Methamphetamine-induced changes in the striatal dopamine pathway in μ-opioid receptor knockout mice
Journal of Biomedical Science
Methamphetamine-induced changes in the striatal dopamine pathway in -opioid receptor knockout mice
Sang Won Park 0
Xine Shen 2
Lu-Tai Tien 1
Richard Roman 0
Tangeng Ma 0
0 Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, MS 39216 , USA
1 School of Medicine, Fu Jen Catholic University , Taipei , Taiwan
2 Department of Physiology, Medical school, Soochow University , Jiangsu, P.R China
Background: Repeated exposure to methamphetamine (METH) can cause not only neurotoxicity but also addiction. Behavioral sensitization is widely used as an animal model for the study of drug addiction. We previously reported that the -opioid receptor knockout mice were resistant to METH-induced behavioral sensitization but the mechanism is unknown. Methods: The present study determined whether resistance of the -opioid receptor (-OR) knockout mice to behavioral sensitization is due to differential expression of the stimulatory G protein a subunit (Gas) or regulators of G-protein signaling (RGS) coupled to the dopamine D1 receptor. Mice received daily intraperitoneal injections of saline or METH (10 mg/kg) for 7 consecutive days to induce sensitization. On day 11(following 4 abstinent days), mice were either given a test dose of METH (10 mg/kg) for behavioral testing or sacrificed for neurochemical assays without additional METH treatment. Results: METH challenge-induced stereotyped behaviors were significantly reduced in the -opioid receptor knockout mice when compared with those in wild-type mice. Neurochemical assays indicated that there is a decrease in dopamine D1 receptor ligand binding and an increase in the expression of RGS4 mRNA in the striatum of METH-treated -opioid receptor knockout mice but not of METH-treated wild-type mice. METH treatment had no effect on the expression of Gas and RGS2 mRNA in the striatum of either strain of mice. Conclusions: These results indicate that down-regulation of the expression of the dopamine D1 receptor and upregulation of RGS4 mRNA expression in the striatum may contribute to the reduced response to METH-induced stereotypy behavior in -opioid receptor knockout mice. Our results highlight the interactions of the -opioid receptor system to METH-induced behavioral responses by influencing the expression of RGS of dopamine D1 receptors.
Amphetamine; ??-opioid receptor; addiction; dopamine receptors
Methamphetamine (METH) is a highly abused CNS
stimulant with high reward properties that leads to
compulsive drug seeking behavior [1,2]. The mechanism of
the additive properties to METH remains to be
determined. Repeated administration of METH results in
behavioral sensitization characterized by persistent
hyperlocomotor activity and stereotyped behaviors [3,4].
Animals remain sensitized for many weeks, suggesting
that the development of sensitization involves
long-lasting neuronal adaptations . The neural alterations
underlying behavioral sensitization are also thought to
contribute to mimic changes associated with the
compulsive drug seeking behavior. Thus, behavioral
sensitization is widely used as an animal model for the study
of drug addiction [5-8] and it is extremely important to
find therapeutic agents for behavioral sensitization to
The dopamine system is generally considered a main
target for amphetamines to stimulate locomotor activity
and stereotyped behaviors. The nigrostriatal
dopaminergic pathway consists of dopaminergic neurons of the
substantia nigra that innervate the striatum  that is
intimately linked to the stereotyped behaviors produced
by psychomotor stimulants . It is well known that
an increase in dopaminergic activity in the central
nervous system (CNS) plays a central role in induction and
expression of behavioral sensitization by psychomotor
stimulants. For example it is known that activation of
dopamine receptors is required for the expression of
behavioral sensitization by METH . METH
stimulates the release of dopamine from dopaminergic
neurons and activates dopamine receptors . Dopamine
receptors as members of the G protein-coupled receptor
(GPCR) superfamily elicit a variety of cellular and
