Effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric...

Effects of co-administration of the GABAB

receptor agonist baclofen and a positive allosteric

modulator of the GABAB receptor, CGP7930, on

the development and expression of amphetamine-

induced locomotor sensitization in rats

Laura N. Cedillo, Florencio Miranda

FES Iztacala, National Autonomous University of México, Av. de los Barrios 1, Los Reyes Iztacala Tlalnepantla,

Edo. de México 54090, México

Correspondence: Florencio Miranda, e-mail: [email protected]

Abstract:

Background: Several of the behavioral effects of amphetamine (AMPH) are mediated by an increase in dopamine neurotransmis-

sion in the nucleus accumbens. However, evidence shows that g-aminobutyric acid B (GABAB) receptors are involved in the behav-

ioral effects of psychostimulants, including AMPH. Here, we examined the effects of co-administration of the GABAB receptor

agonist baclofen and a positive allosteric modulator of the GABAB receptor, CGP7930, on AMPH-induced locomotor sensitization.

Methods: In a series of experiments, we examined whether baclofen (2.0, 3.0 and 4.0 mg/kg), CGP7930 (5.0, 10.0 and 20.0 mg/kg),

or co-administration of CGP7930 (5.0, 10.0 and 20.0 mg/kg) with a lower dose of baclofen (2.0 mg/kg) could prevent the develop-

ment and expression of locomotor sensitization produced by AMPH (1.0 mg/kg).

Results: The results showed that baclofen treatment prevented both the development and expression of AMPH-induced locomotor

sensitization in a dose-dependent manner. Furthermore, the positive allosteric modulator of the GABAB receptor, CGP7930, in-

creased the effects of a lower dose of baclofen on AMPH-induced locomotor sensitization under both conditions.

Conclusion: These data provide further evidence that GABAB receptor ligands may modulate psychostimulant-induced behaviors.

Key words:

amphetamine, sensitization, GABAB receptors

Introduction

Cocaine and amphetamine (AMPH) are indirect

monoamine agonists that exhibit an affinity for dopa-

mine (DA), norepinephrine (NE), and serotonin (5-HT)

transporters, which are involved in neurotransmitter re-

uptake and vesicular storage systems [52]. Cocaine in-

hibits the reuptake of DA, NE, and 5-HT, thereby in-

creasing the synaptic levels of these neurotransmitters.

AMPH blocks the uptake of DA, NE, and 5-HT into

synaptic vesicles, promoting an increase in the cyto-

plasmic concentrations of these monoamines. As the

levels of cytoplasmic monoamines increase, they exit

neurons via reversal of the direction of plasma mem-

brane transporters, which leads to an increase in synap-

tic DA, NE, and 5-HT levels [1, 28, 52].

The mesolimbic DAergic system, particularly the

projection from the ventral tegmental area (VTA) to

the nucleus accumbens (NAcc), is an important locus

for the production of the locomotor, reinforcement,

reward, and discriminative stimulus effects of psy-

1132 Pharmacological Reports, 2013, 65, 1132�1143

Pharmacological Reports2013, 65, 1132�1143ISSN 1734-1140

Copyright © 2013by Institute of PharmacologyPolish Academy of Sciences

chostimulants [17, 20, 35]. The administration of

AMPH or cocaine rapidly increases DAergic neuro-

transmission by interfering with the function of DA

transporters, as described above. Consequently, psy-

chostimulant administration produces an increase in

DAergic signaling in the limbic areas [35, 36].

Recent evidence also suggests a potential role for

g-aminobutyric acid (GABA) neurotransmission in

modulating some of the behavioral effects of psycho-

stimulants. GABAB receptor agonists are reportedly

effective in attenuating some of the behavioral effects

of psychostimulants that may be related to the abuse

of these drugs. For example, the selective GABAB re-

ceptor agonist baclofen (BCF) reduces the reinforcing

effects of cocaine [49], nicotine [19], methAMPH

[48], and AMPH [9]. Furthermore, BCF administra-

tion decreases the conditioned locomotion elicited by

cues associated with cocaine [25]. Other GABAB re-

ceptor agonists also reduce psychostimulant-related

behaviors. Brebner et al. [10] reported that the selec-

tive GABAB receptor agonist CPG44532 was effec-

tive in attenuating cocaine self-administration in rats

subjected to a progressive ratio schedule.

Although some findings have indicated that

GABAB agonists, such as BCF, may be useful in the

treatment of drug abuse, other results have suggested

that the muscle-relaxant properties of BCF, in con-

junction with its sedative and hypothermic effects,

limit its widespread application as a therapeutic agent

in humans and as a tool for behavioral research [16,

26]. However, a novel alternative approach, allosteric

modulation of GABAB receptors, has been suggested.

