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BEHAVIORAL PHARMACOLOGY
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.)
Received March 26, 2004; accepted May 12, 2004.
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Abstract |
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; Di Chiara, 2002; Sidhu et al., 2003). The construction of mutants with targeted gene deletion ("knockout") of each individual dopamine receptor subtype has provided an important approach to addressing this issue (Sibley, 1999; Waddington et al., 2001). However, elucidation of the cellular mechanisms by which events at these subtypes are transducted to ultimately influence behavior presents yet greater challenges.
Integral to these processes is dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32). In response to dopamine, this neuronal phosphoprotein is converted into a potent inhibitor of protein phosphatase-1 (PP-1; Hemmings et al., 1984), a critical determinant of the state of phosphorylation and hence the physiological activity of an array of neuronal phosphoproteins, including neurotransmitter receptors, ion channels, and transcription factors. At this cellular level, D1-like receptors activate the phosphorylation of DARPP-32, via adenylyl cyclase and protein kinase A (PKA), to inhibit PP-1, whereas D2-like receptors dephosphorylate DARPP-32, both via inhibition of PKA and through an adenylyl cyclase-independent pathway, to disinhibit PP-1; thus, DARPP-32 is regarded as an essential mediator of the biological effects of DA (Greengard et al., 1999). To investigate further its functional role in the absence of specific pharmacological tools, DARPP-32-null mice have been constructed (Fienberg et al., 1998). The cellular phenotype of these mutants confirms deletion of functional DARPP-32 in the absence of changes in the number of D1- or D2-like receptors (Fienberg and Greengard, 2000; Svenningsson et al., 2000).
In relation to dopamine-mediated function, studies in mutants present both opportunities and challenges. At the level of behavior, assessment of otherwise undifferentiated "activity" in terms of photobeam interruptions, or observational assessments restricted to operational definitions of gross elements of behavior, over limited time frames, can obscure critical phenotypic effects; these can be addressed by application of ethologically based approaches that resolve all topographies of behavior within the mouse repertoire (i.e., specification of its ethogram) over the prolonged time course of exploration of and subsequent habituation to its environment (Waddington et al., 2001; McNamara et al., 2003). Additionally, the mixed (129/Sv x C57BL/6) genetic background, on which essentially all dopamine-related knockouts have been constructed and examined to date, leaves open the possibility that phenotypic effects might reflect not only the entity deleted but also variations in that genetic background (Kelly et al., 1998; Phillips et al., 1999; Waddington et al., 2001); this potential problem can be overcome in substantial part by repeated back-crossing onto a single strain, usually C57BL/6, to attain essential congenicity (Banbury Conference, 1997; Tomiyama et al., 2002; McNamara et al., 2002, 2003).
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). 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 D2-like-mediated behavior, as induced by selective stimulation of D2-like receptors and attenuated by selective antagonism thereof, remains to be clarified.
Described here are experiments to resolve ethologically the congenic DARPP-32 mutant phenotype after such specific pharmacological manipulation of D2-like receptor systems. These studies use procedures that both address the abovementioned methodological concerns and, additionally, allow systematic comparison with the phenotype of congenic D1, D2, and D3 receptor knockouts, which we have determined using these same procedures (Clifford et al., 2001; McNamara et al., 2002, 2003). They contrast the effects of the selective D2-like receptor agonist RU 24213 (Euvrard et al., 1980; Clifford et al., 2000, 2001; McNamara et al., 2002, 2003) with those of the selective D2-like receptor antagonist YM 09151-2 (Niznik et al., 1985; McNamara et al., 2003) to evaluate shifts in the topography of behavior mediated through D2-like receptors, consequent to the absence of DARPP-32.