behavioral responses through various signaling pathways to
induce behavioral effects . Regulators of G-protein
signaling (RGS) proteins negatively regulate GPCR
signaling, changes in RGS protein levels in the brain are
thought to modulate the intensity and duration of
signaling of cognate receptors . The expression of several
RGS proteins in the brain is rapidly altered in response to
psychostimulants . In addition there is growing
evidence that exposure to amphetamine-like stimulants
influences the expression of dopamine receptors,
G-proteins and RGS in neurons that may contribute to
stimulant-mediated behavioral responses . Chronic
administration of dopamine D1 agonist SKF 38393 results
in enhanced behavioral responses to subsequent
administration of a variety of dopamine agonists [17,18]. Others
have found that stereotypic behavior in response to
amphetamine administration is associated with increased
expression of dopamine D1 receptors  and
hypersensitivity of adenylate cyclase to dopamine stimulation which
is blocked by the dopamine D1 antagonist SCH 23390
It is also clear that there are extensive anatomical and
functional interactions between the dopaminergic
system and other neuronal pathways. For example both
the opioidergic and glutamatergic systems contribute to
the development and maintenance of behavioral
sensitization to METH . Endogenous opioid systems have
been found to play important roles in reward, positive
reinforcement, and additive effects on drugs of abuse
[22-24]. The endogenous opioid systems consist of a
variety of endogenous opioid peptides and receptors. At
least three opioid receptor subtypes (, , and ) are
currently recognized . Enkephalins have high affinity
for - and - opioid receptors whereas dynorphins have
high affinity for -opioid receptors. It has been reported
that amphetamines induce an increase in expression of
the opioid peptide enkephalin precursor
preproenkephalin mRNA in rodent striatum . No behavioral
sensitization to amphetamine was detected in the enkephalin
knockout mice . We also reported that -opioid
receptor (-OR) knockout mice were less sensitive to
the development of behavioral sensitization to METH
. However, it remains to be determined how -OR
contribute to METH-induced behavioral responses. The
present study examined whether METH exposure
causes differential changes in the expression of
stimulatory Ga (Gas; subunit coupled to dopamine D1
receptors) or RGS associated with dopamine D1 receptors in
the CNS that may contribute to the resistance to
METH-induced behavioral sensitization in -OR
Materials and methods
Animals and drug treatments
The -OR knockout mice were originally developed by
Loh et al.  on a C57/BL6 and 129/Ola hybrid genetic
background. Our colony was maintained as heterozygotes
by brother sister mating in the Laboratory Animal Facility
of the University of Mississippi Medical Center (UMMC).
All procedures were approved by Institutional Animal
Care and Use Committee of the UMMC, and performed
in compliance with the NIH Guide for the Care and Use
of Laboratory Animals. Adult male wild-type and -OR
knockout mice were used in this study. -OR knockout
and wild-type mice (n = 12 for each genotype) were given
METH (10 mg/kg, i.p.) once a day for 7 consecutive days
to induce sensitization in order to investigate
METHevoked behavioral response. This dose was chosen on the
basis of previous studies indicating that it was the dose
that induced stereotyped behavioral sensitization to
subchronic administration of METH in mice [28,30]. On day
11, after a 4 day drug washout period, the sensitized mice
were challenged with a i.p. injection of METH (10 mg/kg).
Stereotyped behaviors were monitored for 30 min before
and for 5 hrs after the injection to evaluate the behavioral
The behavior of mice was monitored in a Plexiglas box
equipped with a CCD camera and recorded on video tape,
which was subsequently analyzed by a trained observer.
The intensity of stereotyped activity was scored on 4-point
scale (0 - normal behavior, 1 - periodic sniffing, 2 -
continuous sniffing, 3 - continuous sniffing, periodic licking or
gnawing, 4 - continuous licking or gnawing) as described
by Costall and colleagues .
