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Neuroscience Letters 559 (2014) 67–71

Contents lists available at ScienceDirect

Neuroscience Letters

jou rnal homepage: www.elsevier.com/locate/neulet

l-Stepholidine, a natural dopamine receptor D1 agonist and D2

antagonist, inhibits heroin-induced reinstatement

a a a a a b b

Baomiao Ma , Kai Yue , Lin Chen , Xiang Tian , Qin Ru , Yongping Gan , Daisong Wang ,

a,c a,∗

Guozhang Jin , Chaoying Li

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

h i g h l i g h t s

•

Levo-tetrahydropalmatine attenuates heroin-induced reinstatement of heroin-seeking behavior.

•

Low doses of levo-tetrahydropalmatine do not affect locomotor activity.

•

Levo-tetrahydropalmatine inhibits heroin-induced reinstatement and its potential for the treatment of heroin relapse.

a r t i c l e i n f o a b s t r a c t

Article history: l-Stepholidine (l-SPD), an alkaloid extract of the Chinese herb Stephania intermedia, is the ﬁrst compound

Received 29 July 2013

known to exhibit mixed dopamine D1 receptor agonist/D2 antagonist properties and is a potential medi-

Received in revised form 23 October 2013

cation for the treatment of opiate addiction. The aim of the present study was to investigate the effects of

Accepted 24 October 2013

pretreatment with l-SPD on heroin-seeking behavior induced by heroin priming. Male Sprague-Dawley

rats were trained to self-administer heroin (0.05 mg/kg per infusion) under a ﬁxed ratio 1 schedule for

Keywords:

12 consecutive days and nose-poke responding was extinguished for 12 days, after which reinstate-

l-Stepholidine

ment of drug seeking was induced by heroin priming. Pretreatment with l-SPD (2.5, 5.0 and 10.0 mg/kg,

Heroin

i.p.) inhibited the heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-SPD did not

Dopamine receptor

Self-administration affect locomotion, indicating that the observed effects of -SPD on reinstatement are not the result of

Relapse motor impairments. The present data suggested that l-SPD inhibits heroin-induced reinstatement and

its potential for the treatment of heroin relapse.

1. Introduction to drug-seeking behavior [1,12,21,27,33]. The use of nonselective

dopamine receptor agonists and antagonists in the treatment of

Relapse to drug-seeking behavior is a primary manifestation addiction, however, has been met with very limited clinical success

of drug addiction, and reducing relapse is a clinical index of the [22,31] and may be associated with debilitating side effects [8,32].

success of interventions [19]. Relapse is modeled in rodents by Recent investigation of drugs that target DA has focused on agents

measuring the reinstatement of drug-seeking behavior in animals that function as partial agonists. For example, DA D1 receptor

that have undergone extinction training [6]. Drug-seeking can be partial agonists SKF 38393 and SKF 75670 were shown to reverses

induced by stimuli akin to those that elicit relapse in addicts, such cocaine-conditioned place preference and the behavioral stimulant

as the presentation of drug-associated cues, stress or a single dose effects of cocaine in mice and rodents [10,29]. In cocaine-trained

of the drug itself. animals, DA D1 receptor agonists attenuated the priming effects of

A large body of experimental evidence supports the hypoth- cocaine [25]. Moreover, selective stimulation of DA D2 receptors

esis that the mesocorticolimbic dopamine (DA) system, which mediates cocaine- and heroin-seeking behavior in reinstatement

originates in the ventral tegmental area (VTA) and projects paradigms [4,11,25]. The available data suggest that activation of

rostrally to the nucleus accumbens and the medial prefrontal D2-like receptors is involved in heroin reinstatement [3] and the

cortex, plays an important neurobiological mediator of relapse D2-like receptor antagonist risperidone attenuates cue-induced

reinstatement of heroin seeking [13]. Importantly, several studies

have indicated that DA partial agonists may be devoid of abuse

∗ liability and do not produce extrapyramidal side effects [23]. In

Corresponding author. Tel.: +86 27 84225807; fax: +86 27 84225827.

E-mail address: [email protected] (C. Li). fact, effective pharmacotherapy may require the use of drugs that

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68 B. Ma et al. / Neuroscience Letters 559 (2014) 67–71

target multiple DA receptor subtypes with differing potencies to maintain catheter patency. Following catheter surgery, each rat

and/or intrinsic efﬁcacies. was housed individually in its home cage and was allowed ﬁve to

l-Stepholidine (l-SPD) was isolated from the Chinese herb seven days of recovery during which it received a daily intravenous

Stephania intermedia and characterized as exerting dual action on infusion of gentamicin (0.16 mg/kg) followed by 0.2 ml of a hep-

brain DA receptors; l-SPD acts as a partial D1 receptor agonist and arinized (1%) sterile saline solution to ﬂush the antibiotic through

as a full D2 receptor antagonist [9,35,40]. Preliminary clinical tri- the catheter.