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Materials and Methods |
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). In outline, the targeted gene deletion was constructed in 129/Ola-derived embryonic stem cells and male chimeras mated with C57BL/6J females to produce heterozygous mutants (DARPP-32+/-); these were then backcrossed into C57BL/6J for 10 generations to create a congenic DARPP-32-null line. Congenic, homozygous (DARPP-32--) and wild-type (DARPP-32+/+) breeding pairs were then transported to Dublin, where homozygous mutants were generated from homozygous mutant breeding pairs, whereas wild types were generated from wild-type breeding pairs; the genotype of all progeny was confirmed using PCR analysis of isolated tail DNA. Animals were housed in groups of four to five, with food and water available ad libitum, and maintained at 21 ± 1°C on a 12/12-h (8:00 AM on; 8:00 PM off) light/dark schedule. Young adult mice from litters of the same generational age were used in all studies. These studies were approved by the Research Ethics Committee of the Royal College of Surgeons in Ireland and were conducted under license from the Department of Health and Children in accordance with Irish legislation and the European Communities Council Directive 86/609/EEC for the care and use of experimental animals. Drugs. RU 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine; Aventis, Strasbourg, France) was dissolved in distilled water; YM 09151-2 [cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide; Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan] was dissolved in 0.1 N HCl and made up to volume with distilled water. Drugs and their respective vehicles were injected subcutaneously into the flank in a volume of 2 ml/kg.
Behavioral Assessment. On experimental days mice were removed from their home cage and placed individually in clear glass observation cages (36 x 20 x 20 cm). Mice were allowed to habituate to observation cages for a period of 3 h, to limit topographies of initial exploration before comparison of D2-like receptor agonist and antagonist effects.
Behavioral assessments were carried out using a rapid time-sampling behavioral checklist technique, in a manner similar to that described previously for congenic D1, D2, and D3 receptor mutants given RU 24213 and/or YM 09151-2 (Clifford et al., 2001; McNamara et al., 2002, 2003) and for DARPP-32 mutants given apomorphine (Nally et al., 2003). Immediately after drug challenge, each of 10 randomly allocated mice was observed individually for 5-s periods at 1-min intervals over 15 consecutive minutes using an extended, ethologically based behavioral checklist. This allowed the presence or absence of the following individual behaviors (occurring alone or in combination) to be determined in each 5-s period: sniffing (flaring of nostrils with movement of vibrissae); locomotion (coordinated movement of all four limbs producing a change in location); ponderous locomotion, a "plodding" variant induced in mice by D2-like receptor agonists that differs from normal, fluid ambulation (Clifford et al., 1999, 2000, 2001; McNamara et al., 2002, 2003); total rearing (rearing of any form); rearing seated (front paws reaching upwards with hind limbs on floor in sitting position); rearing free (front paws reaching upwards away from any cage wall while standing on hind limbs); rearing to wall (front paws reaching upwards onto or toward a cage wall while standing on hind limbs); sifting (characteristic sifting movements of the front paws through bedding material on cage floor); grooming (of any form); intense grooming (characteristic pattern of grooming of the snout and then the face with the forepaws, followed by vigorous grooming of the hind flank or anogenital region with the snout); chewing (chewing movements directed onto cage bedding and/or fecal pellets without consumption); stillness (motionless, with no behavior evident).
This cycle of assessment by behavioral checklist over a 15-min period (0-15 min) was repeated twice (20-35 and 40-55 min). For evaluation of agonist/antagonist-induced behavior, mice were used on two occasions only, separated by a drug-free interval of at least 1 wk; on each occasion, mice were allocated randomly to one of the various treatments. All assessments were made by an observer who was unaware of genotype and treatment for each animal.
Data Analysis. For drug-related ethograms, the total "counts" for each individual topography of behavior was determined as the number of 5-s observation windows in which a given behavior was evident, summed over the initial 3 x 15 min (0-15, 20-35, and 40-55 min) cycle periods, and expressed as means ± S.E.M. Counts for individual behaviors in relation to drug dose and genotype were analyzed using analysis of variance after square root transformation (Ross et al., 2000; McNamara et al., 2002, 2003; Tomiyama et al., 2002, 2004; Nally et al., 2003), to allow examination of interaction effects in the absence of nonparametric techniques for interaction terms, followed by Student's t test.