Parallel experiments were performed in another group
of wild-type and -OR knockout mice to assess changes in
the expression of dopamine receptors and mRNA in the
brain. These animals were sensitized using the same 7 day
exposure to METH or vehicle. After a 4 day drug-washout
period, the animals were decapitated and the brains
collected and frozen in liquid nitrogen. Coronal sections
(1420 mm thick) were cut using a cryostat (Tissue-Tek, cyro
2000) at -20C, thaw-mounted on gelatin-coated slides
and stored at -80C for autoradiography and in situ
Dopamine D1 receptor levels were measured using
radiolabeled ligand binding and autoradiography as previously
described by Qian et al. . Briefly, brain sections were
pre-incubated at 4C for 30 min in a 50 mM Tris-HCI
buffer (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 2 mM
CaCl2, and 1 mM MgCl2, and then incubated for 60 min
with 1.6 nM of the labeled dopamine D1 receptor
antagonist [3H]SCH23390 at room temperature. Other sections
were incubated with 30 M of the dopamine D1 receptor
ligand ()SKF38393  to control for nonspecific
binding. The labeled brain sections as well as a set of
[3H]impregnated plastic standards ([3H]Microscale, Amersham
Life Science) were placed on Kodak BioMax MS film for 3
weeks (-80C). The films were developed, and then
analyzed using a scanning densitometer and Image Quant 3.3
program (Molecular Dynamics; Sunnyvale, CA).
In Situ Hybridization
The expression of Gas, RGS2, and RGS4 mRNAs in the
brain were determined using in situ hybridization. The
focus of the present experiment was to examine changes
in the expression of Gas, RGS2, and RGS4 in the striatum
of the mouse brain. We and others have used in situ
hybridization techniques [34-36] to successfully study gene
expression for a wide variety of gene products. The
technique relies on the specificity of the probe. Oligonucleotide
probes complementary to mRNAs encoding mouse Gas
CCGCCGCC-3) , RGS2 (5-GGGCTCCGTGGT
GATCTGTGGCTTTTTACATAAG-3), and RGS4
GAG-3)  were 3 end labeled with [35S]dATP using
terminal deoxynucleotidyltransferase (PerkinElmer Life
Sciences, Shelton, CT) and in situ hybridization was
performed as described earlier . The probes used were
identical to those described by Tervonen et al.  who
verified that they specifically bound to RGS2 and RGS4
and Przewlocka et al.  who tested the Gas probe. We
also BLASTED the sequence of the probes against all of
the sequences in GENBANK and found that they
exhibited a 100% match to the intended target. Only the RGS4
probe exhibited any significant homology (17 of 35 bp) to
another target, i.e. the presenilin-2 gene. However, given
the limited numbers of complementary base pairs, it is
highly unlikely that the RGS4 would bind to this target at
the hybridization temperature used of 38C. Moreover, we
also performed appropriate control experiment to exclude
non-specific binding. The labeled slides were exposed to
Kodak BioMax MR films for 5 days for Gas or 11 weeks
for RGS2 and RGS4, and the films were developed and
fixed. The quantification of the autoradiogram was
performed using the Image Quant software (Molecular
Dynamics, Sunnyvale, CA).
Data are expressed as mean values SEM. The
significance of differences in mean values was analyzed using
a t test (stereotyped behaviors) or a two-way ANOVA
followed by a Student-Newman-Keuls post hoc test. A
P < 0.05 was considered to be significant.
METH-evoked stereotyped behaviors in METH-sensitized
wild-type and -OR knockout mice
Administration of METH in sensitized wild-type animals
produced stereotyped behaviors, characterized by
continuous sniffing and licking that persisted for about
5 hours. In the -OR knockout mice the cumulative
score of stereotyped behaviors was significantly lower
than in the wild-type mice (Figure 1).
[3H]SCH23390 binding in the striatum of METH-sensitized
wild-type and -OR knockout mice
Representative autoradiograms of [3H]SCH23390
binding in the brain of wild-type and -OR knockout mice
are presented in Figure 2. High levels of [3H]SCH23390
binding were seen in the striatum. Basal binding of [3H]
SCH23390 in the striatum was not significantly different
between wild-type and -OR knockout mice treated
with saline. Repeated METH treatment had no
significant effect on D1 receptor binding in wild type mice. In
contrast, the binding of [3H]SCH23390 was markedly
reduced in the -OR knockout in mice sensitized by
repeated exposure to METH.
Figure 1 METH (10 mg/kg)-evoked stereotyped behaviors in
wild-type and -OR knockout mice that were exposed to
METH for 7 days. METH (10 mg/kg)-evoked stereotyped behaviors
in wild-type and -OR knockout mice that were exposed to METH
for 7 days. Mean values SEM are presented. Numbers in
parentheses represent the number of animals studied. * indicates a
significant difference (P < 0.05) from the corresponding value in
METH-sensitized wild-type mice.
