Pharmacology, Biochemistry and Behavior 102 (2012) 15

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Pharmacology, Biochemistry and Behavior

journal homepage: www.elsevier.com/locate/pharmbiochembeh

The dopamine receptor antagonist levo-tetrahydropalmatine attenuates heroin

self-administration and heroin-induced reinstatement in rats
Kai Yue a, Baomiao Ma a, Qin Ru a, Lin Chen a, Yongping Gan b, Daisong Wang b,
Guozhang Jin a, c, Chaoying Li a,
a
b
c

Wuhan Institutes of Biomedical Sciences, Jianghan University, Wuhan 430056, China

Drug Prevention and Education Center, Hubei Public Security Bureau, Wuhan 430070, China
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201213, China

a r t i c l e

i n f o

Article history:
Received 19 January 2012
Received in revised form 13 March 2012
Accepted 17 March 2012
Available online 27 March 2012
Keywords:
Dopamine
Antagonist
Levo-tetrahydropalmatine
Self-administration
Heroin
Relapse

a b s t r a c t
Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levotetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained
in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists,
l-THP has lower afnity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also
binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological prole of l-THP
suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the
effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in
abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found
that l-THP (2.5 and 5 mg/kg, i.p.) decreased heroin self-administration on the xed-ratio 1 schedule and dosedependently (1.25, 2.5 and 5 mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior.
Importantly, l-THP (1.25 and 2.5 mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of
l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that
dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement.
2012 Elsevier Inc. All rights reserved.

1. Introduction
Repeated opiate (e.g. heroin) use tends to result in drug addiction
and treatment failure may result due to relapse which remains a
major challenge in the treatment of drug dependence. Detoxication
is only the rst step in the treatment of drug abuse, while complete
abstinence and prevention of relapse are the ultimate goal (Kosten
et al., 2003).
Many studies demonstrated that treatment with the following
agents can help maintain an opiate-free state: (1) opioid receptor agonists or antagonists, such as methadone (Shi et al., 2007) or naltrexone
(Mannelli et al., 2011); (2) compounds acting on other receptors, such
as 2-adrenoreceptor agonists (Raith and Hochhaus, 2004) and cannabinoid CB1 receptor antagonists (Le Foll, 2004). Although effective to
some extent, medications available so far fail to completely prevent
the relapse of compulsive heroin-seeking behavior (Shalev et al.,
2002). Thus, development of new anti-craving agents for the prevention of heroin relapse remains a subject of active investigation.
Activation of -opioid receptors by heroin indirectly stimulates dopamine (DA) release (Hnasko et al., 2005). Dopaminergic mechanisms

Corresponding author. Tel./fax: + 86 27 84225807.

E-mail address: licy.whibs@yahoo.cn (C. Li).
0091-3057/$ see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.pbb.2012.03.014

presumably play a key role in relapse in opiate addiction (Koob et al.,

1998). A large body of evidence indicates that DA receptor antagonists
may be a promising approach for the management of heroin addiction.
D2 receptor antagonists, such as haloperidol (Ettenberg et al., 1996) and
raclopride (Shaham and Stewart, 1996) block heroin-induced reinstatement. The D1 receptor antagonist SCH 23390 (Shaham and Stewart,
1996) attenuates heroin-induced reinstatement. The D3 receptor antagonist SB-277011A (Ashby et al., 2003) blocks the acquisition and
expression of the conditioned place preference response to heroin. The
non-selective dopamine antagonist upenthixol decanoate (Shaham
and Stewart, 1996) also attenuates heroin-induced reinstatement. These
data suggest that use of DA receptor antagonists is a promising pharmacological strategy for the intervention of heroin addiction.
Tetrahydropalmatine (THP) is a tetrahydroprotoberberine isoquinoline alkaloid, a major active constituent of herbal preparations from
Stephania and Corydalis. Two of these species, Corydalis ambigua (yan
hu suo in Chinese) and Stephania tetranda (fang ji in Chinese), have
been used by traditional Chinese medicine for their sedative, neuroleptic, and analgesic properties (Ding, 1987). In particular, the levo
isomer of THP (l-THP) was shown to be a major contributor to the
therapeutic effects of these preparations. Puried l-THP (Rotundine)
has been approved by the Chinese authorities mainly as an analgestic
agent (Ding, 1987). l-THP is a low-afnity antagonist of D2 receptors
(Jin, 1987) and possesses high-afnity for D1 receptors (Xu et al.,

