effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial...

J Neural Transm (2008) 115: 97–106

DOI 10.1007/s00702-007-0820-7

Printed in The Netherlands

Effects of aripiprazole and terguride on dopamine synthesis in the dorsalstriatum and medial prefrontal cortex of preweanling rats

S. D. Iniguez, A. M. Cortez, C. A. Crawford, S. A. McDougall

Department of Psychology, California State University, San Bernardino, CA, USA

Received 19 June 2007; Accepted 1 September 2007; Published online 12 November 2007

# Springer-Verlag 2007

Summary. The purpose of this study was to determine whether aripipra-

zole, a D2-like partial agonist increasingly prescribed to children, alters DAsynthesis via actions at autoreceptors in the dorsal striatum and medial

prefrontal cortex (mPFC) of preweanling rats. The ability of dopaminergic

agents to alter DOPA accumulation in the striatum and mPFC was measuredafter NSD-1015 on postnatal day (PD) 20. Dopaminergic tone was manipu-

lated by administering reserpine, g-butyrolactone (GBL), or through am-

phetamine withdrawal. Results showed that the partial agonists aripiprazole

and terguride increased striatal DOPA accumulation under normosensitiveconditions, but decreased DOPA accumulation in states of low dopaminer-

gic tone. A different pattern of results was observed in the mPFC, because

terguride and haloperidol, but not aripiprazole, increased DOPA accumula-

tion under normosensitive conditions. In conclusion, the present data showthat aripiprazole affects striatal synthesis modulating autoreceptors in an

adult-typical manner during the late preweanling period. Unlike in adult

rats, however, the mPFC of preweanling rats appears to contain transitory

synthesis modulating autoreceptors that are sensitive to drug manipulation.

Keywords: Aripiprazole; terguride; DOPA accumulation; autoreceptors;ontogeny; dorsal striatum; prefrontal cortex

Introduction

Dopamine (DA) partial agonist drugs have interesting clin-

ical profiles. Initially employed as anti-parkinsonian agents

(Corsini et al. 1985; Brucke et al. 1987; Critchley and

Parkes 1987) D2-like partial agonists, such as aripiprazole,

are commonly prescribed to adults for schizophrenia and

bipolar disorder (Keck et al. 2003; Davies et al. 2004) and

are a potential pharmacotherapy for psychostimulant abuse

(Pulvirenti and Koob 1994; Platt et al. 2003; Feltenstein

et al. 2007). In terms of schizophrenia and drug abuse, the

therapeutic benefits of aripiprazole presumably result from

stabilizing DA functioning at both pre- and postsynaptic

receptors (Burris et al. 2002; Li et al. 2004; Feltenstein

et al. 2007). An even more recent trend is to prescribe

D2-like partial agonists to pediatric populations. In the

United States, aripiprazole is used to treat various childhood

and adolescent disorders, including Tourette syndrome, per-

vasive developmental disorder, conduct disorder, and pedi-

atric bipolar disorder (Findling et al. 2003; Barzman et al.

2004; Stigler et al. 2004; Biederman et al. 2005; Murphy

et al. 2005; Stachnik and Nunn-Thompson 2007). This in-

creased usage is occurring even though D2-like partial

agonists have seldom been examined using developmental

animal models and results from a minority of human clini-

cal studies suggest caution in prescribing aripiprazole to

children (Rugino and Janvier 2005).

Studies employing adult animal models have established

that D2-like partial agonists exhibit low intrinsic activity

(i.e., function as antagonists) at normosensitive DA presyn-

aptic receptors. In this circumstance, terguride and pre-

clamol 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 addition to their antagonistic proper-

ties, D2-like partial agonists are capable of showing high

intrinsic activity at synthesis modulating autoreceptors of

adult rats, but only after manipulations that reduce dopa-

minergic tone. For example, D2-like partial agonists inhib-

it, rather than enhance, dorsal striatal dopamine synthesis

in reserpinized rats (Hjorth et al. 1983, 1988; Svensson

Correspondence: Sanders A. McDougall, Department of Psychology,

California State University, 5500 University Parkway, San Bernardino,CA 92407, USA

e-mail: [email protected]

et al. 1991; Kikuchi et al. 1995). Pretreatment with the

nerve impulse inhibitor g-butyrolactone (GBL) also pro-

duces a state of low dopaminergic tone in which aripipra-

zole and terguride inhibit DA synthesis (Hjorth et al. 1983;

Clark et al. 1985a; Svensson et al. 1991; Kikuchi et al.

1995; Oshiro et al. 1998). In adult rats, therefore, biochem-

ical evidence indicates that D2-like partial agonists exhibit

low intrinsic activity at normosensitive presynaptic recep-

tors, while showing high intrinsic activity at the same re-

ceptors under conditions of reduced dopaminergic tone.