Positive allosteric modulators of GABAB receptors

display no intrinsic activity of their own but can inter-

act synergistically with GABAB agonists, including

BCF, to enhance their effects. One strategy for at-

tempting to overcome the side effects of BCF is to use

lower dosages to reduce unwanted effects of the drug,

in combination with positive allosteric modulators of

GABAB receptors, such as CGP7930 (CGP).

Locomotor sensitization is the progressive and per-

sistent enhancement of a behavioral response to

a drug after repeated and intermittent administration.

This phenomenon has been well characterized for

psychostimulant and cannabinoid drugs [32, 60, 63]

and is thought to reflect neuroadaptations that contrib-

ute to drug addiction and model some aspects of ad-

dictive behaviors, such as drug craving [51]. There-

fore, locomotor sensitization may reflect neurobio-

logical changes related to drug addiction and may be

useful for studying DA-GABA interactions. The pres-

ent study was designed to examine the effects of co-

administration of the GABAB receptor agonist BCF

and CGP, a positive allosteric modulator of the

GABAB receptor, on the development and expression

of AMPH-induced locomotor sensitization.

Materials and Methods

Animals

A total of 400 male Wistar rats that were 120 days old

and weighed 20–250 g at the beginning of the experi-

ments were obtained from the breeding colony of the

FES-Iztacala-UNAM, México. They were individu-

ally housed in stainless steel cages with freely avail-

able food (Teklad LM485 Rat Diet by Harlan, México

City, México) and water and were maintained under

a 12 h light/dark cycle, with the lights turned on at

08:00 h. The room was maintained at a temperature of

21 ± 1°C. All experiments were conducted during the

light phase (between 11:00 a.m. and 1:00 p.m.). Ani-

mal care and handling procedures were performed in

accordance with the Official Mexican Norm (NOM-

062-ZOO-1999) entitled “Technical Specifications

for the Production, Care, and Use of Laboratory Ani-

mals” and all procedures were approved by the local

bioethics committee.

Drugs

The drugs used in this study were D-amphetamine

sulfate, (±)-baclofen (Sigma-Aldrich, St. Louis, MO,

USA), and CGP7930 (Tocris, Ballwin, MO, USA).

(±)-Baclofen and D-AMPH were dissolved in water,

and CGP7930 was dissolved in 2 drops (20 µl/drop)

of ethanol and then in 1% Tween 80. All drugs were

prepared fresh daily and were administered via

intraperitoneal injection (1 ml/kg).

Apparatus

Locomotor activity was measured with an open-field

activity monitoring system (ENV-515 model; Med

Associates, St. Albans, VT. USA). Each Plexiglas

cage (40 × 40 × 30 cm) was equipped with 2 sets of 8

photobeams that were placed 2.5 cm above the sur-

face of the floor on opposite walls to record x–y am-

Pharmacological Reports, 2013, 65, 1132�1143 1133

Effects of BCF and CGP on AMPH-induced locomotor sensitization

Laura N. Cedillo and Florencio Miranda

bulatory movements. Photobeam interruptions were

recorded and translated by software to yield the hori-

zontal distance traveled (in cm), which was the de-

pendent measure used for analysis.

Experimental procedure

The timeline of the general procedure is shown in Figure

1. Each day or session started with a 10 min period of

habituation to the cages, followed by administration of

drug(s) or vehicle (VEH). The rats were returned to the

cages, and their locomotor activity was recorded for 1 h.

On day 1, the rats were habituated to the open-field

cages and injection procedures (habituation session). On

day 2, locomotor activity after VEH administration (lo-

comotor activity baseline) was evaluated. On days 3–7,

the rats received pharmacological compounds and/or

AMPH (for development of AMPH-induced locomotor

sensitization; see Tab. 1). On days 8–9, the rats were left

undisturbed (resting days). In the experiments examin-

ing the development of AMPH sensitization, the rats

were injected with VEH and AMPH on days 10 and 11,

respectively (test days), while in the experiments exam-

ining the expression of AMPH sensitization, the rats

were injected with VEH on day 10 and with pharmacol-

ogical compounds and/or AMPH on day 11 (see Tab. 1).

In all experiments, the rats were injected with CGP and

BCF 1 min before AMPH injection and immediately re-

turned to the cages, where their locomotor activity was

recorded for 1 h.