K. Yue et al. / Pharmacology, Biochemistry and Behavior 102 (2012) 15

1989). A recent study showed that l-THP also bound to D3 receptors,

possibly working as an antagonist (Mantsch et al., 2010). The unique
pharmacological prole of l-THP suggests that l-THP may be useful for
the treatment of opiate addiction. In fact, a recent clinical trial conducted in China found that l-THP reduced drug craving, relieved withdrawal symptoms, and lowered relapse rates in recovering heroin
addicts (Yang et al., 2008). In addition, l-THP has been reported to attenuate the -opioid receptor agonist oxycodone induced conditioned
place preference in rats (Liu et al., 2009). However, the effects of
l-THP on the extinction/reinstatement model of heroin seeking in animals have not been investigated. To further understand the underlying mechanisms by which l-THP works on heroin addiction, this study
examined the inhibitory effect of l-THP on heroin self-administration
(SA) and heroin-induced reinstatement in rats on an extinction/
reinstatement protocol. In addition, we also investigated the effects of
l-THP on locomotor activity to rule out its non-specic (motor) effects.
2. Materials and methods
2.1. Animals
Male SpragueDawley rats, weighing 275300 g at the beginning
of the experiments, were purchased from the Animal Center of the
Tongji Medical College of Huazhong University of Science & Technology,
Wuhan, China. The animals were maintained under a 12 h reversed
light/dark cycle (with darkness starting from 8:00 am) with controlled
room temperature and humidity. Tap water was made available ad
libitum and food was restricted to 20 g per day.
All procedures were performed in accordance with the National
Institutes of Health Guide for the Care and Use of Laboratory Animals.
2.2. Surgery
After 1 week of acclimation, a permanent intravenous catheter
(3.5 cm in length, 0.58 mm in inner diameter, 0.91 mm in outer diameter; BPU-T30, Instech, Plymouth Meeting, PA, USA) was surgically
implanted and secured to the right jugular vein under deep anesthesia
with sodium pentobarbital (50 mg/kg, i.p.). Following surgery, each
rat was housed individually in its home cage and was allowed at least
7 days of recovery during which they received a daily intravenous infusion of gentamicin (0.16 mg/kg) followed by 0.2 ml of a heparinized
(1%) sterile saline solution to ush the antibiotic through the catheter.
2.3. Apparatus
Heroin SA was carried out in operant chambers (29 26 29 cm)
encased in sound- and light-attenuating cubicles which were equipped
with fans that provided ventilation (Anilab Software & Instruments Co.,
Ltd., China) (Wang et al., 2010). The front panel was armed with two
nose-poke operandi (ENV-114M; Med Associates, USA) located 9 cm
above the oor of the chambers. A white stimulus light was placed in
each nose-poke and a red house light was xed on the opposite wall.
A single active nose poke resulted in a 5 s heroin infusion. Concurrently, the red house light was turned off, and the white cue light in
this nose-poke was on for 5 s. A 20 s timeout period was then allowed,
during which the white cue light was turned off and further nose pokes
had no additional consequence, but were recorded. After the timeout
period, the red house light was once again turned on. Inactive nose
pokes were also recorded but had no consequence. Each SA session
started when the red house light was turned on.
2.4. Self-administration training
Animals were allowed to self-administer heroin (30 g/kg per inf)
under an xed-ratio 1 (FR 1) schedule of reinforcement and to nose
poke for 3 h each day. SA sessions were conducted during the dark

phase of the cycle. To ensure patency, catheters were ushed on a

daily basis after each intravenous SA session, with sterile saline solution containing heparin (30 UI).