Few studies have examined the effects of D2-like partial

agonists in developing animals even though aripiprazole is

commonly administered to pediatric populations. Available

evidence suggests that terguride, like haloperidol, increases

dorsal striatal DA synthesis of preweanling rats under nor-

mosensitive conditions (Yoshida et al. 2006). Conversely,

terguride significantly reduces dorsal striatal DA synthesis

after either one or five days of reserpine treatment (Yoshida

et al. 2006). These agonistic effects at synthesis modulating

autoreceptors are short-lived, because terguride only in-

creases DA synthesis when measured 5 h and 24 h after

conclusion of a 5-day reserpine regimen (Farley et al.

2006). Terguride also decreases striatal DA synthesis after

GBL treatment, an effect that is antagonized by haloperidol

(Yoshida et al. 2006). In conclusion, results suggest that

terguride affects dorsal striatal D2-like receptors of pre-

weanling and adult rats in a generally similar manner,

although other brain regions and more therapeutically rele-

vant partial agonist compounds (e.g., aripiprazole) have not

been examined.

The purpose of the present study was to further examine

the effects of D2-like partial agonists on the synthesis mod-

ulating autoreceptors of preweanling rats during states of

high and low dopaminergic tone. Low dopaminergic tone

was induced by reserpine, GBL, or by administering an

escalating amphetamine regimen that is purported to cause

a withdrawal state after drug discontinuation (Barr and

Phillips 1999; Orsini et al. 2001). Because low, but not

high, doses of aripiprazole have been reported to increase

DA efflux in the medial prefrontal cortex (mPFC) of adult

rats, we also examined the effects of various doses of ari-

piprazole and terguride on DA synthesis in the dorsal stria-

tum and mPFC of rats on postnatal day (PD) 20. The mPFC

was of special interest, because (a) increasing DA neuro-

transmission in the mPFC is of presumed therapeutic

benefit (Jordan et al. 2004; Zocchi et al. 2005) and (b)

D2-like synthesis modulating autoreceptors in the mPFC

exist in functional quantities during the preweanling period

(Andersen et al. 1997), but are either absent or occur in

greatly reduced numbers during adulthood (Bannon et al.

1981; Galloway et al. 1986; but see Fadda et al. 1984). In

all experiments, rats were tested on PD 20 because this age

corresponds with ‘‘childhood’’ in humans (Andersen 2003).

Materials and methods

Subjects

Preweanling rats (n! 221) of Sprague-Dawley descent (Charles River,

Hollister, CA, USA) were obtained from the breeding colony at California

State University, San Bernardino (CSUSB). Litters were culled to ten pupsat postnatal day (PD) 3 (day of parturition is PD 0). Rat pups were kept with

the dam except when undergoing experimental manipulation. 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 animalcare’’ (NIH publication no. 86-23, revised 1985) under a research protocol

approved by the Institutional Animal Care and Use Committee of CSUSB.

Drugs

R(#)-Terguride, haloperidol, and reserpine were dissolved in a minimal

amount of glacial acetic acid and diluted with saline; whereas, D-amphet-

amine sulfate salt, quinpirole, and 3-hydroxybenzylhydrazine hydrochloride

(NSD-1015) were dissolved in saline. Aripiprazole was dissolved in (2-hydropropyl)-b-cyclodextrin solution (HBC, 45% (w=v) solution in water).

g-Butyrolactone (GBL) was at an initial density of 1.12 g=ml. All drugs

were injected intraperitoneally (i.p.) at a volume of 5ml=kg. With the

exception of aripiprazole (Toronto Research Chemicals, Toronto, Canada),all drugs were purchased from Sigma (St. Louis, MO, USA).

Experimental protocols

Experiment 1: Effects of D2-like partial agonists on DOPA

accumulation after saline, amphetamine, or reserpine pretreatment

Rats (n! 103) were randomly assigned to one of three pretreatment condi-

tions: amphetamine withdrawal, reserpine, or saline controls. To induce a

state of amphetamine withdrawal, rats were injected with an escalating

regimen of amphetamine (starting at 1mg=kg and increasing by 1 unitintervals until 10mg=kg was administered) beginning on PD 16 (see also

Barr and Phillips 1999; Orsini et al. 2001). More specifically, on PD 16-PD

18 rats were injected three times per day (at 800, 1600, and 2400 h) with

amphetamine. The initial dose of amphetamine was 1mg=kg, with eachsubsequent dose of amphetamine increasing by 1mg=kg. On PD 19, rats

received their tenth and last injection of vehicle or amphetamine (in this

case, 10mg=kg) at 800h. Rats in the reserpine condition, received a singleinjection of reserpine at 800h on PD 19. Half of the rats in the saline

condition received a single injection of saline at 800 h on PD 19 (i.e., at

the same time as rats in the reserpine condition), while the other half of the

control rats were given 10 injections of saline on PD 16-PD 20 (i.e., at thesame time as rats in the amphetamine withdrawal condition).

