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Abstract. The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol ...
J Neural Transm (2010) 117:573–583 DOI 10.1007/s00702-010-0396-5

BASIC NEUROSCIENCES, GENETICS AND IMMUNOLOGY - ORIGINAL ARTICLE

Effects of repeated and acute aripiprazole or haloperidol treatment on dopamine synthesis in the dorsal striatum of young rats: comparison to adult rats Taleen Der-Ghazarian • Sergios Charntikov Fausto A. Varela • Cynthia A. Crawford • Sanders A. McDougall



Received: 30 December 2009 / Accepted: 17 March 2010 / Published online: 6 April 2010 Ó Springer-Verlag 2010

Abstract The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol alters dopamine (DA) synthesis characteristics in the dorsal striatum of young rats. To this end, rats received a daily pretreatment regimen of aripiprazole or haloperidol on postnatal days (PD) 10–20 and were tested 24 or 72 h later after an acute injection of vehicle, aripiprazole, haloperidol, or quinpirole (a D2 agonist). For comparison purposes, adult rats were pretreated with an 11-day regimen of saline or haloperidol on PD 70–80 and DA synthesis was measured after acute drug treatment on PD 83. Dorsal striatal DA synthesis was determined by measuring L-dihydroxyphenylalanine accumulation after NSD-1015 treatment. In a separate experiment, the ability of repeated drug treatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats 72 h after drug discontinuation. The major findings of this study were that: (a) acute treatment with haloperidol and aripiprazole increased DA synthesis while quinpirole reduced it; (b) pretreatment with haloperidol and aripiprazole blunted the synthesis-modulating effects of acutely administered dopaminergic drugs; and (c) DA synthesis of young and adult rats was affected in a qualitatively similar manner by DA agonist, antagonist, and partial agonist drugs. In conclusion, results from the present study suggest that

S. Charntikov Department of Psychology, University of Nebraska-Lincoln, 238 Burnett Hall, Lincoln, NE 68588, USA T. Der-Ghazarian  F. A. Varela  C. A. Crawford  S. A. McDougall (&) Department of Psychology, California State University San Bernardino, 5500 University Parkway, San Bernardino, CA 92407, USA e-mail: [email protected]

synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by the end of the preweanling period and DA synthesis declines to near basal levels during the course of repeated aripiprazole treatment. Keywords Aripiprazole  Haloperidol  DOPA accumulation  Autoreceptors  Ontogeny  Dorsal striatum

Introduction D2 partial agonist drugs (most notably aripiprazole) are widely administered to adults and, to an increasing extent, are being prescribed to children and adolescents. In the United States, for example, aripiprazole is used to treat pediatric bipolar disorder (Barzman et al. 2004; Biederman et al. 2005; Tramontina et al. 2009), autism and other pervasive developmental disorders (Stigler et al. 2004, 2009; Stachnik and Nunn-Thompson 2007; Marcus et al. 2009; Masi et al. 2009), Asperger’s syndrome (Stigler et al. 2009), Tourette’s syndrome (Murphy et al. 2005; Budman et al. 2008), tic disorder (Murphy et al. 2009), conduct disorder (Findling et al. 2003, 2009), and early-onset schizophrenia (Findling et al. 2008). Presumably, the therapeutic benefits of aripiprazole result from stabilizing dopamine (DA) functioning at both the pre- and postsynaptic DA receptor (Burris et al. 2002; Li et al. 2004; Feltenstein et al. 2007). In adult rodents, aripiprazole and other D2 partial agonists (e.g., terguride and preclamol) act as agonists at DA presynaptic receptors during states of low dopaminergic tone [e.g., after reserpine or c-butyrolactone (GBL) treatment], while functioning as antagonists at the same receptors during states of high dopaminergic tone (for reviews, see Clark et al. 1985a, b; Hoyer and Boddeke

