, indicating some specific involvement of DARPP-32 in mediating this topography of behavior; additionally, there were overall reductions in levels of sniffing, total rearing, rearing seated, and grooming in DARPP-32 mutants that were unrelated to the dose of apomorphine administered, indicating broader topographical effects following the stress of the injection procedure relative to more naturalistic conditions. The developmental absence of DARPP-32 following targeted gene deletion appears to be associated with compensatory processes that maintain certain topographies of spontaneous and agonist-induced DAergic function, while other topographies remain impaired.

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

“…In initial studies with dopaminergic agents, the acute stimulatory response to the nonselective, indirect dopaminergic agonist amphetamine, and catalepsy induced by lower but not higher doses of the antipsychotic raclopride, seemed reduced in DARPP-32 mutants (Fienberg and Greengard, 2000;Svenningsson et al, 2003). In our own studies (Nally et al, 2003), we reported ethologically based alterations in the topography of behavioral responsivity to the nonselective dopamine receptor agonist apomorphine in DARPP-32 mutants. However, the role of DARPP-32 in mediating distinct topographies of D 2 -like-mediated behavior, as induced by selective stimulation of D 2 -like receptors and attenuated by selective antagonism thereof, remains to be clarified.…”

“…On this basis, we have recently studied congenic DARPP-32 mutants at an ethological level, with the resultant ethogram revealing only subtle phenotypic effects at the level of spontaneous behavior (Nally et al, 2003). In initial studies with dopaminergic agents, the acute stimulatory response to the nonselective, indirect dopaminergic agonist amphetamine, and catalepsy induced by lower but not higher doses of the antipsychotic raclopride, seemed reduced in DARPP-32 mutants (Fienberg and Greengard, 2000;Svenningsson et al, 2003).…”

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

“…No statistically significant differences were found in gait analysis or rotarod testing in MUT mice examined at 10-11 or 17-21 wk (SI Text). Separate cohorts of WT and MUT animals were assessed at two different age ranges by using a standardized ethological assay (22)(23)(24). At 6-9 wk, there was an increase in total rearing and a decrease in sifting and chewing (Fig.…”

Disruption of orofacial movement topographies in congenic mutants with dopamine D5 but not D4 receptor or DARPP-32 transduction ‘knockout’

“…Topographical responses to A 68930 were unaltered, with an effect of genotype in the absence of any dose × genotype interaction indicating an overall increase in horizontal jaw movements in DARPP-32 mutants that was unrelated to treatment; this echoes a similar increase in general topographies of behaviour in DARPP-32 mutants that we have reported previously using an ethologically based paradigm, and which may reflect a subtle action of the stress of the injection procedure to reveal phenotypic effects not present under other conditions (Nally et al, 2003(Nally et al, , 2004.…”

“…and analysed using repeated-measures analysis of variance (ANOVA) after square-root transformation in the absence of appropriate non-parametric techniques; univariate comparisons were made where overall effects on ANOVA were significant, using Student's t-test or Mann-Whitney U-test after Kruskal-Wallis analysis as appropriate Ross et al, 2000;Tomiyama et al, 2001Tomiyama et al, , 2002Tomiyama et al, , 2004Makihara et al, 2004;Nally et al, 2003Nally et al, , 2004O'Sullivan et al, 2004O'Sullivan et al, , 2005. Fienberg et al, 1998;Nally et al, 2003Nally et al, , 2004.…”