Acute effects of BCF and CGP on locomotor activity

The locomotor activity in groups of animals (n = 10

rats per group) was assessed once in response to each

different dose of BCF (0.0, 2.0, 3.0, and 4.0 mg/kg)

and CGP (0.0, 5.0, 10.0, and 20.0 mg/kg).

Experiment 1: Effects of BCF and CGP co-administration on the development of AMPH-induced locomotor sensitization (see Tab. 1 forthe schedule of drug treatment for Experiment 1and Experiment 2)

a) Effects of BCF on the development of AMPH-

induced locomotor sensitization. On the days where

the development of sensitization was examined,

groups of rats (n = 10 rats per group) received one of

the following treatments: VEH + VEH (group 2V),

VEH + AMPH (1.0 mg/kg; group VA), BCF (2.0 mg/

kg) + AMPH (1.0 mg/kg; group B2A), BCF (3.0 mg/

kg) + AMPH (1.0 mg/kg; group B3A), or BCF

(4.0 mg/kg) + AMPH (1.0 mg/kg; group B4A).

b) Effects of CGP on the development of AMPH-


the development of sensitization was examined,

groups of rats (n = 10 rats per group) received one of

the following treatments: VEH + VEH (group 2V),

VEH + AMPH (1.0 mg/kg; group VA), CGP (5.0 mg/

kg) + AMPH (1.0 mg/kg; group C5A), CGP (10.0 mg/

kg) + AMPH (1.0 mg/kg; group C10A), or CGP

(20.0 mg/kg) + AMPH (1.0 mg/kg; group C20A).

c) Effects of the co-administration of CGP and

BCF on the development of AMPH-induced locomo-

tor sensitization. On the days where the development

of sensitization was examined, groups of rats (n = 10

rats per group) received one of the following treat-

ments: VEH + VEH + VEH (group 3V), VEH + VEH

+ AMPH (1.0 mg/kg; group 2VA), VEH + BCF

(2.0 mg/kg) + AMPH (1.0 mg/kg; group VB2A), CGP

(5.0 mg/kg) + BCF (2.0 mg/kg) + AMPH (1.0 mg/kg;

group C5B2A), CGP (10.0 mg/kg) + BCF (2.0 mg/kg)

+ AMPH (1.0 mg/kg; group C10B2A), or CGP

(20.0 mg/kg) + BCF (2.0 mg/kg) + AMPH (1.0 mg/

kg; group C20B2A).

Experiment 2: Effects of BCF and CGP co-administration on the expression of AMPH-induced locomotor sensitization

a) Effects of BCF on the expression of AMPH-


the development of sensitization was examined (3–7),

one group (n = 10 rats) received an injection of VEH

+ VEH, and the other groups of rats (n = 10 rats per

group) received an injection of VEH + AMPH

(1.0 mg/kg) (see Tab. 1 for details). On day 10, all

groups were injected with VEH. On day 11, each

group of rats received one of the following treat-


1 2 3 4 5 6 7

Development of

sensitization

Test

Days

Resting

days

ABL

8 9 10 11

H V

1 2 3 4 5 6 7DAYS

Development of

sensitization

Test

Days

Resting

days

ABL

8 9 10 11

H V

Fig. 1. Schematic diagram illustrating the timeline of AMPH (1 mg/kg)-induced locomotor sensitization. H – habituation, BL – baselinelocomotor activity, V – vehicle, A – amphetamine

ments: VEH + AMPH (group V-VA), VEH + AMPH

(1.0 mg/kg; group A-VA), BCF (2.0 mg/kg) + AMPH

(1.0 mg/kg; group B2A), BCF (3.0 mg/kg) + AMPH

(1.0 mg/kg; group B3A), or BCF (4.0 mg/kg) +

AMPH (1.0 mg/ kg; group B4A).

b) Effects of CGP on the expression of AMPH-

induced locomotor sensitization. On the days where the

development of sensitization was examined, one group

(n = 10 rats) received an injection of VEH + VEH, and

the other groups of rats (n = 10 rats per group) received




Tab. 1. Experimental design of development and expression of AMPH-induced locomotor sensitization

Nameof groups

Repeated treatment Challenge

Days 3 to 7 Day 10 Day 11

Development of sensitization

2V VEH + VEH VEH AMPH(1.0)

VA VEH + AMPH(1.0) VEH AMPH(1.0)

B2A BCF(2.0) + AMPH(1.0) VEH AMPH(1.0)



2V VEH + VEH VEH AMPH(1.0)

VA VEH + AMPH(1.0) VEH AMPH(1.0)

C5A CGP(5.0) + AMPH(1.0) VEH AMPH(1.0)