After 24 h (i.e., on PD 20), rats from each pretreatment condition were

further subdivided (n! 5–7 per group) and injected with saline vehicle,

HBC vehicle, quinpirole (0.5mg=kg, i.p.), haloperidol (0.5mg=kg, i.p.),terguride (1.5mg=kg, i.p.), or aripiprazole (3 or 10mg=kg, i.p.) fol-

lowed, 30min later, by an injection of the DOPA decarboxylase inhibitor

NSD-1015 (100mg=kg, i.p.). Rats were killed by rapid decapitation

30min after NSD-1015 treatment and their dorsal striata and prefrontalcortices were removed on an ice-cold dissection plate and stored at

$80"C until assay.

To determine whether amphetamine withdrawal altered DA levels, anadditional 48 rats were injected with an escalating regimen of amphetamine

98 S. D. Iniguez et al.

or saline in the manner described previously. Rats were killed by rapiddecapitation 12, 24, 48, or 72 h after the final amphetamine (n! 8 per

group) or saline (n! 4 per group) injection. Dorsal striata were removed

and stored at $80"C until assay.

Experiment 2: Low-dose effects of aripiprazole on DOPA

accumulation after saline or reserpine pretreatment

On PD 19, rats (n! 47) received a single injection of reserpine or saline at800 h. After 24 h (i.e., on PD 20), rats from each pretreatment condition

were further subdivided (n! 7–8 per group) and injected with saline vehi-

cle, HBC vehicle, terguride (1.5mg=kg, i.p.), or aripiprazole (0.1, 0.3, 3 or10mg=kg, i.p.) followed, 30min later, by an injection of the DOPA decar-

boxylase inhibitor NSD-1015 (100mg=kg, i.p.). The doses of aripiprazole

were based on previous studies (Li et al. 2004; Zocchi et al. 2005). Rats

were killed by rapid decapitation 30min after NSD-1015 treatment and theirdorsal striata and prefrontal cortices were removed on an ice-cold dissection

plate and stored at $80"C until assay.

Experiment 3: Effects of D2-like partial agonists on DOPA

accumulation after GBL treatment

On PD 20, rats (n! 71) were injected with saline vehicle, HBC vehicle,quinpirole (0.5mg=kg, i.p.), haloperidol (0.5mg=kg, i.p.), terguride (0.005,0.015, or 1.5mg=kg, i.p.), or aripiprazole (0.1, 0.3, or 10mg=kg, i.p.)

(n! 6–8 per group) followed, 25min later, by an injection of the nerve

impulse inhibitor GBL (625mg=kg, i.p.). After 5min, rats were injectedwith NSD-1015 (100mg=kg, i.p.). Rats were killed by rapid decapitation

30min after NSD-1015 treatment and their dorsal striata and prefrontal

cortices were removed and stored at $80"C until assay.

HPLC conditions

DOPA accumulation and DA content were determined using high-perfor-

mance liquid chromatography (HPLC). Frozen tissue samples were sonicat-ed in 0.1N HClO4 (dorsal striatum, 10 volumes; mPFC, 5 volumes) and

centrifuged at 20,000g for 30min at 4"C. The supernatant was then filtered

through a 0.22mm centrifugation unit at 2000g for 5min at 4"C. Twenty

microliters of the resulting extract was assayed for DOPA or DA using aBreezeTM HPLC system (Waters, Milford, MA, USA), with a Coulochem II

electrochemical detector (ESA, Chelmsford, MA, USA). For dorsal striatal

samples, the mobile phase consisted of 75mM NaH2PO4, 1.4mM 1-octane

sulfonic acid, 10mM ethylenediamine tetraacetic acid (EDTA), and 10%acetonitrile (pH 3.1). The mobile phase for mPFC samples was adjusted to

75mMNaH2PO4, 0.75mM 1-octane sulfonic acid, 10mMEDTA, and 1.5%

acetonitrile (pH 3.1) to increase peak latency. Both mobile phases were

pumped at a rate of 0.5ml=min.

Statistical evaluation

Assignment of subjects was random, with an equal number of male and

female rats being placed in each group. Individual groups included no morethan one subject from a particular litter and, when possible (i.e., in experi-

ments with ten or fewer groups), each litter provided one subject per group.