Figure 2 Binding of dopamine D1 ligand [3H]SCH23390 in the brains of METH-sensitized wild-type and -OR knockout mice. Binding of
dopamine D1 ligand [3H]SCH23390 in the brains of METH-sensitized wild-type and -OR knockout mice. Both strains of mice were pretreated
with daily injections saline or METH (10 mg/kg) for 7 consecutive days. Mice were killed 4 days after the final injection and brain tissues were
taken for autoradiographic analysis of [3H]SCH23390 binding. Representative autoradiograms of [3H]SCH23390 binding are shown on the top.
Mean values SEM are presented. Numbers in parentheses represent the number of animals/brains studied. * indicates a significant difference (P
< 0.05) from METH-sensitized wild-type mice; # indicates a significant difference (P < 0.05) from saline-treated -OR knockout mice.
The expression of the stimulatory G protein a subunit
(Gas) mRNA in the striatum of METH-sensitized wild-type
and -OR knockout mice
Representative autoradiograms of in situ hybridization of
Gas mRNA in the brain of wild-type and -OR knockout
mice are presented in Figure 3. Gas mRNA is widely
expressed in most brain areas including striatum and
cerebral cortex. The expression of Gas in the striatum was
similar in both wild-type and -OR knockout animals
treated with saline. METH treatment did not alter the
Figure 3 The expression of Gas mRNA in the brains of METH-sensitized wild-type and -OR knockout mice. The expression of Gas
mRNA in the brains of METH-sensitized wild-type and -OR knockout mice. Animal treatments were the same as described in Fig. 2. Gas mRNA
levels in the brain sections were analyzed by in situ hybridization analysis. Representative autoradiograms of Gas mRNA expression in the brain
of mice are presented at the top of the figure. Mean values SEM are presented. Numbers in parentheses represent the number of animals/
expression of Gas mRNA in the striatum wild type mice
or in -OR knockout mice.
The expression of RGS2 and RGS4 mRNAs in the striatum
of METH-sensitized wild-type and -OR knockout mice
Representative autoradiograms of in situ hybridization
signals for RGS2 and RGS4 mRNAs in the brain of wild-type
and -OR knockout animals are presented in Figures 4
and 5, respectively. Both of RGS2 and RGS4 mRNAs were
highly expressed in the striatum. There was no significant
difference in the expression of RGS2 mRNA in the
striatum of -OR knockout or wild-type mice treated with
saline or METH. Basal expression of RGS4 was also similar
in -OR knockout and wild-type mice treated with saline.
However, the expression of RGS4 mRNA in the striatum
increased in -OR knockout mice treated with METH but
Figure 4 The expression of RGS2 mRNA in the brains of METH-sensitized wild-type and -OR knockout mice. The expression of RGS2
mRNA in the brains of METH-sensitized wild-type and -OR knockout mice. Animal treatments and preparation of brain sections for analysis of
RGS2 mRNA levels were the same as described in Fig. 3. Representative autoradiograms of RGS2 mRNA expression in the brain of mice are
presented at the top of the figure. Mean values SEM are presented. Numbers in parentheses represent the number of animals/brains studied.
The CNS stimulant-METH induces behavioral
sensitization which is associated persistent hyperlocomotor
activity and stereotyped behaviors. Behavior sensitization is a
widely used in rodents model for study of drug addiction
and drug seeking behaviors [5,37]. In the present study
we confirmed previous finding that -OR knockout mice
demonstrate significantly decreased behavioral
sensitization to METH as compared with wild-type mice. This
was associated with a significant reduction in dopamine
D1 receptor density in the striatum of approximately 30%
in -OR knockout mice when compared to wild-type
mice exposed to METH. By way of contrast, METH had
Figure 5 The expression of RGS4 mRNA in the brains of METH-sensitized wild-type and -OR knockout mice. The expression of RGS4
mRNA in the brains of METH-sensitized wild-type and -OR knockout mice. Animal treatments and preparation of brain sections for analysis of
RGS4 mRNA levels were the same as described in Fig. 3. Representative autoradiograms of RGS4 mRNA expression are shown at the top. Mean
values SEM are presented. Numbers in parentheses represent the number of animals/brains studied. * indicates a significant difference (P <
0.05) from METH-sensitized wild-type mice; # indicates a significant difference (P < 0.05) from saline-treated -OR knockout mice.
no effect on dopamine D1 receptor density in the
striatum of wild-type mice.