3V VEH + VEH + VEH VEH AMPH(1.0)

2VA VEH + VEH + AMPH(1.0) VEH AMPH(1.0)

VB2A VEH + BCF(2.0) + AMPH(1.0) VEH AMPH(1.0)

C5B2A CGP(5.0) + BCF(2.0) + AMPH(1.0) VEH AMPH(1.0)



Expression of sensitization

V-VA VEH + VEH VEH VEH + AMPH(1.0)

A-VA VEH + AMPH(1.0) VEH VEH + AMPH(1.0)

B2A VEH + AMPH(1.0) VEH BCF(2.0) + AMPH(1.0)



V-VA VEH + VEH VEH VEH + AMPH(1.0)

A-VA VEH + AMPH(1.0) VEH VEH + AMPH(1.0)

C5A VEH + AMPH(1.0) VEH CGP(5.0) + AMPH(1.0)



2VA VEH + VEH + VEH VEH VEH + VEH + AMPH(1.0)

A-2VA VEH + VEH + AMPH(1.0) VEH VEH + VEH + AMPH(1.0)

VB2A VEH + VEH + AMPH(1.0) VEH VEH + BCF(2.0) + AMPH(1.0)

C5B2A VEH + VEH + AMPH(1.0) VEH CGP(5.0) +BCF(2.0) + AMPH(1.0)

C10B2A VEH + VEH + AMPH(1.0) VEH CGP10.0) + BCF(2.0) + AMPH(1.0)

C20B2A VEH + VEH + AMPH(1.0) VEH CGP(20.0) + BCF(2.0) + AMPH(1.0)

VEH: appropiate vehicle; AMPH: amphetamine; in parentheses doses: mg/kg; ip

an injection of VEH + AMPH (1.0 mg/kg). On day

10, all groups were injected with VEH. On day 11,

each group of rats received one of the following treat-

ments: VEH + AMPH (group V-VA), VEH + AMPH

(1.0 mg/kg; group A-VA), CGP (5.0 mg/kg) + AMPH

(1.0 mg/kg; group C5A), CGP (10.0 mg/kg) + AMPH

(1.0 mg/kg; group C10A), or CGP (20.0 mg/kg) +

AMPH (1.0 mg/kg; group C20A).

c) Effects of CGP and BCF co-administration on

the expression of AMPH-induced locomotor sensiti-

zation. On the days where the development of sensiti-

zation was examined, one group (n = 10 rats) received

an injection of VEH + VEH + VEH, and the other

groups of rats (n = 10 rats per group) received an in-

jection of VEH + VEH + AMPH (1.0 mg/kg). On day

10, all groups were injected with VEH. On day 11,

each group of rats received one of the following treat-

ments: VEH + VEH + AMPH (group 2VA), VEH

+ VEH + AMPH (1.0 mg/kg; group A-2VA), VEH

+ BCF (2.0 mg/kg) + AMPH (1.0 mg/kg; group

VB2A), CGP (5.0 mg/kg) + BCF (2.0 mg/kg)

+ AMPH (1.0 mg/kg; group C5B2A), CGP (10.0

mg/kg) + BCF (2.0 mg/kg) + AMPH (1.0 mg/kg;

group C10B2A), or CGP (20.0 mg/kg) + BCF (2.0

mg/kg) + AMPH (1.0 mg/kg; group C20B2A).

Data analysis

The results of the investigated measure (distance trav-

eled, in cm) are expressed as the mean ± SEM. The

data obtained during the development of locomotor

sensitization were analyzed via two-way ANOVA for

repeated measures, with the group as the first factor

and the day as the second factor. The data obtained

during the baseline and testing days were analyzed

through one-way ANOVA. When the ANOVA results

were significant, Tukey’s test (p < 0.05) was used to

perform a posteriori comparisons.

Results

Acute effects of BCF and CGP on locomotor

activity

The results of this experiment revealed that neither BCF

[F (3, 39) = 0.896, p > 0.05] nor CGP [F (3, 39) = 0.892,

p > 0.05] altered the locomotor activity of the rats.

EXPERIMENT 1

a) Effects of BCF on the development of AMPH-

induced locomotor sensitization.