In the initial experiments, DOPA accumulation data (ng=mg wet weight

tissue) were analyzed using two-way analyses of variance (ANOVA)(Pretreatment Condition % Drug Group) and further analyzed using sepa-

rate one-way ANOVAs for each pretreatment condition. In the GBL experi-

ment, DOPA accumulation data were analyzed using a one-way randomized

block ANOVA, with litter serving as the blocking factor (Hughes 1979). Forpresentation purposes, DOPA accumulation data were converted to percent

of vehicle controls (see also Baldessarini et al. 1994; Clark et al. 1991).

Saline and HBC vehicle had similar effects on DOPA accumulation, there-

fore data from the two vehicle groups were combined for each experiment.Preliminary statistical analyses showed that DOPA accumulation data did

not vary according to sex of the animals, so the sex variable was excluded

from later analyses. Post hoc analysis of neurochemical data was made

using Newman-Keuls tests (p<0.05).

Results

Experiment 1: Effects of D2-like partial agonists

on DOPA accumulation after saline, amphetamine,

or reserpine pretreatment

Overall, the dopaminergic compounds differentially af-

fected dorsal striatal DOPA accumulation depending on

pretreatment condition (see Fig. 1) [F(10,85)! 13.08,

p<0.001]. In the saline pretreatment condition, quinpirole

(0.5mg=kg) caused a significant reduction in striatal DOPAaccumulation relative to vehicle controls, whereas haloper-

idol (0.5mg=kg) increased DOPA accumulation (see upper

graph, Fig. 1) [F(5,32)! 160.42, p<0.001]. Both D2-like

partial agonists increased striatal DOPA accumulation, but

the magnitude of the increase was less for terguride (217%

increase relative to vehicle controls) and aripiprazole

(3mg=kg: 260%; 10mg=kg: 208%) than for the full an-

tagonist haloperidol (427%). Rats in the amphetamine

withdrawal condition responded essentially the same as rats

in the saline pretreatment condition, because terguride and

aripiprazole caused a significant increase in DOPA ac-

cumulation that was approximately half as robust as the

haloperidol-induced increase (see middle graph, Fig. 1)

[F(5,26)! 74.56, p<0.001]. The quinpirole-induced re-

duction in striatal DOPA was only marginally significant

[p<0.07], but quinpirole did cause significantly less stria-

tal DOPA accumulation than the partial agonists. Unlike

amphetamine withdrawal, reserpine produced a state in

which aripiprazole and terguride caused agonist-like de-

creases in striatal DOPA accumulation (see lower graph,

Fig. 1). Specifically, terguride and the higher dose of ari-

piprazole (10mg=kg) reduced striatal DOPA accumulation

relative to vehicle controls [F(5,27)! 81.30, p<0.001].

Reserpine did not cause a qualitatively different pattern

of effects in rats given direct acting compounds, because

haloperidol increased, while quinpirole decreased, DOPA

accumulation in reserpinized rats. Therefore, in saline- and

amphetamine-pretreated rats aripiprazole and terguride

caused antagonist-like increases in striatal DOPA accumula-

tion, but in reserpinized rats the partial agonists functioned

in the same manner as the D2-like agonist quinpirole.

In the mPFC, the DA agonists and antagonists produced

different patterns of effects according to pretreatment con-

dition (see Fig. 2) [F(5,84)! 2.67, p<0.01]. In the saline

Effects of D2-like partial agonists on DA synthesis 99

pretreatment condition, both haloperidol and terguride in-

creased DOPA accumulation in the mPFC (see upper

graph, Fig. 2) [F(1,28)! 4.94, p<0.01]. Interestingly, at

neither of the doses tested did aripiprazole (3 or 10mg=kg)enhance DOPA accumulation in the mPFC, while quinpi-

role caused only a nonsignificant decline in DOPA values

(60% of controls) [p< 0.1]. A different pattern of effects

was evident during amphetamine withdrawal, because ter-

guride-treated rats exhibited greater DOPA accumulation

than haloperidol- and vehicle-treated rats (see middle

graph, Fig. 2) [F(1,27)! 3.95, p<0.01]. No differences

in DOPA accumulation were observed in the reserpine con-

dition, since the various DA compounds did not alter mPFC

DOPA accumulation relative to vehicle control values (see

lower graph, Fig. 2).

In order to determine whether DA levels were reduced

during amphetamine withdrawal, striatal DA content of

saline- and amphetamine-pretreated rats was measured

50

00.5 1.5 3 10 0.5

Fig. 2. Mean mPFC DOPA accumulation of PD 20 rats injected with

vehicle, haloperidol (Hal), terguride (Terg), aripiprazole (Aripip), or quin-pirole (Quin) 24 h after conclusion of saline, amphetamine, or reserpine

pretreatment. Data are expressed as percent of vehicle controls (&SEM)

and doses are in mg=kg. 'p<0.05 vs vehicle controls (indicated by the

dashed line); yp<0.05 vs haloperidol

Fig. 1. Mean striatal DOPA accumulation of PD 20 rats injected with

vehicle, haloperidol (Hal), terguride (Terg), aripiprazole (Aripip), or quin-pirole (Quin) 24 h after conclusion of saline, amphetamine, or reserpine

pretreatment. Data are expressed as percent of vehicle controls (&SEM)

and doses are in mg=kg. 'p<0.05 vs vehicle controls (indicated by the

dashed line); yp<0.05 vs haloperidol; zp<0.05 vs quinpirole


12, 24, 48, or 72 h after final injection. As can be seen in

Table 1, amphetamine withdrawal did not alter striatal DA

levels at any time point.