2.4.1. Acquisition
The acquisition sessions were carried out until stable heroin intake
was reached (typically within 1214 days). Responding was considered stable when animals displayed accurate discrimination between
the active and the inactive nose-poke, with the day-to-day difference
in the number of active nose pokes of less than 15% for 3 days in a row.
Rats not satisfying the acquisition criterion were excluded from the
experiment.

2.4.2. Maintenance
Twenty-eight rats developed a stable pattern of heroin intake. The
average numbers of active nose pokes and inactive nose pokes for 3
consecutive days were used as the active nose poke baseline and inactive nose poke baseline, respectively. Thereafter, these rats were randomly divided into four groups (n = 7 per group). No signicant
differences in the active and inactive nose poke baselines were observed among the four groups (F3,24 = 1.56, p > 0.05, for active nose
poke baseline; F3,24 = 0.06, p > 0.05, for inactive nose poke baseline).
The animals were intra peritoneal injected with l-THP 30 min before
the experimental sessions. Four different doses of l-THP were used
(0, 1.25, 2.5 and 5 mg/ kg, i.p.), with each animal tested for one
dose. Rats were then allowed to return to their basal rate of responding
to heroin before being switched to the subsequent extinction phase.

2.4.3. Extinction
The response to heroin was extinguished by replacing heroin with
physiological saline solution, with all the other experimental parameters unchanged. Heroin-reinforced behavior was considered to be extinguished when the number of the active nose poke was decreased by at
least 85% compared to the baseline for 3 consecutive days, which, in
most cases, took place at around day 12.

2.4.4. Reinstatement
After extinction, heroin-induced reinstatement was examined by
a subcutaneous injection of heroin at 0.25 mg/kg before the rats
were placed in the operant-conditioning chambers for 2 h, during
which nose pokes had no programmed consequences. The effects of
l-THP on reinstatement were examined by intra peritoneal injection of
l-THP, at 0, 1.25, 2.5 and 5 mg/kg, for 30 min before heroin injection.
It was reported that l-THP at 7.5 mg/kg produced a sedative effect
(Mantsch et al., 2007) so the effects on reinstatement at this dose
were not examined.

2.5. Locomotor testing

To further characterize the sedative properties of l-THP, thirty-two
heroin-free rats were tested for the effects of l-THP on locomotor activity. Rats were tested for their locomotor responses using an automated
photocell system (Anilab Software & Instruments Co., Ltd., China) consisting of eight identical black Plexiglas chambers (43 43 35 cm) in
light- and sound-controlled cubicles (Cheng et al., 2011). Each chamber
was equipped with a video camera on the top, which was interfaced
with a computer to record the movement of the rats in the chambers.
The locomotor activity of each rat was analyzed by employing an AniLab
ver 4.3 analysis software package (Anilab Software & Instruments Co.,
Ltd., China) (Zhang, 2006) and was expressed as the total distance
traveled (in millimeters) during a 2-h period that began 30 min after
l-THP administration.

K. Yue et al. / Pharmacology, Biochemistry and Behavior 102 (2012) 15

2.6. Drugs
Diacetylmorphine HCl (heroin) was obtained from the Hubei Public
Security Bureau and was dissolved in 0.9% NaCl. l-THP was acquired
from the Shanghai Institute of Materia Medica, Chinese Academy of
Sciences (Shanghai, China) and was dissolved in sterile water. The purity of l-THP was 99.97%, as determined by HPLC (Jin, 1987).
2.7. Statistical analysis
The data were expressed as mean SEM. The differences in total
active responses, inactive responses, and locomotor activity were
analyzed by one-way analysis of variance (ANOVA), followed by the
Least Signicant Difference (LSD) post hoc test. All statistical analyses
were performed by utilizing SPSS for Windows, version 11.5 (SPSS
Inc., Chicago, IL, USA). The level of signicance was set at p b 0.05.
3. Results
3.1. Effect of l-THP on heroin self-administration of rats on a xed-ratio 1
schedule