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1993). In the latter situation (i.e., during periods of high dopaminergic tone), D2 partial agonists increase dorsal striatal DA synthesis and reverse the quinpirole-induced inhibition of DOPA accumulation (Hjorth et al. 1983; Kehr 1984; Clark et al. 1991; Svensson et al. 1991, 1993). In general, young rats appear to be affected by acute treatment with D2 partial agonists in a manner similar to adults. For example, aripiprazole and terguride reduce the dorsal striatal DA synthesis of young rats after reserpine and GBL treatment, while increasing DA synthesis under normosensitive conditions (Farley et al. 2006; Yoshida et al. 2006; In˜iguez et al. 2008). Interestingly, aripiprazole does not decrease DA synthesis in young rats experiencing highdose amphetamine withdrawal (In˜iguez et al. 2008), a manipulation that induces a state of low dopaminergic tone in adult rats (Orsini et al. 2001). In both young and adult rats, the effects of D2 partial agonists on presynaptic functioning have almost exclusively been studied after acute, rather than repeated, drug treatment (for an exception, see Nakai et al. 2003). This omission is significant because (a) young and adult animals often respond in either a quantitatively or qualitatively different manner after repeated treatment with DA-acting drugs (for reviews, see Spear 1979; Tirelli et al. 2003; Andersen 2005) and (b) pharmacotherapies involving partial DA agonists almost inevitably involve long-term drug administration. Therefore, the purpose of the present study was to assess the effects of repeated aripiprazole treatment on the synthesis-modulating autoreceptors of rats tested on postnatal day (PD) 21 or PD 23 [this age range corresponds to ‘‘childhood’’ in humans (Andersen 2003)]. More specifically, dorsal striatal DA synthesis was measured in rats given a pretreatment regimen of aripiprazole or haloperidol (a D2 receptor antagonist) on PD 10–20. After 24 or 72 h, rats were acutely injected with vehicle, aripiprazole, haloperidol, or quinpirole (a D2 receptor agonist) and DA synthesis was assessed 60 min later. For comparison purposes, adult rats were given a pretreatment regimen of saline or haloperidol on PD 70–80 and DA synthesis was assessed after an acute injection of aripiprazole, haloperidol, or quinpirole on PD 83. Because it is uncertain whether D2 partial agonists and antagonists up-regulate D2 receptors in young rats (see Friedhoff and Miller 1983; Kostrzewa and Saleh 1989), dorsal striatal D2 binding sites were measured on PD 23 and PD 83.

Materials and methods Subjects Subjects were 78 adult rats and 256 young rats of SpragueDawley descent (Charles River, Hollister, CA, USA), born

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and raised at California State University, San Bernardino (CSUSB). Litters were culled to ten pups at PD 3 (day of parturition is PD 0). Young rats (130 males and 126 females) were tested between PD 10–23, while adult rats (41 males and 37 females) were tested between PD 70–83. Young rats were kept with the dam except when undergoing experimental manipulation. Rats tested in adulthood were weaned at PD 25 and kept with same sex littermates. Both preweanling and postweanling rats were housed on racks in large polycarbonate maternity cages (56 9 34 9 22 cm) with wire lids and Tek-FreshÒ bedding (Harlan). Food and water were freely available. The colony room was maintained at 21–23°C and kept under a 12 h dark/light cycle. Subjects were treated according to the ‘‘Principles of laboratory animal care’’ (NIH publication No. 86-23, revised 1985) under a research protocol approved by the Institutional Animal Care and Use Committee of CSUSB. Drugs Haloperidol was dissolved in a minimal amount of glacial acetic acid and diluted with saline; whereas, quinpirole and 3-hydroxybenzylhydrazine hydrochloride (NSD-1015) were dissolved in saline. Aripiprazole was dissolved in (2hydropropyl)-b-cyclodextrin solution [HBC, 45% (w/v) solution in water]. All drugs were injected intraperitoneally (i.p.) at a volume of 2.5 ml/kg for young rats and 1 ml/kg for adult rats. With the exception of aripiprazole (Toronto Research Chemicals, Toronto, Canada), all drugs were purchased from Sigma (St. Louis, MO, USA). Dopamine synthesis experiments In Experiment 1, adult male and female rats (N = 64) were given a daily pretreatment injection of vehicle or haloperidol (1 mg/kg, i.p.) on PD 70–80. After a 72 h interval (i.e., on PD 83), rats from each pretreatment condition were further subdivided and injected with saline vehicle (n = 4 per group), HBC vehicle (n = 4), 1 mg/kg quinpirole (n = 8), 10 mg/kg aripiprazole (n = 8), or 1 mg/kg haloperidol (n = 8). After 30 min, all rats were injected with the DOPA decarboxylase inhibitor NSD-1015 (100 mg/kg, i.p.). Rats were killed by rapid decapitation 30 min after NSD-1015 treatment and their dorsal striata were removed on an ice-cold dissection plate and stored at -80°C until assay. In Experiment 2, young male and female rats (N = 96) were given a daily pretreatment injection of vehicle, aripiprazole (10 mg/kg, i.p.), or haloperidol (1 mg/kg, i.p.) on PD 10–20. After a 72 h interval (i.e., on PD 23), rats were injected with saline vehicle (n = 4 per group), HBC vehicle (n = 4), 1 mg/kg quinpirole (n = 8), 10 mg/kg