We also found that the expression of Gas mRNA was
unaltered by METH exposure in wild type or knockout
mice, as was the expression of mRNA of the regulator
of G-protein signaling, RGS2. However, the expression
of RGS4 mRNA was significantly increased in the
striatum of METH treated -OR knockout mice as
compared to saline treated controls, whereas METH
treatment had no effect on RGS4 mRNA in wild-type
controls. These data suggest that in -OR knockout
mice dopamine D1 receptor function in the striatum
can be more readily down-regulated than in wild- type
mice after repeated METH exposure. This may, in part,
explain the decreased behavioral sensitization observed
after METH treatment of -OR knockout mice.
Dopamine is an important neurotransmitter in the
CNS where it plays essential roles in numerous
physiological, neuronal, and behavioral processes. One important
component of the pathways in the CNS is the
nigrostriatal dopaminergic system, projecting from the substantia
nigra to the striatum (putamen and caudate nucleus) that
is known to be crucial for the induction of stereotyped
behaviors . Previously, we and others have performed
dose response studies and found that 2.5 mg/kg METH
is sufficient to elicit a locomotor response [28,38] but
higher doses (10 mg/kg) are needed to induce behavioral
sensitization to METH [28,30]. Repeated stimulation of
dopamine receptors with agonists has been shown to
cause down-regulation in expression of these receptors
. As an indirect dopamine receptor agonist, METH is
known to stimulate the release and inhibit reuptake of
dopamine from synaptic cleft , increasing
extracellular dopamine levels and activating postsynaptic striatal
dopamine receptors. Thus, repeated METH exposure
lead to down regulation of the expression of dopamine
receptors in the striatum. In other studies, we found that
METH (10 mg/kg) was associated with decreased
tyrosine hydroxylase (the rate limiting enzyme of dopamine
synthesis) in wild-type mice but not in the -OR
knockout mice. These results along with our present findings
indicate that the changes of dopaminergic system in mice
chronically exposed to METH is related to a decrease in
the expression of the enzyme involved in the synthesis of
dopamine and its actions on dopamine D1 receptors
rather than to the loss of dopaminergic neurons.
Nonetheless, these data demonstrate that the -opioid receptor
modulates the response of dopamine neurons to METH.
There are two types of dopamine receptors in the
striatum: D1 and D2. Striatonigral neurons largely express
dopamine D1 receptors whereas most striatopallidal
neurons express dopamine D2 receptors . Although
concurrent activation of dopamine D1 and D2 receptors is
thought to be required for the full induction of stereotyped
behaviors , activation of dopamine D1 receptors is
primarily responsible for the induction of dopamine-mediated
stereotypy . Therefore, the down regulation of
dopamine D1 receptor we found in the striatum of
METH-sensitized -OR knockout mice compared with wild-type is
consistent with the view that this contributes to the less of
METH-induced stereotyped behaviors in this strain of
mice. Surprisingly, METH exposure in wild-type mice did
not down-regulate D1 dopamine receptors. Previously our
lab reported that quantitative autoradiographic analysis of
striatum and nucleus accumbens showed that METH
treatment leads to a decrease in dopamine D1 receptor
ligand binding in -OR knockout mice but not in
wildtype mice at low concentration (0.4 nM) of dopamine D1
receptor antagonist SCH 23390 . This suggests that
interactions between opiodergic receptors/neurons and
neurons of the nigrostriatal pathway occur that stabilize
receptor density. These interactions between these
pathways and the mechanisms involved deserve further study.