The data obtained from the baseline locomotor

activity measurements were similar in all groups

[F (4, 49) = 0.781, p > 0.05]. Repeated administration

of AMPH resulted in the development of sensitization

to locomotor activity. However, administration of

BCF at doses of 3.0 and 4.0 mg/kg, but not at

2.0 mg/kg, attenuated the locomotor activity produced

by AMPH treatment. Two-way ANOVA for repeated

measures indicated significant effects of the group

[F (4, 45) = 25.516, p < 0.05], day [F (4, 180) = 8.483,

p < 0.05], and the group × day interaction [F (16, 180)

= 3.999, p < 0.05]. The results of the VEH test are

shown in Figure 2A. Animals that were treated with

either AMPH alone or AMPH in combination with

BCF showed conditioned locomotion. Here, one-way

ANOVA indicated a significant group effect [F (4, 49)

= 3.58, p < 0.05], and Tukey’s test revealed that all

other groups were significantly different from the 2V

group. The results of the administration of AMPH on

day 11 are shown in Figure 2B. When BCF was

administered for 5 days in combination with AMPH

injection, it was observed that BCF reduced the

AMPH-induced locomotor activity in a dose-depend-

ent manner [F (4, 49) = 2.921, p < 0.05]. Tukey’s test

revealed that the VA group was different from the 2V

group and that the B3A and B4A groups were differ-

ent from the VA group.

b) Effects of CGP on the development of AMPH-

induced locomotor sensitization. The baseline locomo-

tor activity was similar in all groups [F (4, 49) = 0.264,

p > 0.05]. Repeated administration of AMPH induced

the development of sensitization to locomotor activity.

The AMPH-induced locomotor sensitization was not

altered after the administration of CGP (a positive al-

losteric modulator of GABAB receptors) at different

doses. Two-way ANOVA for repeated measures indi-

cated significant effects of the group [F (4, 45) =

34.367, p < 0.05], day [F (4, 180) = 6.721, p < 0.05],

and the group × day interaction [F (16, 180) = 1.306,

p < 0.05]. The results of the VEH test are shown in

Figure 2C. Animals treated with either AMPH alone or

AMPH in combination with CGP showed conditioned

locomotion. One-way ANOVA indicated a significant

group effect [F (4, 49) = 3.79, p < 0.05], and Tukey’s

test revealed that all other groups were different from

the 2V group. The results of the administration of


AMPH on day 11 are shown in Figure 2D. When CGP

was administered for 5 days in combination with

AMPH injection, it was found that CGP did not re-

duce the AMPH-induced locomotor activity [F (4, 49)

= 5.313, p < 0.05]. Tukey’s test revealed that the VA

group was different from the 2V group.


the development of AMPH-induced locomotor sensi-

tization. The baseline locomotor activity was similar

in all groups [F (5, 59) = 1.30, p > 0.05]. Repeated ad-

ministration of AMPH resulted in the development of

sensitization to locomotor activity. AMPH-induced

locomotor sensitization was affected by the admini-

stration of the combination of CGP at different dos-

ages and a lower dose of BCF. Two-way ANOVA for

repeated measures indicated significant effects of the

group [F (5, 54) = 26.98, p < 0.05], day [F (4, 216) =

11.002, p < 0.05], and the group × day interaction

[F (20, 216) = 3.74, p < 0.05], and Tukey’s test re-

vealed that the C20B2A group was different than the

2VA group. The results of the VEH test are shown in

Figure 2E. Animals treated with either AMPH alone

or AMPH in combination with CGP and BCF exhib-

ited conditioned locomotion. One-way ANOVA indi-




Fig. 2. Results for challenge days after the development of AMPH-induced locomotor sensitization. The bars represent the mean ± SEM from10 rats. A, C and E represent the vehicle test. B, D and F represent the AMPH test. * p < 0.05, different from the 2V or 3V group based on one-way ANOVA followed by Tukey’s post-hoc test. + p < 0.05, different from the VA or 2VA group based on one-way ANOVA followed by Tukey’spost-hoc test. The name of the groups refers only the treatment received during the development of AMPH-induced locomotor sensitization(see Tab. 1 for further details)

cated significant differences between groups [F (4, 49)

= 3.37, p < 0.05]. Tukey’s test revealed that all groups

were different from the 3V group. The results of ad-

ministration of AMPH on day 11 are shown in Figure

2F. After 5 days of AMPH administration in combina-

tion with CGP and BCF, it was observed that CGP in-

creased the effects of BCF on AMPH-induced loco-

motor activity [F (5, 59) = 4.332, p < 0.05]. Tukey’s

test revealed that locomotor activity differed between

the 2VA group and the 3V group and that the C20B2A

group was different from the 2VA group.

cated significant differences between groups [F (4, 49)

= 3.37, p < 0.05]. Tukey’s test revealed that all groups

were different from the 3V group. The results of ad-

ministration of AMPH on day 11 are shown in Figure

2F. After 5 days of AMPH administration in combina-

tion with CGP and BCF, it was observed that CGP in-

creased the effects of BCF on AMPH-induced loco-

motor activity [F (5, 59) = 4.332, p < 0.05]. Tukey’s

test revealed that locomotor activity differed between

the 2VA group and the 3V group and that the C20B2A

group was different from the 2VA group.