Effects of repeated and acute aripiprazole or haloperidol treatment

aripiprazole (n = 8), or 1 mg/kg haloperidol (n = 8) followed, 30 min later, by an injection of NSD-1015 (100 mg/kg). Experiment 3 (N = 136) was essentially the same as Experiment 2 except that: (a) an additional aripiprazole (3 mg/kg) pretreatment regimen was added to the protocol, (b) rats were tested 24 h after conclusion of the pretreatment regimen (i.e., on PD 21), and (c) the saline vehicle and HBC vehicle groups included eight subjects per group. In both experiments, young rats were killed by rapid decapitation 30 min after NSD-1015 treatment and their dorsal striata were removed on an ice-cold dissection plate and stored at -80°C until assay. DOPA accumulation was determined using high-performance liquid chromatography (HPLC). Frozen tissue samples were sonicated in 10 volumes of 0.1 N HClO4 and centrifuged at 20,000g for 30 min at 4°C. The supernatant was then filtered through a 0.22 lm centrifugation unit at 2,000g for 5 min at 4°C. Twenty microliters of the resulting extract was assayed for DOPA using a BreezeTM HPLC system (Waters, Milford, MA, USA), with a Coulochem II electrochemical detector (ESA, Chelmsford, MA, USA). The mobile phase consisted of 75 mM NaH2PO4, 1.4 mM 1-octane sulfonic acid, 10 mM ethylenediamine tetracetic acid (EDTA), and 10% acetonitrile (pH 3.1) and was pumped at a rate of 0.5 ml/min. D2 homogenate ligand binding experiments Young rats (N = 24) were given a daily pretreatment injection of vehicle, aripiprazole (10 mg/kg, i.p.), or haloperidol (1 mg/kg, i.p.) on PD 10–20, whereas adult rats (N = 14) were pretreated with vehicle or haloperidol (1 mg/kg, i.p.) on PD 70–80. After a 72 h interval (i.e., on PD 23 or PD 83), rats were killed by rapid decapitation and their dorsal striata were removed on an ice-cold dissection plate and stored at -80°C. On the day of assay, tissue was thawed on ice and striatal samples were homogenized in 100 volumes of 50 mM Tris–HCl buffer (pH 7.4) for approximately 20 s using a Brinkmann Polytron. The homogenates were centrifuged at 20,000g for 20 min. The pellet was resuspended in 100 volumes of the same buffer and centrifuged again at 20,000g for 20 min. The final pellet was suspended in approximately 30 volumes of buffer (pH 7.4). Protein concentrations for the final pellet were determined using the Bio-Rad Protein Assay, based on the method of Bradford (1976), with BSA as the standard. Tissue suspensions were added to duplicate tubes containing 50 mM Tris, 2 mM NaCl2, 5 mM KCl, 1 mM MgSO4, and 2 mM CaCl2 (pH 7.4) at a final volume of 1 ml. The tubes also included [3H]-spiperone (Amersham, Piscataway, NJ) in concentrations ranging from 0.5 to 2.5 nM. Nonspecific binding was determined in the

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presence of 10 lM (-)-sulpiride. Incubation time for the assay was 30 min at 37°C. Incubation was terminated by vacuum filtration over glass fiber filters (Whatman GF/B, pretreated with 0.1% polyethylenimine). Filters were washed twice with ice-cold Tris–HCl buffer and radioactivity was measured by liquid scintillation spectrometry. Statistical evaluation Assignment of subjects was random, with an approximately equal number of male and female rats being placed in each group. Individual groups typically included no more than one subject from a particular litter. When this procedure was not possible (i.e., analysis of body weights), a single litter mean was calculated from multiple littermates assigned to the same group (Holson and Pearce 1992; Zorrilla 1997). In the DA synthesis experiments, DOPA accumulation data (ng/mg wet weight tissue) were analyzed using two-way (pretreatment 9 test drug) analyses of variance (ANOVA). Saline and HBC vehicle had similar effects on DOPA accumulation, therefore data from the two vehicle groups were combined for each experiment. For presentation purposes, DOPA accumulation data were converted to percent of vehicle controls (see also Clark et al. 1991; Baldessarini et al. 1994). For the receptor ligand experiments, DA binding sites (Bmax) and affinity (KD) were determined using nonlinear regression with Prism (GraphPad Software, San Diego, CA, USA). Bmax and KD were analyzed using one-way (pretreatment) randomized block ANOVAs at each age. Each assay was treated as a separate block, thus the variance between assays was removed from the error term (Kirk 1982). Preliminary statistical analyses showed that DOPA accumulation data and receptor binding data did not vary according to sex of the animals, so the sex variable was excluded from later analyses. Body weight data from the pretreatment phase were combined across experiments and analyzed using three-way (sex 9 pretreatment 9 day) repeated measures ANOVAs for each age. Test day body weight data were analyzed using two-way ANOVAs (sex 9 pretreatment). Tukey tests were used for making post hoc comparisons (P \ 0.05).

Results Effects of haloperidol pretreatment on DOPA accumulation in adult rats after acute injection of saline, quinpirole, aripiprazole, or haloperidol: 72 h interval When collapsed across the pretreatment condition, an acute injection of quinpirole (1 mg/kg) caused a significant