Chronic treatment (2-3 weeks) with dopamine D1
receptor antagonist SCH 23390 has been reported to
increase the expression of mRNA for preproenkephalin in
the rat striatum [43,44]. Recently, we found that there was
an increase in expression of preproenkephalin mRNA in
the nucleus accumbens and striatum in METH-sensitized
wild-type mice but not in -OR knockout mice . Also,
METH induced hyperlocomotor activity at low doses and
stereotyped behaviors at high doses in wild-type mice 
but not in -OR knockout mice. These results indicate
that a decrease in striatal and nucleus accumbens D1
receptors in METH-sensitized -OR knockout mice is
associated with a decrease in the behavioral response in
these animals. The exact mechanism of how the -opioid
system modulates dopaminergic neurotransmission and
thus influences METH-produced behavioral responses is
unclear. Based on data in the literature, however, it can be
proposed that METH-induced changes in G protein
signaling and RGS proteins might play a role in the
development of behavioral sensitization to the drug.
Dopamine receptors are members of the GPCR family.
Stimulation of the dopamine D1 receptors activates
adenylyl cyclase via Gas, increasing intracellular cAMP that
activates cAMP-dependent protein kinase A and its
down-stream effectors . There is evidence that G
protein signaling may be disrupted in drug addiction and
neuropsychiatric disorders [46,47]. For example,
postmortem brain studies have revealed increased levels of
Gas in bipolar disorder, a type of mood disorder with
unknown etiology as well as being inducible by CNS
stimulants . Elevation of Gas levels is thought to
enhance signaling through the dopamine D1 receptor
and contribute to dopamine D1 receptor
activationmediated behavioral responses . Therefore, we
examined the expression of Gas mRNA in the striatum of
METH-sensitized mice. The results of the present study
indicate that the expression of Gas mRNA in the
striatum was not altered by repeated METH exposure in
either -OR knockout or wild-type mice.
Another possible effect of repeated METH exposure is
to alter the activity of the Ga protein. The primary
regulators of GTPase activity of Ga-subunits are RGS
proteins that rapidly terminate receptor-activated GaGTP
signaling by accelerating the hydrolysis of GTP to GDP
[50,51]. More than 30 mammalian RGS proteins have
been identified [50,52]. Gene expression studies
demonstrate that RGS2 and RGS4 are avidly expressed in
cortex, striatum, and several thalamic regions of the brain
[53,54]. The available evidence suggests that activation of
dopamine D1 and D2 receptors in the striatum of rat is
coupled to RGS2 and RGS4 .
Amphetamine-like stimulants alters RGS mRNA
expression in the brain and triggers GPCR signaling
[56-58]. There are several lines of evidence that acute or
repeated treatment with amphetamine modulates
druginduced behavioral and changes in gene and protein
expression of RGS4 in prefrontal cortex and dorsal
striatum [59-61]. RGS4 mRNA was decreased in the
striatum lasting from 1 to 6 hr after acute amphetamine
. RGS4 may belong to the growing family of factors
regulating convergence of dopamine signaling in the
In the present study, METH (10 mg/kg) exposure had
no influence on the expression of RGS2 mRNA in the
striatum of either -OR knockout or wild-type mice.
However, there was a higher expression of RGS4 mRNA
in the striatum of METH-sensitized -OR knockout
mice but not of wild-type mice. Increased expression of
RGS4 is consistent with a reduction in signaling via
dopamine D1 receptors in the striatum that may already
be reduced due to the decreased density of dopamine
D1 receptors in METH treated -OR knockout mice.
Down-regulation of dopamine D1 receptor binding in
combination with increased RGS4 mRNA levels is
consistent with diminished dopamine D1 receptor function
in METH-exposed -OR knockout mice that would
decrease the occurrence of behavioral sensitization.
In conclusion, the present study indicates that knockout
of -OR in mice reduces their sensitivity to
METHinduced stereotyped behaviors. Down-regulation of the
expression of the dopamine D1 receptor in combination
with up-regulation of the expression of RGS4 in the
striatum of METH-sensitized -OR knockout mice may
contributes to the resistance to the behavioral responses
to METH in this strain. The results suggest that the
opioid system and RGS proteins might be targets for the
development of drugs that might reduce the reward
potential and compulsive drug seeking behavior in
SP carried out the in situ hybridization studies, performed the statistical
analysis, and drafted the manuscript. XS participated in the animal treatment
and study. LT carried out the ligand binding assay. RR participated in the
data analysis and editing the manuscript. TM conceived the study and
supervised the study. All authors read and approved the final manuscript.
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