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Results |
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). Ethogram of Responsivity to RU 24213. Administration of RU 24213 (0.3-10.0 mg/kg; Figs. 1 and 2) exerted a biphasic effect on sniffing: there was inhibition at lower doses and stimulation at higher doses (effect of dose, F4,70 = 9.19; p < 0.001); overall levels of sniffing were reduced in congenic DARPP-32-null mice throughout the dose range (effect of genotype, F1,70 = 11.44; p < 0.005; no dose x genotype interaction); in particular, sniffing was reduced in vehicle-treated DARPP-32 mutants (p < 0.05). Rearing topographies were inhibited by increasing doses of RU 24213, among which rearing seated was the primary component (effect of dose, F4,70 = 3.18; p < 0.05); overall levels of rearing seated were reduced in DARPP-32 mutants throughout the dose range (effect of genotype, F1,70 = 14.75; p < 0.001; no dose x genotype interaction); in particular, rearing seated was reduced in vehicle-treated DARPP-32-null mice (p < 0.01). Levels of rearing free and rearing to wall were too low for meaningful analysis (data not shown). These doses of RU 24213 exerted a polyphasic effect on locomotion: there was inhibition of locomotion at lower doses, which reversed to normal levels at an intermediate dose, before diminishing again at the highest dose with transition to ponderous locomotion (effect of dose, F4,70 = 7.90; p < 0.001); overall levels of locomotion were reduced in DARPP-32 mutants throughout the dose range (effect of genotype, F1,70 = 4.35; p < 0.05; no dose x genotype interaction); ponderous locomotion was induced in a dose-dependent manner that did not differ between the genotypes (effect of dose, F4,70 = 11.28; p < 0.001; no effect of genotype or dose x genotype interaction).
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Grooming topographies were inhibited by increasing doses of RU 24213 (effect of dose, F4,70 = 12.72; p < 0.001), and this effect did not differ between the genotypes (no effect of genotype or dose x genotype interaction); levels of intense grooming syntax were too low for meaningful analysis. Sifting was inhibited similarly (effect of dose, F4,70 = 10.09; p < 0.001), although this inhibition was diminished in DARPP-32 mutants at an intermediate dose of RU 24213 (dose x genotype interaction, F4,70 = 2.68; p < 0.05). Chewing was inhibited by RU 24213 throughout this dose range, in a manner that did not differ between the genotypes (effect of dose, F4,70 = 10.94; p < 0.001; no effect of genotype or dose x genotype interaction).
These doses of RU 24213 exerted a biphasic effect on stillness: because this category integrates the absence of the above-mentioned topographies of behavior, it was increased at lower doses and decreased at higher doses (effect of dose, F4,70 = 9.76; p < 0.001); in keeping with overall reductions in levels of sniffing, rearing seated and locomotion, overall levels of stillness were increased in DARPP-32 mutants throughout the dose range (effect of genotype, F1,70 = 13.69; p < 0.001; no dose x genotype interaction); in particular, stillness was increased in vehicle-treated DARPP-32 mutants (p < 0.05), which paralleled decreased levels of sniffing and rearing seated under this condition.
General Parameters: YM 09151-2 Challenge. On examining 20 female congenic DARPP-32-null mice, mean body weight (22 ± 1 g; mean age 176 ± 10 days) did not differ relative to 20 female wild types (23 ± 1 g; mean age 188 ± 6 days).
Ethogram of Responsivity to YM 09151-2. In wild types, YM 09151-2 (0.005-0.625 mg/kg; Figs. 3 and 4) readily and dose dependently reduced sniffing and rearing topographies, among which rearing seated was the primary component, but it was without effect in DARPP-32-null mice (sniffing: effect of dose, F4,70 = 8.35, p < 0.001; dose x genotype interaction, F4,70 = 7.82, p < 0.001; rearing seated: effect of dose, F4,70 = 10.57, p < 0.001; dose x genotype interaction, F4,70 = 5.21, p < 0.005); there were reduced levels of sniffing and rearing seated in vehicle-treated DARPP-32 mutants (p < 0.05), which, because of this lack of effect of YM 09151-2, endured across its dose range to ultimately exceed (p < 0.05) that in wild types receiving higher doses. Levels of rearing free and rearing to wall were too low for meaningful analysis (data not shown). There was also a dose-dependent reduction in locomotion, which did not differ between the genotypes (effect of dose, F4,70 = 4.16, p < 0.005; no effect of genotype or dose x genotype interaction); ponderous locomotion was absent.