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reduction in the dorsal striatal DOPA accumulation of adult rats, relative to saline/HBC controls (see Table 1) [test drug main effect, F(3, 56) = 204.27, P \ 0.001]. In contrast, acute treatment with aripiprazole (10 mg/kg) or haloperidol (1 mg/kg) increased DA synthesis, with haloperidol (370.4%) producing a greater increase in DOPA accumulation than aripiprazole (182.8%) (Tukey tests, P \ 0.05). Pretreating adult rats with haloperidol for 11 days (PD 70–80) caused an overall decrease in dorsal striatal DOPA accumulation (see Fig. 1, compare the upper and lower graphs) [Pretreatment main effect, F(1, 56) = 20.82, P \ 0.001]. More specifically, haloperidol-pretreated rats tested with saline/HBC or aripiprazole had significantly less DOPA accumulation than vehicle-pretreated rats tested with the same compounds [pretreatment 9 test drug interaction, F(3, 56) = 3.74, P \ 0.05]. In vehicle-pretreated adult rats (see upper graph, Fig. 1), both aripiprazole and haloperidol increased DOPA accumulation while quinpirole decreased it (Tukey tests, P \ 0.05). Among haloperidol-pretreated rats (see lower graph, Fig. 1), neither quinpirole or aripiprazole significantly affected DOPA accumulation, although an acute injection of haloperidol did increase dorsal striatal DOPA accumulation (Tukey tests, P \ 0.05). Effects of aripiprazole and haloperidol pretreatment on DOPA accumulation in young rats after acute injection of saline, quinpirole, aripiprazole, or haloperidol: 72 h interval When tested on PD 23, acute treatment with haloperidol caused a substantial elevation in dorsal striatal DOPA accumulation (see Table 2) [test drug main effect, F(3, 84) = 688.09, P \ 0.001]. A test day injection of aripiprazole produced a more modest increase in DOPA accumulation that was intermediate between the haloperidol and saline/HBC groups (Tukey tests, P \ 0.05). As was apparent in adult rats, an acute injection of quinpirole Table 1 Dorsal striatal DOPA accumulation of PD 83 rats (n = 16) tested with saline/HBC, quinpirole, aripiprazole, or haloperidol Test drug

DOPA accumulation

Saline/HBC

100.0% (±6) 64.0%a (±2)

Quinpirole (1 mg/kg) Aripiprazole (10 mg/kg)

182.8%a (±16)

Haloperidol (1 mg/kg)

370.4%ab (± 6)

Adult rats were pretreated with vehicle or haloperidol for an 11-day period that culminated 72 h prior to testing. Data are expressed as percent of saline/HBC controls, ±SEM a

Significantly different from saline/HBC group

b

Significantly different from aripiprazole group

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Fig. 1 Mean dorsal striatal DOPA accumulation of adult rats tested with saline/HBC (Sal/HBC), quinpirole (Quin), aripiprazole (Aripip), or haloperidol (Hal) 72 h after conclusion of an 11-day vehicle or haloperidol regimen. Data are expressed as percent of Vehicle-Saline/ HBC controls (±SEM). a P \ 0.05 versus similarly treated rats in the vehicle control condition (i.e., groups depicted in the upper graph); b P \ 0.05 versus the saline/HBC group

significantly reduced dorsal striatal DOPA accumulation on PD 23 (72 h after conclusion of vehicle, aripiprazole, or haloperidol pretreatment) (Tukey tests, P \ 0.05). DA synthesis was impacted by the 11-day (PD 10–20) pretreatment regimen. When compared to the vehicle-pretreated condition (see Fig. 2), test day DOPA accumulation was reduced by aripiprazole pretreatment and even further reduced by haloperidol pretreatment [pretreatment main effect, F(2, 84) = 23.14, P \ 0.001]. Specifically, aripiprazole- and haloperidol-pretreated rats tested with saline/ HBC had less striatal DOPA accumulation on PD 23 than vehicle-pretreated rats tested with saline/HBC [pretreatment 9 test drug interaction, F(6, 84) = 4.22, P \ 0.01]. Haloperidol-pretreated rats tested with aripiprazole or haloperidol also showed reduced DOPA accumulation when compared to similarly treated rats from the vehicle condition (Tukey tests, P \ 0.05). In vehicle-pretreated rats tested on PD 23 (see upper graph, Fig. 2), aripiprazole and haloperidol increased DOPA accumulation while quinpirole decreased it [pretreatment 9 test drug interaction, F(6, 84) = 4.22,

Effects of repeated and acute aripiprazole or haloperidol treatment

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Table 2 Dorsal striatal DOPA accumulation of PD 23 rats (n = 24) tested with saline/HBC, quinpirole, aripiprazole, or haloperidol Test drug

DOPA accumulation

Saline/HBC

100.0% (±4) 60.9%a (±1)

Quinpirole (1 mg/kg) Aripiprazole (10 mg/kg)

202.4%a (±12)

Haloperidol (1 mg/kg)

501.8%ab (±15)

Postnatal rats were pretreated with vehicle, aripiprazole, or haloperidol for an 11-day period that culminated 72 h prior to testing. Data are expressed as percent of saline/HBC controls, ±SEM a