dose-dependent manner (F3.24 = 28.43, p b 0.01). The lowest dose

(1.25 mg/kg) signicantly decreased the number of active nose
pokes as compared with vehicle group (p b 0.01) while the other
two higher doses (2.5 and 5 mg/kg) produced even more intense
effects in comparison with vehicle group (p b 0.01). By contrast, no
signicant differences were observed in the number of inactive nose
pokes (F3,24 = 0.52, p > 0.05) during reinstatement, suggesting that
rats retained a good discrimination between the active nose-poke
and inactive nose-poke.
3.3. Effect of l-THP on locomotor activity
To further examine the sedative properties of l-THP, the effects of
intravenous injection of l-THP at 0, 1.25, 2.5 and 5 mg/kg on locomotor
activity (total distance traveled/2 h) were examined and are shown in
Fig. 3 (n = 8).The results of the Post hoc test showed that only 5 mg/kg
(p b 0.05), but not 1.25 and 2.5 mg/kg of l-THP signicantly reduced
locomotor activity compared to vehicle group.
4. Discussion

After extinction, heroin-induced reinstatement was examined by

a subcutaneous injection of heroin at 0.25 mg/kg before rats were
put back into the operant-conditioning chambers for 2 h, during
which nose pokes had no programmed consequences. The effects of
l-THP on reinstatement were examined by intra peritoneal injection
of l-THP, at 0, 1.25, 2.5 and 5 mg/kg, for 30 min before heroin injection. The effects of l-THP on heroin-induced reinstatement are
shown in Fig. 2. Pretreatment with l-THP at 1.25, 2.5 and 5 mg/kg reduced heroin-induced reinstatement of heroin-seeking behavior in a

Since the 1970s, puried l-THP (Rotundine) has been approved by

the Chinese government for medical use for its sedative, neuroleptic,
and analgesic properties (Ding, 1987). A recent clinical trial conducted
in China administered l-THP (60 mg, b.i.d.) or a placebo to 119 heroindependent inpatients over a period of 1 month, and found that l-THP
signicantly alleviated withdrawal symptoms, especially heroin craving
(Yang et al., 2008). In addition, compared to the placebo controls, l-THP
increased the abstinence rate (14.8% for placebo vs 46.2% for l-THP)
among the heroin users as evaluated 3 months after the subjects were
discharged (Yang et al., 2008). However, so far there are no reports concerning the effects of l-THP on heroin reinforcement or reinstatement in
animal models. In this study, we investigated the effects of l-THP on heroin SA and heroin-induced reinstatement in rats. Moreover, since l-THP
possesses sedative properties, we also examined the effects of l-THP on
locomotor activity to assess the possible non-specic (motor) effects.
Our study, for the rst time, demonstrated that l-THP attenuates
heroin SA and heroin-induced reinstatement in rats. We found that
2.5 and 5 mg/kg of l-THP signicantly decreased heroin SA, measured
at a single dose, as demonstrated by a signicant decrease in the
number of active nose pokes. Although reductions in SA by l-THP likely
reect reductions in the reinforcing effects of heroin, without a heroin
doseresponse curve, it is difcult to predict the effect of l-THP on
heroin reinforcement (Mello and Negus, 1996). In addition, we found
that all three doses (1.25, 2.5 and 5 mg/kg) of l-THP reduced heroin-

Fig. 1. l-THP attenuated heroin self-administration under a xed-ratio 1 schedule of reinforcement in rats. Values are given in mean SEM of seven animals. p b 0.01, as
compared with 0.0 mg/kg l-THP pretreatment group. @@p b 0.01, as compared with
2.5 mg/kg l-THP pretreatment group.