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In wild types, YM 09151-2 readily and dose dependently reduced grooming topographies, but it was without effect in DARPP-32-null mice, such that overall levels in mutants exceeded those in wild types (effect of dose, F4,70 = 10.51, p < 0.001; effect of genotype, F1,70 = 4.87, p < 0.05; dose x genotype interaction, F4,70 = 3.32, p < 0.05); levels of intense grooming syntax were too low for meaningful analysis. Low levels of sifting showed an overall increase in DARPP-32 mutants (effect of genotype, F1,70 = 7.47, p < 0.01; no effect of dose or dose x genotype interaction), whereas low levels of chewing was unaltered (no effect of genotype, dose or dose x genotype interaction).
These doses of YM 09151-2 readily and dose dependently increased levels of stillness in wild types, but they were without effect in DARPP-32-null mice (effect of dose, F4,70 = 8.88, p < 0.001; dose x genotype interaction, F4,70 = 5.51, p < 0.005). DARPP-32 mutants evidenced an increased level of stillness relative to wild types after vehicle treatment (p < 0.05) which paralleled their decreased levels of sniffing and rearing seated, and a decreased level of stillness relative to wild types after treatment with high doses of YM 09151-2 (p < 0.01), which paralleled their increased levels of sniffing and rearing seated.
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; Clifford and Waddington, 1998); conversely, stillness was decreased by higher doses of RU 24213, in keeping with increases in the above-mentioned topographies of behavior via stimulation of postsynaptic D2-like receptors, which synergize with endogenous dopaminergic transmission through D1-like receptors in their genesis (Waddington et al., 1994, 1995). This profile is in accordance with our previous studies in wild type counterparts of congenic D1 (McNamara et al., 2003), D2 (Clifford et al., 2001), and D3 (McNamara et al., 2002) receptor mutants.
These topographical effects of RU 24213 were not altered to any material extent in DARPP-32-null mice, which thus seemed to evidence an essentially unaltered ethogram in response to selective stimulation of D2-like receptors in the absence of DARPP-32. Activation of D2-like receptors activates the dephosphorylation of DARPP-32 at Thr-34 and disinhibition of PP-1 via two synergistic mechanisms: 1) inhibition of D1-like receptor-mediated stimulation of adenylyl cyclase and PKA; and 2) increase in intracellular calcium, which activates calcium-dependent protein phosphatase-2B (Greengard, 2001). Because the phosphorylation state of DARPP-32 at Thr-34 and the degree of inhibition of PP-1 are critical regulators of dopamine-mediated function (Greengard et al., 1999; Greengard, 2001), the present "normal" D2-like receptor agonist-mediated ethogram in the absence of DARPP-32 seems paradoxical. Although explanations in terms of mutant genetic background, insensitivity of the ethologically based techniques used, or overinterpretation of the functional role of DARPP-32 do not seem likely, other possibilities such as the operation of compensation processes consequent to the developmental absence of DARPP-32 should be considered; these issues have been discussed in detail elsewhere (Nally et al., 2003). Also, as in all such mutant studies, some influence of modifier genes associated with the DARPP-32 locus may carry with the mutation over repeated back-crosses to influence the resultant phenotype.