Significantly different from saline/HBC group

b

Significantly different from aripiprazole group

P \ 0.01]. Among aripiprazole- and haloperidol-pretreated rats (see middle and lower graphs, Fig. 2), both aripiprazole and haloperidol increased DOPA accumulation relative to the saline/HBC group, while quinpirole was without significant effect (Tukey tests, P \ 0.05). Effects of aripiprazole and haloperidol pretreatment on DOPA accumulation in young rats after acute injection of saline, quinpirole, aripiprazole, or haloperidol: 24 h interval When tested on PD 21 (i.e., after a 24 h interval), acute treatment with aripiprazole and haloperidol increased DA synthesis in the dorsal striatum (see Table 3), with haloperidol pretreatment producing a greater enhancement in DOPA accumulation than aripiprazole [test drug main effect, F(3, 120) = 191.37, P \ 0.001]. Post hoc comparisons based on the omnibus ANOVA suggested that quinpirole did not affect DA synthesis; however, a supplemental ANOVA comparing only the quinpirole and saline/HBC groups showed that an acute injection of quinpirole significantly reduced DOPA accumulation to 75.8% of control values [test drug main effect, F(1, 64) = 5.23, P \ 0.05]. The 11-day drug pretreatment regimen altered DA synthesis on PD 21 (see Fig. 3), because aripiprazole (10 mg/kg) and haloperidol pretreatment caused an overall reduction in dorsal striatal DOPA accumulation [pretreatment main effect, F(3, 120) = 18.89, P \ 0.001]. When compared to vehicle-pretreated groups, the ability of acutely administered aripiprazole and haloperidol to enhance DOPA accumulation was attenuated in aripiprazole- and haloperidol-pretreated rats [pretreatment 9 test drug interaction, F(9, 120) = 4.71, P \ 0.001]. In vehicle-pretreated rats, acute treatment with haloperidol caused a substantial enhancement in DOPA accumulation (see upper graph, Fig. 3), while aripiprazole increased DOPA accumulation to a level that was intermediate between the haloperidol and saline/HBC groups

Fig. 2 Mean dorsal striatal DOPA accumulation of young rats tested with saline/HBC (Sal/HBC), quinpirole (Quin), aripiprazole (Aripip), or haloperidol (Hal) 72 h after conclusion of an 11-day vehicle, aripiprazole, or haloperidol regimen. Data are expressed as percent of Vehicle-Saline/HBC controls (±SEM). a P \ 0.05 versus similarly treated rats in the vehicle control condition (i.e., groups depicted in the upper graph); b P \ 0.05 versus the saline/HBC group

[pretreatment 9 test drug interaction, F(9, 120) = 4.71, P \ 0.001]. Among aripiprazole (3 or 10 mg/kg) and haloperidol-pretreated rats, acute administration of aripiprazole did not significantly enhance DOPA accumulation (relative to the saline/HBC group). An acute injection of haloperidol, on the other hand, increased DOPA accumulation regardless of pretreatment condition, but the magnitude of haloperidol’s effects were reduced in rats pretreated with either 10 mg/kg aripiprazole or 1 mg/kg haloperidol (Tukey tests, P \ 0.05). Although quinpirole

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Table 3 Dorsal striatal DOPA accumulation of PD 21 rats (n = 32– 40) tested with saline/HBC, quinpirole, aripiprazole, or haloperidol Test drug

DOPA accumulation

Saline/HBC

100.0% (±6) 75.8%a (±1)

Quinpirole (1 mg/kg) Aripiprazole (10 mg/kg)

146.4%a (±12)

Haloperidol (1 mg/kg)

333.6%ab (±17)

Postnatal rats were pretreated with vehicle, aripiprazole (3 or 10 mg/kg), or haloperidol for an 11-day period that culminated 24 h prior to testing. Data are expressed as percent of saline/HBC controls, ±SEM a

Significantly different from saline/HBC group

b

Significantly different from aripiprazole group

caused an overall reduction in DOPA accumulation, this effect was not apparent in rats pretreated with aripiprazole (3 or 10 mg/kg) or haloperidol. Effects of aripiprazole and/or haloperidol pretreatment on dorsal striatal D2 receptor binding in young and adult rats When assessed on PD 23, D2 binding site densities in the dorsal striatum were not significantly affected by a pretreatment regimen of either aripiprazole or haloperidol (see Table 4). Both compounds increased Bmax values to some degree, but this effect was not statistically significant (P = 0.14). D2 receptor affinity was not altered by aripiprazole or haloperidol pretreatment, with the overall KD value being 0.214 (±0.060) nM. In contrast, pretreating rats with haloperidol on PD 70– 80 caused a significant increase in dorsal striatal D2 binding site densities that were detectable on PD 83 (see Table 4) [test drug main effect, F(1, 6) = 15.08, P \ 0.01]. KD values were somewhat enhanced after haloperidol pretreatment, but this effect did not reach statistical significance (P [ 0.05). Effects of aripiprazole and haloperidol pretreatment on test day body weights of young and adult rats When measured on PD 21 or PD 23 (24 or 72 h after conclusion of the pretreatment regimen), body weights of aripiprazole- and haloperidol-pretreated rats did not differ significantly from vehicle controls (see Table 5). Male rats weighed significantly more than female rats on PD 21 [pretreatment main effect, F(1, 118) = 6.47, P \ 0.05], but not on PD 23 [pretreatment main effect, P = 0.15]. This discrepancy can be explained by the number of subjects tested at each age (PD 21, N = 120; PD 23, N = 74) and the resulting impact on statistical power. Body weights of rats tested on PD 83 were also not affected by the drug pretreatment regimen (see Table 6); however, male rats