EXPERIMENT 2

a) Effects of BCF on the expression of AMPH-

induced locomotor sensitization. The baseline loco-

motor activity on day 2 was similar in all groups

[F (4, 49) = 1.370, p > 0.05]. Repeated administration

of AMPH led to the development of sensitization to

locomotor activity in all groups, except the V-VA

group. Two-way ANOVA for repeated measures indi-

cated significant effects of the group [F (4, 45) =

16.356, p < 0.05], day [F (4, 180) = 8.54, p < 0.05],

and the group × day interaction [F (16, 180) = 1.80, p

< 0.05], and Tukey’s test revealed that the V-VA

group was different from all other groups. The results

of the VEH test on day 10 are shown in Figure 3A.

Animals treated with AMPH exhibited conditioned

locomotion. One-way ANOVA indicated the exis-

tence of significant differences between groups

[F (4, 49) = 5.16, p < 0.05], and Tukey’s test revealed

that all other groups were different from the V-VA

group. The results of the administration of either

AMPH or different doses of BCF and AMPH on day

11 are shown in Figure 3B. Administration of BCF

led to a dose-dependent reduction in the expression of

AMPH-induced locomotor activity [F (4, 49) = 5.05 p

< 0.05]. Tukey’s test revealed that the A-VA group

was different than the V-VA group and that the B3A

and B4A groups were different than the A-VA group.

b) Effects of CGP on the expression of AMPH-


The baseline locomotor activity on day 2 was simi-

lar in all groups [F (4, 49) = 1.378, p > 0.05], and re-

peated administration of AMPH resulted in the devel-

opment of sensitization to locomotor activity in all

groups, except the V-VA group. Two-way ANOVA for

repeated measures indicated a significant effect of the

group [F (4, 45) = 27.74, p < 0.05] and day [F (4, 180)

= 9.27, p < 0.05], but the group × day interaction was

not significant [F (16, 180) = 1.32, p > 0.05]. Tukey’s

test revealed that the V-VA group was different from

all other groups. The results of the VEH test on day

10 are shown in Figure 3C. Animals treated with

AMPH presented conditioned locomotion. One-way

ANOVA indicated significant differences between

groups [F (4, 49) = 3.84, p < 0.05], and Tukey’s test

revealed that all groups were different from the V-VA

group. The results obtained following the administra-

tion of AMPH or different doses of CGP and AMPH

on day 11 (see Fig. 3D) showed that CGP does not af-

fect the expression of AMPH-induced locomotor ac-

tivity [F (4, 49) = 3.74, p < 0.05], and Tukey’s test re-

vealed that the A-VA group was different from the

V-VA group.


the expression of AMPH-induced locomotor sensiti-

zation. The baseline locomotor activity on day 2 was

similar in all groups [F (5, 59) = 1.48, p > 0.05]. Re-

peated administration of AMPH led to the develop-

ment of sensitization to locomotor activity in all

groups, except the 2VA group. Two-way ANOVA for

repeated measures indicated significant effects of the

group [F (5, 54) = 18.563, p < 0.05] and day

[F (5, 216) = 10.24, p < 0.05], but the group × day in-

teraction was not significant [F (14, 216) = 1.22, p >

0.05]. Tukey’s test revealed that the 2VA group was

different from all other groups. The results of the

VEH test on day 10 are shown in Figure 3E. Animals

treated with AMPH displayed conditioned locomo-

tion. One-way ANOVA indicated significant differ-

ences between groups [F (4, 49) = 5.54, p < 0.05], and

Tukey’s test revealed that all other groups were differ-

ent from the 2VA group. The results of the administra-

tion of different doses of CGP, BCF2.0, and AMPH

on day 11 are shown in Figure 3F. Administration of

CGP increased the effects of BCF on the expression

of AMPH-induced locomotor activity [F (5, 59) =

2.21, p < 0.05]. Tukey’s test revealed that the A-2VA

group was different from the 2VA group and that the

C20B2A group was different from the A-2VA group.