Experiment 2: low-dose effects of aripiprazole on DOPA

accumulation after saline or reserpine pretreatment

Terguride (1.5mg=kg) and aripiprazole (0.1, 0.3, 3, or

10mg=kg) differentially affected striatal DOPA accumula-

tion depending on whether rats were pretreated with sa-

line or reserpine (see Fig. 3) [F(5,82)! 27.93, p<0.001].

Among the saline-pretreated groups, aripiprazole caused a

dose-related increase in DOPA values (see upper graph,

Fig. 3). Specifically, the two lower doses of aripiprazole

(0.1 and 0.3mg=kg) had effects similar to vehicle, while

the two higher doses of aripiprazole (3 and 10mg=kg) andterguride (1.5mg=kg) significantly enhanced striatal DOPA

accumulation relative to vehicle controls [F(5,41)! 26.18,

p<0.001]. Reserpinized rats exhibited a different pattern

of effects, because striatal DOPA accumulation was sig-

nificantly reduced after treatment with 1.5mg=kg ter-

guride or 10mg=kg aripiprazole (see lower graph, Fig. 3)

[F(5,41)! 6.50, p<0.001].

In the mPFC, DOPA accumulation did not differ accord-

ing to pretreatment condition [p>0.05], but DOPA levels

were differentially affected by partial agonist administra-

tion (see Fig. 4) [F(5,79)! 5.21, p<0.001]. In the vehicle

pretreatment condition, 1.5mg=kg terguride significantly

enhanced DOPA accumulation in the mPFC [F(5,39)!

Table 1. Dorsal striatal DA content (expressed as ng=mg wet weighttissue, &SEM) of rats given an escalating regimen of amphetamine (1–

10mg=kg) or saline on PD 16-PD 19

Pretreatment Withdrawal perioda

12 h 24 h 48 h 72 h

Saline (n! 4) 5.02 (&0.2) 5.12 (&0.2) 5.47 (&0.4) 5.23 (&0.2)

Amphetamine(n! 8)

5.13 (&0.2) 5.07 (&0.2) 5.26 (&0.1) 5.31 (&0.2)

a Samples were taken 12, 24, 48, or 72 h after the final amphetamine orsaline injection.


vehicle, terguride (Terg), or aripiprazole (Aripip) 24 h after conclusion ofsaline or reserpine pretreatment. Data are expressed as percent of vehicle

controls (&SEM) and doses are in mg=kg. 'p<0.05 vs vehicle controls

(indicated by the dashed line)


vehicle, terguride (Terg), or aripiprazole (Aripip) 24 h after conclusion ofsaline or reserpine pretreatment. Data are expressed as percent of vehicle

controls (&SEM) and doses are in mg=kg. 'p<0.05 vs vehicle controls

(indicated by the dashed line)


3.38, p<0.05], while all doses of aripiprazole (0.1–10mg=kg) were without effect (upper graph, Fig. 4). Because there

was a nonsignificant trend towards increased DOPA ac-

cumulation at the 10mg=kg dose, additional groups of

saline-pretreated rats were tested with vehicle or 30mg=kgaripiprazole. Relative to vehicle controls, DOPA accu-

mulation of the 30mg=kg aripiprazole group was slightly

reduced in the mPFC (89.7% of control values), although

this did not represent a statistically significant decline

[p>0.05]. Among the reserpine-pretreated groups, ter-

guride significantly increased DOPA accumulation in the

mPFC while aripiprazole had no effect (lower graph, Fig. 4)

[F(5,40)! 2.69, p<0.05]. The former result, showing that

terguride increased DOPA accumulation in reserpinized

rats, was not consistent with results from Experiment 1;

therefore, we did an additional experiment in which rats

were pretreated with reserpine and tested with vehicle,

1.5mg=kg terguride, or 30mg=kg aripiprazole. In this cir-

cumstance, terguride caused a 123% increase in DOPA

accumulation, while aripiprazole produced a slight, albeit

nonsignificant, decline (91.2% of control values) in DOPA

accumulation.