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Fig. 3 Mean dorsal striatal DOPA accumulation of young rats tested with saline/HBC (Sal/HBC), quinpirole (Quin), aripiprazole (Aripip), or haloperidol (Hal) 24 h after conclusion of an 11-day vehicle, aripiprazole, or haloperidol regimen. Data are expressed as percent of Vehicle-Saline/HBC controls (± SEM). a P \ 0.05 versus similarly treated rats in the vehicle control condition (i.e., groups depicted in the upper graph); b P \ 0.05 versus the saline/HBC group

Effects of repeated and acute aripiprazole or haloperidol treatment Table 4 Effect of drug pretreatment regimen on D2 receptor density (fmol/mg protein, ±SEM) and affinity (nM, ±SEM) in the dorsal striatum of young and adult rats (n = 7–8 per group) Pretreatment

Bmax

579 Table 5 Effect of drug pretreatment regimen on body weights (g) of male and female young rats Pretreatment

Male

Female

KD PD 21 (N = 126)

PD 23

Vehicle

59.7 (±2)

58.3 (±1)

Vehicle

415.8 (±93)

0.205 (±0.07)

Aripiprazole (3 mg/kg)

60.8 (±2)

56.4 (±2)

Aripiprazole (10 mg/kg) Haloperidol (1 mg/kg)

561.0 (±176) 614.6 (±168)

0.230 (±0.07) 0.207 (±0.09)

Aripiprazole (10 mg/kg)

57.6 (±2)

55.8 (±2)

Haloperidol (1 mg/kg) xðV;A;A;HÞ

59.6 (±2)

54.9 (±1)

59.4 (±1)

56.4a (±1)

PD 83 Vehicle Haloperidol (1 mg/kg)

919.6 (±191)

0.100 (±0.03)

1250.8a (±243)

0.185 (±0.04)

PD 23 (N = 74) Vehicle

Rats were pretreated with vehicle, aripiprazole, or haloperidol for an 11-day period that culminated 72 h prior to testing a

Significantly different from vehicle-pretreated rats of the same age

weighed more than female rats on the test day [pretreatment main effect, F(1, 40) = 333.78, P \ 0.001]. In sum, repeated haloperidol and aripiprazole treatment did not alter the body weights of young or adult male and female rats.

66.8 (±3)

64.2 (±2)

Aripiprazole (10 mg/kg)

63.0 (±2)

60.5 (±2)

Haloperidol (1 mg/kg) xðV;A;HÞ

66.4 (±2)

62.8 (±2)

65.5 (±1)

62.5 (±1)

Postnatal rats were pretreated with vehicle, aripiprazole (3 or 10 mg/kg), or haloperidol for an 11-day period that culminated 24 h (i.e., on PD 21) or 72 h (i.e., on PD 23) prior to testing a

Significantly different from male rats of the same age

Table 6 Effect of drug pretreatment regimen on body weights (g) of male and female adult rats Pretreatment

Discussion In general, age-dependent differences in DA synthesis were not apparent when young and adult rats were injected with DA agonist, antagonist, or partial agonist drugs. In normosensitive young rats, the D2 agonist quinpirole decreased dorsal striatal DA synthesis to 57.1% of control values, whereas the D2 antagonist haloperidol increased DA synthesis to 405.8% of control values. The D2 partial agonist aripiprazole acted as a weak antagonist in vehiclepretreated young rats, with aripiprazole (10 mg/kg) increasing DA synthesis in a manner similar to haloperidol (but to only 202.5% of control values). Vehicle-pretreated adult rats showed the same general pattern of effects as young rats. That is, quinpirole decreased DA synthesis in the dorsal striatum of adult rats to 54.9% of control values, while aripiprazole and haloperidol increased DA synthesis by 192.2 and 327.8%, respectively (see also Magnusson et al. 1987; Svensson et al. 1991). Thus, these results suggest that synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by PD 21 and that acute treatment with aripiprazole increases DA synthesis in normosensitive rats during both the late preweanling period and in adulthood. Pretreatment with haloperidol or aripiprazole on PD 10–20 substantially altered the synthesis-modulating effects of acutely administered dopaminergic drugs. Two effects of repeated drug treatment were of special note: first, haloperidol and aripiprazole pretreatment affected DA synthesis in the same general manner, although haloperidol’s effects

PD 83 (N = 44) Male

Female

Vehicle

450.0 (±12)

267.8 (±6)

Haloperidol (1 mg/kg) xðV;HÞ

433.2 (±12)

273.9 (±6)

441.6 (±8)

270.9a (±4)

Adult rats were pretreated with vehicle or haloperidol for an 11-day period that culminated 72 h prior to testing a