Discussion

The purpose of the present study was to examine the

effects of the co-administration of the GABAB recep-

tor agonist BCF with CGP, a positive allosteric modu-


lator of GABAB receptors, on AMPH-induced loco-

motor sensitization. We found that AMPH increased

locomotor activity and that BCF treatment resulted in

prevention of both the development and the expres-

sion of AMPH-induced locomotor sensitization in

a dose-dependent manner, whereas CGP had no effect

on either the development or the expression of

AMPH-induced locomotor activity. We also observed

that administration of the positive allosteric modula-

tor CGP increased the effects of a lower dose of BCF

on AMPH-induced locomotor sensitization under

both conditions. Additionally, an increase in locomo-

tor activity was detected during the VEH test (day

10), which is interpreted as conditioned locomotion

[58] and could mask the main effects of the drugs

tested on day 11. However, although this possibility

cannot be completely ruled out, we found that BCF

and/or CGP reduced, rather than increased, AMPH-




Fig. 3. Results for challenge days during the expression of AMPH-induced locomotor sensitization. Bars represent the mean ± SEM from10 rats. A, C and E represent the vehicle test. B, D and F represent the results obtained during treatment with pharmacological compoundsand/or following AMPH injection. * p < 0.05, different from the V-VA or 2VA group based on one-way ANOVA followed by Tukey’s post- hoc test.+ p < 0.05, different from the A-VA or A-2VA group based on one-way ANOVA followed by Tukey’s post-hoc test. The name of the groups refersonly the treatment received during the expression of AMPH-induced locomotor sensitization (see Tab. 1 for further details)

induced locomotor activity in a dose-dependent man-

ner, in terms of both the development and expression

of AMPH-induced locomotor sensitization.

The behavioral results described above are consis-

tent with those of previous studies demonstrating that

the GABAB receptor agonist BCF attenuates AMPH-

induced locomotor sensitization. For example, it has

been reported previously that BCF prevents both the

development [3] and expression [4] of sensitization to

the locomotor effects of AMPH. BCF also attenuates

the sensitization to the locomotor stimulant effects of

cocaine [23], morphine [5, 24], and ethanol [13].

Furthermore, BCF attenuates psychostimulant-

related behaviors associated with drug addiction. BCF

pre-treatment reduces cocaine self-administration in

rats responding under fixed ratio schedules [11], pro-

gressive ratio schedules [2, 50], discrete trial sched-

ules of reinforcement [10], and second-order sched-

ules [18]. Additionally, BCF decreases AMPH self-

administration under a fixed ratio or progressive ratio

schedule [9] and attenuates conditioned locomotion in

response to cues associated with cocaine administra-

tion [25]. Moreover, BCF attenuates the behavioral

effects of ethanol [15], nicotine [44], and heroin [18],

and we found in a previous study that BCF reduces

the discriminative stimulus properties of AMPH [41].

The mechanism underlying the observed effects of

BCF on AMPH-induced locomotor sensitization may

involve GABAergic modulation of DAergic transmis-

sion within the VTA. Several lines of evidence sup-

port this notion. First, the mesolimbic DA system,

particularly the projection from the VTA to the NAcc,

is an important locus in the production of the locomo-

tor, reinforcement, and reward effects of psy-

chostimulants such as cocaine and AMPH [17, 31,

35], and this system plays an important role in both

the development and expression of psychostimulant-

induced locomotor sensitization [46]. Second, the

VTA contains primary DAergic neurons, which re-

lease DA in the NAcc and prefrontal cortex, and sec-

ondary GABAergic interneurons, which reduce the

firing rate of DAergic neurons in the VTA. In addi-

tion, GABAergic neurons arising from the NAcc proj-

ect to DAergic neurons within the VTA [29, 33]. This

loop represents an important locus in the production

of certain abuse-related behavioral effects of psy-

chostimulants [35]. Third, anatomical evidence sug-

gests that GABAB receptors are located within the

VTA [8, 27, 29, 42]. Fourth, biochemical and behav-

ioral studies have found that infusion of BCF into the

VTA decreases DA release in the NAcc [59, 62],

which suggests that the activation of GABAB recep-

tors located on the cell bodies of mesolimbic DAergic

neurons is involved in the biochemical effects of BCF.