Experiment 3: Effects of D2-like partial agonists

on DOPA accumulation after GBL treatment

In the dorsal striatum, GBL (3.80 ng=mg, &0.20) caused a

373% increase in DOPA accumulation relative to vehicle

controls (1.02 ng=mg, &0.05). Haloperidol significantly

increased DOPA accumulation in GBL-treated rats, while

quinpirole induced a dramatic decline in DOPA levels (see

Fig. 5) [F(8,55)! 29.73, p<0.001]. Although quinpirole’s

effects were more robust, terguride (0.015 and 1.5mg=kg)and aripiprazole (10mg=kg) also reduced DOPA accumu-

lation relative to vehicle controls.

In GBL-treated rats, DOPA accumulation in the mPFC

(0.277 ng=mg, &0.01) was 199% greater than in vehicle

controls (0.139 ng=mg, &0.02). There was a nonsignificant

trend for haloperidol increasing, and quinpirole decreasing,

DOPA accumulation (see Fig. 6). When compared to

the vehicle group, the only significant effect was an aripi-

prazole-induced reduction in DOPA accumulation at the

10mg=kg dose [F(8,53)! 3.09, p<0.01].

Discussion

Results from the present study show that aripiprazole and

terguride function as prototypical partial agonists at syn-

thesis modulating D2-like autoreceptors in the dorsal stria-

tum of preweanling rats (for a summary of results, see

Table 2). When tested under normosensitive conditions

(i.e., in a state of high dopaminergic tone), terguride and

aripiprazole (3 and 10mg=kg) increased DA synthesis in

the dorsal striatum, while lower doses of aripiprazole (0.1

and 0.3mg=kg) were without impact. Reducing dopami-

nergic tone caused a different pattern of effects because

terguride and aripiprazole (10mg=kg) decreased dorsal

striatal DA synthesis in reserpinized rats, with lower doses

of aripiprazole (0.1, 0.3, and 3mg=kg) again having no


vehicle, haloperidol (Hal), terguride (Terg), aripiprazole (Aripip), or quin-

pirole (Quin) 30min after GBL treatment. Data are expressed as percent ofvehicle controls (&SEM) and doses are in mg=kg. 'p<0.05 vs vehicle

controls (indicated by the dashed line); yp<0.05 vs haloperidol; zp<0.05

vs quinpirole


vehicle, haloperidol (Hal), terguride (Terg), aripiprazole (Aripip), or quin-pirole (Quin) 30min after GBL treatment. Data are expressed as percent of

vehicle controls (&SEM) and doses are in mg=kg. 'p<0.05 vs vehicle

controls (indicated by the dashed line); yp<0.05 vs haloperidol; zp<0.05

vs quinpirole


effect. Pretreatment with the nerve impulse inhibitor GBL

caused actions similar to reserpine, as terguride (0.015

and 1.5mg=kg) and aripiprazole (10mg=kg) reduced, rath-er than enhanced, DA synthesis in the dorsal striatum.

Therefore, these results show that synthesis modulating

autoreceptors are found in the dorsal striatum during the

preweanling period (see also Shalaby et al. 1981; Andersen

and Gazzara 1993, 1994; Andersen et al. 1997), and that

full (quinpirole) and partial (aripiprazole and terguride) DA

agonists and antagonists (haloperidol) affect dorsal striatal

synthesis modulating autoreceptors of young and adult rats

in a qualitatively similar manner. It is noteworthy that in

GBL-treated rats the full agonist quinpirole reduced DA

synthesis to a greater extent than terguride or aripiprazole

(see Fig. 5), whereas under normosensitive conditions the

full antagonist haloperidol increased DA synthesis to a

greater extent than either partial agonist compound (see

Fig. 1). This pattern of results is consistent with terguride

and aripiprazole functioning as partial agonists at dorsal

striatal D2-like receptors (Svensson et al. 1991).

As was true for the dorsal striatum, terguride and halo-

peridol increased DA synthesis in the mPFC during a state

of high dopaminergic tone, thus providing additional evi-

dence that transitory D2-like synthesis modulating autore-

ceptors are found in the mPFC during the preweanling

period (Andersen et al. 1997). In many ways, however,

DA synthesis characteristics varied between the mPFC

and dorsal striatum, with drugs typically having a more

blunted effect in the mPFC than the dorsal striatum (for a

summary of results, see Table 3). For example, quinpirole

did not significantly reduce DA synthesis in the mPFC

under normosensitive conditions (there was a 40% decline),

nor did haloperidol cause an exaggerated increase in DOPA

accumulation relative to the terguride group (see Fig. 2).

Svensson et al. (1991) previously reported the same pattern

of drug-induced effects in the whole cortex of adult rats.