Significantly different from male rats

were more robust. Second, repeated treatment with haloperidol and aripiprazole appeared to attenuate the acute effects of dopaminergic drugs. In young rats, the impact of repeated drug treatment was most prominent 24 h after drug discontinuation. For example, at the 24 h time point acute injections of quinpirole or aripiprazole did not alter the dorsal striatal DA synthesis of young rats. At the same 24 h time point, acutely administered haloperidol enhanced DA synthesis, but the effect was less robust in haloperidol- and aripiprazole-pretreated rats (i.e., when compared to vehiclepretreated controls). When DA synthesis characteristics were assessed 72 h after drug discontinuation two major findings were apparent. First, young rats pretreated with aripiprazole and, to a lesser extent, haloperidol showed some recovery at the 72 h time point (i.e., acutely administered DA-acting drugs were more likely to modulate DA systems in a normal or near-normal fashion). Second, young and adult rats were affected in a qualitatively similar manner by haloperidol pretreatment. In terms of young rats, basal as well as

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haloperidol- and aripiprazole-induced DA synthesis remained depressed 72 h after haloperidol pretreatment. Even so, some recovery from haloperidol pretreatment was apparent, since an acute injection of aripiprazole increased DA synthesis in the dorsal striatum of young rats after 72 h. Recovery was greater among young rats pretreated with aripiprazole, because acutely administered quinpirole decreased, while aripiprazole and haloperidol increased, dorsal striatal DA synthesis. In fact, the only impact of repeated aripiprazole treatment at the 72 h time point was a reduction in the basal DA synthesis of young rats. As mentioned above, DA synthesis characteristics of young and adult rats were affected in a qualitatively similar manner by drug pretreatment regimen. For example, basal and aripiprazole-induced DA synthesis of adult rats, like young rats, was still reduced 72 h after discontinuation of haloperidol pretreatment. Moreover, neither quinpirole or aripiprazole were able to significantly alter DA synthesis in haloperidol-pretreated adult rats. The finding that basal rates of DA synthesis were reduced after repeated haloperidol treatment has been reported before using both in vitro and in vivo techniques (Scatton et al. 1975; Stock et al. 1980; Lappalainen et al. 1990). However, it has also been reported that acute administration of apomorphine to haloperidol-pretreated rats causes a potentiated reduction in DA synthesis (Bannon et al. 1980; Reches et al. 1985), which is contrary to our results using quinpirole. In fact, a potentiated quinpirole-induced decline in DA synthesis did not occur after haloperidol pretreatment in either young or adult rats (i.e., the quinpirole and saline/HBC control groups did not differ at either age). In addition to measuring DA synthesis, the ability of haloperidol pretreatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats. In adults, an 11-day pretreatment regimen of haloperidol (1 mg/kg per day) caused a 36% increase in the density of D2 receptors in the dorsal striatum (see Table 4), an increase that is consistent with literature values (Huang et al. 1997; Szczepanik and Wilmot 1997; Vital et al. 1998; Geurts et al. 1999; Vasconcelos et al. 2003). Although not assessed in the present study, repeated treatment with aripiprazole (1.5 mg/kg, i.p.) also up-regulates D2 receptors in the dorsal striatum of adult rats (Seeman 2008). This finding contrasts with results from an earlier study showing that oral administration of aripiprazole (100 mg/kg 9 21 days) does not alter D2 receptor numbers (Inoue et al. 1997). In terms of young rats, repeated treatment with dopamine receptor antagonists has alternately been reported to upregulate dorsal striatal D2 receptors (Rosengarten and Friedhoff 1979; Kajiyama and Nomura 1981; Friedhoff and Miller 1983), induce a dramatic reduction in D2 receptors (Kostrzewa and Saleh 1989; Saleh and Kostrzewa 1989), or leave D2 receptor numbers unaffected (Coyle et al. 1981).