However, it must be emphasized that targeted gene deletion of DARPP-32 is not phenotypically "silent". In particular, after vehicle challenge levels of sniffing and rearing seated were reduced, and levels of stillness increased, in DARPP-32 mutants; yet under nonchallenge conditions, such mutants evidenced little or no change in these topographies of behavior (Nally et al., 2003). It seems that the injection procedure constitutes a "stressor" that is able to reveal topographically specific phenotypic effects of DARPP-32 deletion that are not apparent under more naturalistic conditions; thus, DARPP-32, or at least the developmental absence of DARPP-32, may interact importantly with the biological substrate(s) of this and potentially other stress-related processes in the regulation of individual topographies of behavior. Acute, unavoidable stress is associated with increased release of dopamine (Deutch and Roth, 1990; Kalivas and Duffy, 1995). This may be a component of the vehicle-challenge aspect of the DARPP-32-null phenotype and of previously reported phenotypic effects of DARPP-32 deletion such as reduction in otherwise undifferentiated "repetitive movements" in response to the nonselective dopamine-releasing agent amphetamine (Svenningsson et al., 2003).
Furthermore, there was an overall reduction in levels of sniffing, rearing seated, and locomotion in DARPP-32 mutants that was unrelated to the dose of RU 24213 administered and that echoes the similar effect noted in our previous study with apomorphine (Nally et al., 2003). This emphasizes that the phenotype of DARPP-32 deletion at the level of behavior is accentuated under stressful relative to nonstressful conditions, in a topographically specific manner, and is manifest even under conditions of D2-like receptor agonist-induced activation. It should be noted that the above-mentioned phenotypic effects were assessed in female mutants. In our initial studies on the phenotype of DARPP-32-null mice at the level of the topography of spontaneous behavior, gender-specific effects were encountered. As these related to phenotypic effects expressed in females but not in males (Nally et al., 2003), our previous drug challenge studies with apomorphine and the present studies with RU 24213 and YM 09151-2 used females. It would be necessary to conduct similar drug challenge studies in males before such findings could be generalized unequivocally across the genders.
However, a yet greater paradox is apparent. Whereas this D2-like receptor agonist-mediated ethogram was essentially conserved, the corresponding D2-like receptor antagonist-mediated ethogram was altered substantively in the absence of DARPP-32; this echoes in part a previous note that catalepsy induced by lower, but not higher, doses of the D2-like receptor antagonist raclopride seemed reduced in DARPP-32 mutants (Feinberg et al., 1998). Here, the ethogram of the selective D2-like receptor antagonist YM 09151-2 to readily reduce sniffing, rearing seated, and grooming in wild types, as described previously for wild-type counterparts of congenic D1 mutants (McNamara et al., 2003), was essentially absent in DARPP-32 mutants; these effects seemed topographically specific, in that locomotion evidenced an intermediate phenotype, whereas low levels of chewing and sifting evidenced an alternative phenotype. In particular, after vehicle challenge levels of sniffing and rearing seated were again reduced and levels of stillness were increased in DARPP-32 mutants; these altered baseline levels remained entirely uninfluenced by pretreatment with any dose of YM 09151-2.
How might this paradox be resolved? As for the majority of such studies, although RU 24213 and YM 09151-2 are recognized as "selective" D2-like receptor agonists and antagonists, respectively (see Introduction), we cannot exclude incontrovertibly some influence from as yet unknown properties of these agents. More specifically, for the D2-like receptor agonist-mediated ethogram to be essentially conserved but with the major elements of the corresponding D2-like receptor antagonist-mediated ethogram essentially absent in DARPP-32-null mice argues against explanation in terms of a unitary compensatory mechanism consequent to the developmental absence of DARPP-32. Rather, this profile suggests some relationship to extent of tonic dopaminergic activation of DARPP-32-related mechanisms. It has been argued that in vivo DARPP-32 phosphorylation is kept low by tonic dopaminergic activation of D2-like receptors (Svenningsson et al., 2000). Additionally, compensatory mechanisms consequent to the developmental absence of DARPP-32 (Nally et al., 2003) may emerge to varying extents to act differentially on individual elements of the DARPP-32/PP-1 regulatory system. An interaction between such processes might influence the phenotypic effect of DARPP-32 deletion toward reduced consequence for D2-like receptor agonist and greater consequence for D2-like receptor antagonist effects. Independent of such considerations, the present data indicate critically that the phenotypic effects of a given targeted gene deletion obtained using an agonist acting on the system disrupted cannot be generalized to a corresponding antagonist, and vice versa.
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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.
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
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, p < 0.05; 