Perhaps of most interest was the finding that a broad dose-

range of aripiprazole (0.1–30mg=kg) did not alter DA

synthesis in the mPFC of preweanling rats under normo-

sensitive conditions. We had originally hypothesized that

aripiprazole, at least at low doses, would increase DA syn-

thesis in the mPFC. The rationale for this hypothesis was

partially based on reports that 0.3mg=kg aripiprazole in-

creased DA efflux in the mPFC (Li et al. 2004; Zocchi et al.

2005; Huang et al. 2006), while higher doses of aripipra-

zole decreased, or did not alter, dialysate levels of DA

(Semba et al. 1995; Jordan et al. 2004; Li et al. 2004;

Zocchi et al. 2005). Of course, low doses of aripiprazole

could increase DA efflux via actions at nonDA receptors

(e.g., 5-HT1A and=or 5-HT2A receptors) as well as by an-

tagonism of cortical D2-like receptors (Li et al. 2004).

Nonetheless, the finding that terguride and haloperidol in-

Table 2. Actions of full (quinpirole) and partial (aripiprazole and terguride) DA agonists and antagonists (haloperidol) on DA synthesisin the dorsal striatum

Pretreatment Treatment

Haloperiodol Quinpirole Terguride Aripiprazole (high dose) Aripiprazole (low dose)

Control " # " " !Amphetamine " # " " !Reserpine " # # # !GBL " # # # !

Preweanling rats were tested under normosensitive conditions, during amphetamine withdrawal, or after reserpine or GBL pretreatment.Symbols: " increased DOPA accumulation; # decreased DOPA accumulation;! no effect.

Table 3. Actions of full (quinpirole) and partial (aripiprazole and terguride) DA agonists and antagonists (haloperidol) on DA synthesis

in the medial prefrontal cortex (mPFC)

Pretreatment Treatment

Haloperiodol Quinpirole Terguride Aripiprazole (high dose) Aripiprazole (low dose)

Control " #' " ! !Amphetamine ! ! " ! !Reserpine ! ! "! ! !GBL ! ! " # !

Preweanling rats were tested under normosensitive conditions, during amphetamine withdrawal, or after reserpine or GBL pretreatment.

Symbols: " increased DOPA accumulation; # decreased DOPA accumulation;! no effect. '(p<0.1).


creased DA synthesis in the mPFC, while aripiprazole

(0.1–30mg=kg) did not, is surprising and suggests that

nonDA receptors may mediate some of these effects.

When tested under conditions of low dopaminergic tone

the full agonist and antagonist compounds had only minor

effects on DA synthesis in the mPFC. More specifically,

neither quinpirole nor haloperidol significantly altered DA

synthesis in the mPFC of reserpine- or GBL-treated pre-

weanling rats, although nonsignificant trends were some-

times apparent. These results are more consistent with the

adult rat literature, because full D2-like agonists and an-

tagonists either do not alter DA synthesis in the mPFC after

reserpine or GBL treatment (Bannon et al. 1981; Galloway

et al. 1986; Svensson et al. 1991) or have reduced effects

when compared to actions in the dorsal striatum (Fadda

et al. 1984). In partial contrast to our results, Andersen

et al. (1997) reported that the full D2-like agonists (&)-

7-OH-DPAT and quinpirole dramatically reduced DA

synthesis in the mPFC of GBL-treated 15-day-old rats;

however, the dose of quinpirole (5mg=kg) needed to fully

reverse GBL-induced DOPA accumulation was substantial-

ly larger than the dose (0.5mg=kg) employed in the present

study.

In terms of the partial agonist compounds, terguride

and aripiprazole had opposing effects on DA synthesis

in the mPFC under conditions of low dopaminergic tone.

Specifically, 1.5mg=kg terguride enhanced DOPA accumu-

lation in the mPFC of GBL-treated preweanling rats, while

10mg=kg aripiprazole significantly reversed the GBL-

induced increase in DOPA accumulation. In reserpinized

rats, aripiprazole had minimal effects on DA synthesis in

the mPFC, while 1.5mg=kg terguride increased DA syn-

thesis (see Fig. 4). The latter effect was not observed in

Experiment 1 (see Fig. 2), so we did an additional ex-

periment employing the same procedures and found that

1.5mg=kg terguride increased DOPA accumulation in the

mPFC by 123% relative to reserpinized controls. In the

mPFC, therefore, terguride was probably responsible for

marginal increases in DA synthesis under conditions of

low dopaminergic tone, while aripiprazole decreased DA

synthesis in GBL-treated rats. The reason why these two

partial agonists had divergent effects is uncertain, but it

may have been due to the nondopaminergic actions of these

compounds (e.g., see Stark et al. 2007).