Fig. 2. l-THP attenuated heroin-induced reinstatement in rats. Values are given in

mean SEM of seven animals. pb 0.01, as compared with 0.0 mg/kg l-THP pretreatment
group. @@pb 0.01, as compared with 1.25 mg/kg l-THP pretreatment group. ##pb 0.01, as
compared with 2.5 mg/kg l-THP pretreatment group.

Once rats (n = 28) developed a stable pattern of heroin intake, the

effects of four doses of l-THP (0, 1.25, 2.5 and 5 mg/ kg, i.p., 30 min
before the experimental session) on heroin intake were tested. The effects of acute administration of l-THP on heroin SA of rats on an FR 1
schedule are shown in Fig. 1. l-THP signicantly decreased the number
of active nose pokes (F3.24 = 44.37, p b 0.01). Comparisons revealed
signicant differences between l-THP groups and the vehicle group in
the number of active nose pokes at doses of 2.5 mg/kg (p b 0.01) and
5 mg/kg (p b 0.01). No signicant differences were observed in the number of inactive nose pokes (F3,24 =1.63, p >0.05).
3.2. Effect of l-THP on heroin-induced reinstatement of heroin-seeking
behavior

K. Yue et al. / Pharmacology, Biochemistry and Behavior 102 (2012) 15

Fig. 3. Effects of l-THP on locomotor activity. Data are given in meanSEM (cm, total
distance traveled in 2 h) of eight animals after l-THP i.p. administration (at 0.0, 1.25,
2.5 and 5 mg/kg; after 30 min pretreatment). l-THP at 5 mg/kg signicantly reduced locomotor activity as compared to 0.0 and 1.25 mg/kg l-THP pretreatment group
(p b 0.05).

induced reinstatement of heroin-seeking behavior. However, given that

l-THP has sedative properties, proper interpretation of the suppression
of SA and reinstatement entails a concurrent examination of the potential sedative effects of l-THP. In the locomotor activity test, we found
that only 5 mg/kg, but not 1.25 and 2.5 mg/kg of l-THP, signicantly decreased total distance traveled in heroin-free rats. All these data indicate
that 2.5 mg/kg of l-THP attenuated heroin SA, and 1.25 and 2.5 mg/kg of
l-THP reduced heroin-induced reinstatement in rats, without affecting
motor activity.
It has been reported that l-THP also attenuates cocaine SA and
cocaine-induced reinstatement (Mantsch et al., 2007). Interestingly,
the doses of l-THP used to attenuate cocaine SA and cocaine-induced reinstatement (Mantsch et al., 2007) were higher than the doses used in
the present study. Similar phenomena were also observed in other
studies in which the doses of D1 receptor antagonist SCH 39166, D2 receptor antagonist eticlopride and non-selective DA receptor antagonist
upenthixol, which are required to attenuate opiates SA, were lower
than that for cocaine SA (Winger, 1994). One possible reason for the
greater potency of l-THP in suppressing heroin-maintained response,
as compared with cocaine-maintained response, is that heroin's own
rate-suppressant effects might contribute to the rate suppressant effect
of l-THP (Winger, 1994). In addition, when self-administered, cocaine is
able to antagonize the rate-suppressing effect of l-THP, a property that
heroin apparently does not possess (Winger, 1994).
Dopamine D1, D2 and D3 receptors have been implicated in heroin's
reinforcing and reinstatement effects (Heidbreder et al., 2005; Rowlett
et al., 2007; Tobin et al., 2009). For example, morphine SA can not be
established in knockout mice lacking dopamine D2 receptors
(Maldonado et al., 1997). The D1 receptor antagonist SCH 23390 blocks
morphine-induced conditioned place preference in rats (Beninger and
Miller, 1998). The D2 receptor antagonist eticlopride reduces the number of infusions of heroin in rats (Hemby et al., 1996). The D2 partial
antagonist terguride decreases heroin SA in rats (Zhang et al., 2010).
The D3 receptor antagonist SB-277011A (Ashby et al., 2003) prevents
the development and expression of the conditioned place preference to
heroin. The non-selective dopamine antagonist alpha-upenthixol reduces heroin SA in rats (Ettenberg et al., 1982). All these data indicate
that blocking dopamine activity might attenuate the rewarding effect
of opiates. However, it has been reported that D1 receptor antagonist
SCH 39166 increases alfentanil SA in Rhesus monkeys (Winger, 1994),
which is at odds with the aforementioned ndings and the results of
the present study. This discrepancy might be due to, at least in part, the
differences in the doses of opiates, medication doses, animal species or
experimental procedures. In other studies, DA receptor antagonists have