Furthermore, microinjection of BCF into the VTA re-

duces cocaine self-administration under fixed ratio

[53] and progressive ratio schedules [12], and micro-

injection of BCF was also found to reduce heroin

self-administration [61] and AMPH-induced motor

activity [30]. Altogether, these data support the hy-

pothesis that the activation of GABAB receptors on

the cell bodies of DAergic neurons in the VTA plays

an important role in the suppressive effects of BCF on

both the development and the expression of AMPH-


In this study, it was also observed that a positive al-

losteric modulator of GABAB receptors, CGP, in-

creased the effects of a lower dose of BCF on

AMPH-induced locomotor sensitization. It is worth

noting that CGP did not alter AMPH-induced locomo-

tor sensitization at any of the tested dosages. These

results are consistent with those of at least one previ-

ous study, in which the combination of a lower dose

of BCF with a dose of CGP reduced ethanol self-

administration [39]. Furthermore, it has been reported

that CGP injections lead to a reduction of ethanol in-

take in ethanol-preferring rats [39, 43], of cocaine

self-administration in rats responding under several

schedules of reinforcement [22, 54], of cocaine-

seeking behavior [21], of nicotine-induced locomotor

stimulation in mice [40], and of nicotine self-adminis-

tration [45]. In addition, CGP treatment was shown to

produce approximately 41% BCF-appropriate re-

sponses but also to enhance the discriminative stimu-

lus effects of BCF in pigeons trained to discriminate

BCF from saline [34].

The above findings together with the present data

provide behavioral evidence that BCF and related

compounds, such as CGP, may represent potential

pharmacological treatments for drug addiction. Posi-

tive allosteric modulators of GABAB receptors, such

as CGP, display no intrinsic activity of their own but

can modulate the activity of GABA or GABAB ago-

nists, such as BCF, while avoiding the possible ad-

verse side effects of BCF administration. In contrast

to the data cited above, recent studies have shown that

the administration of GS39783 alone, which is an-

other positive modulator of GABAB receptors, signifi-

cantly attenuates the locomotor activity induced by

a single cocaine treatment and reduces modest co-


caine-induced locomotor sensitization [38]. It has also

been reported that GS39783 reduces the locomotor

activity arising from acute ethanol administration,

without any effects on ethanol-induced locomotor

sensitization, whereas when GS39783 is administered

in conjunction with ethanol, it potentiates ethanol-

induced locomotor sensitization [37].

It is important to note that the GABAB receptor is

a G protein-coupled heterodimer composed of GABAB1and GABAB2 subunits, which have different functions

[7]. The GABAB1 subunit is essential for ligand bind-

ing, while the GABAB2 subunit provides the G pro-

tein-coupling mechanism and incorporates an alloste-

ric modulatory site [47]. It has been suggested that the

G protein-coupling mechanism of the GABAB2 sub-

unit involves an interaction with the extracellular do-

main of the GABAB1 subunit, and as a result of this

interaction, agonist affinity and coupling efficacy are

increased [6]. In line with this suggestion, it has been

reported that CGP is effective in facilitating the in-

hibitory effects of BCF on the spontaneous firing

rates of VTA DAergic neurons. CGP shifts the BCF

concentration-response curve to the left but has no ef-

fect when administered alone [14]. According to the

authors, the reason that CGP alone does not cause any

change in the spontaneous firing rate of VTA DAergic

neurons is most likely that the amount of GABA re-

leased onto these neurons is too low to activate the

GABAB receptors. Positive modulators of GABAB re-

ceptors, such as CGP, are devoid of intrinsic activity,

and their actions are dependent on the presence of en-

dogenous GABA or other GABAB agonists [56, 57].

It is well known that DAergic neurons are tonically

inhibited by GABAergic interneurons within the VTA

[27] and that the VTA DAergic neurons receive inputs

from GABAergic neurons that originate in the NAcc

[55]. This circuit provides the endogenous levels of

GABA required to activate GABAB receptors. The in-

hibitory control of GABA over the VTA DAergic neu-

rons can be enhanced in the presence of a positive al-

losteric modulator of GABAB receptors, such as CGP.

Therefore, these previous observations could explain

the results of the current study and of some studies in

which CGP was administered alone, if CGP acts syn-

ergistically with GABA or with a GABAB agonist, de-

spite displaying no intrinsic activity of its own.

In conclusion, the results of the present study dem-

onstrated that the GABAB receptor agonist BCF pre-

vented both the development and the expression of

AMPH-induced locomotor sensitization in a dose-

dependent manner. Furthermore, CGP, a positive al-

losteric modulator of GABAB receptors, increased the

effects of a lower dose of BCF on AMPH-induced lo-

comotor sensitization under both conditions. These

data provide further evidence that GABAB receptor

ligands may modulate psychostimulant-induced be-

haviors and that positive allosteric modulators of

GABAB receptors may present pharmacological po-

tential when combined with the use of conventional

GABAB agonists, such as BCF.

Acknowledgments:

This study was supported by grant 60872 from CONACyT (México)

and a doctoral fellowship awarded to the first author (CONACyT,

México).

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Received: June 22, 2012; in the revised form: April 5, 2013;

accepted: May 13, 2013.




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