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These studies vary greatly in terms of methodology (route of drug administration, length of neuroleptic exposure, etc.), but the study with procedures (i.e., haloperidol was injected in an escalating dose from PD 15 to PD 24) most similar to ours found that haloperidol caused a 34.0% increase in the number of dorsal striatal D2 receptors on PD 28 (Kajiyama and Nomura 1981). In the present study, dorsal striatal D2 receptor densities of young rats were enhanced after both haloperidol (47.8%) and aripiprazole (34.9%) pretreatment, but the effects were not statistically significant due to excessive within-groups variance in two pairs of rats (P = 0.14). Unfortunately, these receptor ligand studies do not differentiate between pre- and postsynaptic receptors. In this regard, it is interesting that D2short mRNA levels, which may be predominately associated with presynaptic receptors (Centonze et al. 2003; Lindgren et al. 2003), are elevated in the dorsal striatum of adult rats after conclusion of a 16-day haloperidol regimen (Fishburn et al. 1994). In past studies, the ability of repeated haloperidol treatment to modulate DA synthesis is typically ascribed to receptor supersensitivity (Bannon et al. 1980; Stock et al. 1980; Stock and Kummer 1981; Reches et al. 1985) or depolarization block (Lappalainen et al. 1990). Depolarization block (i.e., a time-dependent inactivation of nigrostriatal neurons) requires more than 15 days of neuroleptic treatment (Onn and Grace 1995), so receptor supersensitivity is a more viable explanation for the present results. Specifically, haloperidol- or aripiprazole-induced supersensitivity would be expected to cause: (1) a reduction in basal DA synthesis (e.g., Lappalainen et al. 1990), (2) a diminished response to acute treatment with a DA receptor antagonist (e.g., Stock et al. 1980), and (3) a potentiated reduction in DA synthesis after acute treatment with a DA agonist (e.g., Bannon et al. 1980; Reches et al. 1985). Results from the present study are consistent with a receptor supersensitivity explanation, except for the finding that quinpirole did not induce a potentiated reduction in DA synthesis after haloperidol or aripiprazole pretreatment. The reason for this unanticipated result is uncertain, especially since apomorphine inhibits DA synthesis to a greater extent in haloperidol-pretreated rats than in vehicle controls (Bannon et al. 1980; Reches et al. 1985). Quinpirole more potently reduces DA synthesis than apomorphine in normosensitive rats (Heidbreder and Baumann 2001), thus a possible explanation for these divergent findings is that there was a ‘‘basement’’ effect whereby quinpirole was unable to reduce DA synthesis rates below the already low levels caused by repeated aripiprazole or haloperidol treatment. Lastly, according to a supersensitivity explanation acute treatment with a partial agonist should decrease, rather than increase, DA synthesis in haloperidol- and aripiprazolepretreated rats (i.e., aripiprazole should begin to function

Effects of repeated and acute aripiprazole or haloperidol treatment

like an agonist due to the up-regulated D2 receptors). For example, aripiprazole, like quinpirole, reduces DA synthesis in young and adult rats after reserpine or GBL treatment (Svensson et al. 1991; Kikuchi et al. 1995; Oshiro et al. 1998; In˜iguez et al. 2008). At least two explanations have been proposed to account for the actions of partial agonists: First, past low receptor occupancy, which is a consequence of repeated haloperidol or reserpine treatment, may cause conformational changes in the state of the receptor that allows agonists with low intrinsic activity to induce agonist-like behavioral effects (Carlsson 1983; Clark et al. 1985b); and, second, agonists with low intrinsic activity may induce agonist-like effects in the presence of a receptor reserve or a super-abundance of receptors (Meller et al. 1987; Drukarch and Stoof 1990; Hoyer and Boddeke 1993). In the present study, aripiprazole had a diminished effect on DA synthesis after repeated haloperidol and aripiprazole treatment, but the partial agonist did not decrease DA synthesis relative to controls (i.e., aripiprazole did not function like an agonist). It is possible that aripiprazole would have exhibited agonist-like properties if the manipulation (i.e., repeated haloperidol and aripiprazole treatment) had induced a greater up-regulation or supersensitivity of D2 receptors. In clinical terms, the therapeutic benefits of aripiprazole are typically linked to changes in prefrontal cortex functioning, while alterations in dorsal striatal functioning are most often associated with side-effects of dopaminergic drugs (Nakai et al. 2003; Li et al. 2004). For this reason, it may be beneficial that the dorsal striatal DA synthesis of young rats declined to near basal levels during the course of repeated aripiprazole treatment. In both normal humans and schizophrenics, positron emission tomography (PET) studies have shown that aripiprazole, at therapeutically relevant doses, occupies more than 90% of striatal and extrastriatal D2 receptor sites (Yokoi et al. 2002; Mamo et al. 2007; Gru¨nder et al. 2008; Kegeles et al. 2008). To date, PET studies have yet to examine differences in the occupancy rate of aripiprazole at pre- and postsynaptic D2 receptors nor the effects of aripiprazole on DA synthesis capacity. Such studies have been undertaken with haloperidol and risperidone, however, and it has been shown that neither drug causes an overall change in DA synthesis capacity in humans (Vernaleken et al. 2008; Ito et al. 2009). Instead, these PET studies found that haloperidol and risperidone had a stabilizing effect, whereby low or high basal DA synthesis capacity was normalized by drug treatment (Vernaleken et al. 2008; Ito et al. 2009). A stabilization-like effect was also apparent in the present study, because dorsal striatal DA synthesis of adult and preweanling rats approached basal values after repeated haloperidol or aripiprazole treatment (see Figs. 1, 2, 3). Thus, data from both human and nonhuman studies are consistent

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with the hypothesis that aripiprazole and other antipsychotic drugs are capable of stabilizing the functioning of presynaptic, as well as postsynaptic, D2 receptors (see Burris et al. 2002; Li et al. 2004; Feltenstein et al. 2007; Ito et al. 2009). In summary, the D2 partial agonist aripiprazole and the D2 antagonist haloperidol caused similar changes in dorsal striatal DA synthesis, although haloperidol’s effects were typically more robust and long-lasting. To the extent that it was examined, DA synthesis characteristics of young and adult rats were affected in a qualitatively similar manner by DA-acting drugs, thus indicating that synthesis-modulating autoreceptors are functionally mature by the end of the preweanling period.

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