been shown to attenuate heroin-induced reinstatement. For instance,

the D1 receptor antagonist SCH23390 (Shaham and Stewart, 1996) and
the D2 receptor antagonist raclopride (Shaham and Stewart, 1996)
attenuate heroin-induced reinstatement.
l-THP works on heroin SA and heroin-induced reinstatement possibly through its action on DA receptors (Yang et al., 2008). A number
of reports demonstrated that l-THP binds to D1, D2 and D3 receptors
(Guo et al., 1997; Mantsch et al., 2007; Xu et al., 1989). Meanwhile,
there is evidence suggesting that l-THP is an antagonist of D1
(Mantsch et al., 2007) and D2 (Jin, 1987) receptors. A recent study
showed that l-THP might be an antagonist of D3 receptors (Mantsch
et al., 2010). In addition to its actions on DA receptors, l-THP has
been found to interact with other receptors, especially adrenergic receptors, at which l-THP functions as an antagonist (Lu et al., 1996),
and serotonin receptors (Liu et al. , 2012). It has been reported that
the alpha-1 adrenergic receptor antagonist prazosin reduces heroin
SA (Greenwell et al., 2009), and the serotonin reuptake inhibitor venlafaxine attenuates the acquisition of heroin SA (Magalas et al., 2005).
These studies indicate that the interaction between l-THP and alpha-1
and serotonin receptors might contribute to the attenuated heroin SA
and heroin-induced reinstatement after pretreatment with l-THP. The
underlying mechanisms by which l-THP attenuates the heroin SA and
heroin-induced reinstatement in rats warrant further investigation.
Dopamine antagonists, however, have not been successfully used for
the treatment of heroin addiction due to their undesirable side effects
such as dyskinesia (Haile et al., 2008). In contrast with other DA receptor antagonists, l-THP may have a more desirable safety prole (Wang
and Mantsch, 2012). l-THP has been extensively used as an analgesic
agent in China over the past 40 years with few adverse effects reported
(Yang et al., 2008). No interaction of l-THP with opioid receptors has
been documented, and its analgesic effects are naloxone-independent
(Hu and Jin, 1999). A recent study reported that 3.75 mg/kg of l-THP
had little or no effects on food reinforcement (Mantsch et al., 2010).
All these data suggest that l-THP is safe when used at the right dosage
and in pure form and might also reduce the safety concerns associated
with the use of l-THP.
5. Conclusion
This study demonstrates that l-THP attenuates heroin SA and
heroin-induced reinstatement, which is consistent with a recent clinical
report (Yang et al., 2008) demonstrating that l-THP has therapeutic utility for the treatment of heroin addiction. Although l-THP has been
reported to have sedative properties, we found that 2.5 mg/kg of l-THP
was able to attenuate heroin SA, and 1.25 and 2.5 mg/kg of l-THP was
able to diminish heroin-induced reinstatement without affecting the
locomotor activity in rats. These results suggest that l-THP acts directly,
not through its sedative effect, on heroin SA and heroin-induced reinstatement. l-THP, as a DA receptor antagonist, works on heroin SA and
heroin-induced reinstatement possibly via its action on DA receptors.
Compared with other DA receptor antagonists, l-THP has a better safety
prole, and is a promising alternative anti-craving agent for the management of heroin addiction.
Acknowledgements
This work was supported by the Wuhan Science and Technology
Foundation (20115069918923) and Wuhan Education Foundation
(2010002).
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