In adult rats, amphetamine withdrawal has been reported

to reduce dopaminergic tone to such an extent that partial

agonists will stimulate, rather than antagonize, D2-like re-

ceptors. Specifically, aripiprazole and terguride were able

to reverse the decline in saccharin-reinforced bar press

responding that was evident during amphetamine with-

drawal (Orsini et al. 2001; Schwabe and Kock 2007; see

also Hoefer et al. 2006). In the present study, the identical

amphetamine withdrawal paradigm did not induce a state

in which D2-like partial agonists were able to stimulate the

synthesis modulating autoreceptors of preweanling rats. In

the dorsal striatum, for example, terguride and aripiprazole

(3 and 10mg=kg) increased DOPA accumulation in am-

phetamine- and saline-pretreated rats, whereas the same

partial agonists decreased DOPA accumulation in reserpi-

nized rats (see Fig. 1). The inability of D2-like partial

agonists to stimulate presynaptic receptors during amphet-

amine withdrawal was probably not surprising, because

endogenous DA levels in the dorsal striatum of preweanl-

ing rats were not altered during amphetamine withdrawal

(Table 1). In comparison, reserpine (1mg=kg) causes a

substantial reduction in dorsal striatal DA content (to about

10% of control values) when measured 24 h later on PD 20

(Wacan et al. 2006). The relative impact of these pretreat-

ments (i.e., amphetamine withdrawal vs reserpine) on DA

content is meaningful, because D2-like partial agonists typ-

ically exhibit enhanced intrinsic activity only under condi-

tions of past low receptor occupancy (e.g., after reserpine

treatment or 6-OHDA lesions) (Carlsson 1983; Clark et al.

1985b). Meller et al. (1987) have also proposed that manip-

ulations (e.g., reserpine) which increase the receptor re-

serve are needed before partial agonists will exhibit high

intrinsic activity at synthesis modulating autoreceptors.

Regardless of explanation, amphetamine withdrawal was

unable to induce a state in which terguride or aripiprazole

stimulated, rather than antagonized, the synthesis modulat-

ing autoreceptors of preweanling rats.

Although there is substantial evidence that terguride and

aripiprazole act as partial agonists at D2-like receptors,

both drugs exhibit high affinity for other receptor types.

In addition to being partial agonists at D2, D3, and D4

receptors (Newman-Tancredi et al. 2002a; Shapiro et al.

2003), terguride and aripiprazole function as antagonists

at the 5-HT2B receptor and as partial agonists at the

5-HT1A receptor (Jordan et al. 2002; Newman-Tancredi

et al. 2002b; Shapiro et al. 2003). Actions at the 5-HT1A

receptor may be relevant because R(#)-8-OH-DPAT (a

5-HT1A receptor agonist with some D2 agonist properties)

has been reported to decrease DOPA accumulation in the

mPFC (Kuroki et al. 2000; see also Hillegaart et al. 2000).

Both partial agonists also have significant affinity for

a1A-adrenergic and histamine receptors (Millan et al. 2002;

Newman-Tancredi et al. 2002a; Shapiro et al. 2003).

Perhaps of most interest is the finding that aripiprazole is

an antagonist at 5-HT2A receptors (Burris et al. 2002; Byars

et al. 2002), whereas Newman-Tancredi et al. (2002b) re-


port that terguride is a potent agonist at human 5-HT2A

receptors. Whether differential actions at the 5-HT2A re-

ceptor are responsible for some of the disparate effects of

terguride and aripiprazole is uncertain. Interestingly, Urban

et al. (2007) have proposed that aripiprazole has a unique

role as a ‘‘functionally selective D2 ligand’’ rather than as a

‘‘simple partial agonist’’ (see also Lawler et al. 1999).

According to this hypothesis, aripiprazole is capable of ex-

hibiting different intrinsic activities at a given receptor type

depending on the effector system being measured. Because

terguride has the characteristics of a ‘‘simple partial ago-

nist’’, it is possible that some of the differential effects of

terguride and aripiprazole at synthesis modulating auto-

receptors, especially in the mPFC, may be due to aripipra-

zole’s actions as a functionally selective D2-like ligand.

In conclusion, partial agonist compounds affected the

synthesis modulating autoreceptors of the dorsal striatum

in an adult-typical manner during the preweanling period.

In the mPFC aripiprazole was without significant action,

while terguride and haloperidol increased DA synthesis

under normosensitive conditions. The latter results are con-

sistent with studies showing that synthesis modulating D2-

like autoreceptors are functional in the mPFC by PD 10

and are able to mediate agonist-induced decreases in DA

synthesis until at least PD 30 (Andersen et al. 1997). That

aripiprazole did not alter DA synthesis characteristics in the

mPFC under normosensitive conditions may have relevance

to pediatric clinical populations, because these results sug-

gest that aripiprazole has similar actions at the synthesis

modulating autoreceptors of young and adult animals.

Acknowledgments

We thank Faiza Furqan for technical contributions. This work was partially

supported by a grant (GM073842) from the National Institutes of Health.

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