als and animal experiments suggest that l-SPD not only improves

both the positive and negative symptoms of schizophrenia without 2.4. Heroin self-administration

producing signiﬁcant extrapyramidal side effects but also allevi-

ates functional cognitive impairment [2]. Several recent studies Forty-two rats were trained to self-administer heroin during

have shown that l-SPD blocks morphine-induced CPP [14,30] and daily 3 h sessions under a ﬁxed ratio 1 schedule of reinforcement

inhibits amphetamine-induced DA neuron ﬁring in the VTA [7]. as previously described [37,38]. Rats received a single heroin infu-

This is also in agreement with an earlier study, which reported sion (0.05 mg/kg) following an active nose-poke. Each infusion was

that l-THP, an analog of l-SPD, inhibited the drug-induced rein- paired with a 5 s illumination of a light in combination with the

statement of cocaine-seeking [16,17], the oxycodone-induced CPP noise of the infusion pump; together these stimuli served as a

[14] and heroin-induced reinstatement of heroin-seeking [36]. This discrete conditioned cue paired with the drug infusion. Following

phenomenon has also been reported for other THPBs [15]. Recently, infusions, a time-out period was imposed for 20 s, during which

our lab found that doses of 2.5, 5 and 10 mg/kg of l-SPD signiﬁcantly responding was recorded but produced no programmed conse-

decreased the number of active nose pokes under an ﬁxed-ratio 1 quences.

schedule of heroin self-administration and reduced cue-induced Rats were put back into their individual home cages shortly

reinstatement of heroin-seeking behavior without affecting loco- after the session. An acquisition criterion required that subjects’

motor activity in rats (in press). However, the effects of l-SPD on active nose-pokes vary by ≤10% over the course of three consecu-

heroin-primed reinstatement of heroin seeking in animals have not tive maintenance days. Rats not meeting the acquisition criterion

been investigated. were excluded from the experiment (n = 10).

Therefore, in the present study, we used an animal model of

heroin-induced reinstatement of drug-seeking behavior to study 2.5. Extinction

whether l-SPD alters heroin-seeking behavior.

After stable responding for i.v. heroin was established, rats

2. Materials and methods underwent extinction training for 2 h daily without any lights and

drugs for 12 consecutive days in the operant chamber. During

2.1. Animals the extinction sessions, responses on the active nose poke were

recorded but had no program consequence. Extinction criterion

The subjects were Male Sprague-Dawley rats (270–300 g, pur- was that subjects touch the active nose-poke <10% of the average

chased from the Animal Center of the Tongji Medical College of responding on the active nose-poke during maintenance.

Huazhong University of Science & Technology, Wuhan, China)

that were housed individually in home cages in a temperature- 2.6. Heroin-induced reinstatement

controlled ventilated colony room with a reversed 12-h light/dark

cycle (lights onset 21:00 h, offset 09:00 h). Food and water were After meeting this extinction criterion, the rats (n = 8 in each

freely available except when speciﬁed. All experimental proce- group) were injected with -SPD (2.5, 5.0 or 10.0 mg/kg) or vehicle

dures followed the guidelines of the Principles of Laboratory Animal 30 min prior to a heroin-induced reinstatement session in which

Care (National Institutes of Health publication number 86–23, all rats were injected with heroin (0.25 mg/kg s.c.) and then placed

1996). into the operant chamber for 2 h, during which time the nose pokes

had no programmed consequences.

2.2. Drugs

2.7. Locomotor test

Diacetylmorphine HCl (heroin) was obtained from the Hubei

Public Security Bureau and was dissolved in 0.9% NaCl. l-SPD Immediately after the heroin-induced reinstatement test, the

was acquired from the Shanghai Institute of Materia Medica, rats were subjected to a locomotor activity test according to the

Chinese Academy of Sciences (Shanghai, China). The l-SPD was method described previously [24]. The rats were tested for their

99.97% pure, as determined by HPLC. l-SPD was dissolved in locomotor responses using an automated photocell system (Ani-

0.1 M H2SO4 and then diluted and adjusted to a pH of 5.0 with lab Software & Instruments Co., Ltd., China) consisting of eight

× ×

0.1 M NaOH [7]. identical black Plexiglas chambers (43 43 35 cm) in light- and

sound-controlled cubicles. Each chamber was equipped with a

2.3. Surgery video camera on the top, which was interfaced with a computer to

record the movement of the rats in the chambers. Rats (n = 8 in each

The rats were anesthetized with sodium pentobarbital group) were then injected with l-SPD (0.0, 2.5, 5.0 or 10.0 mg/kg

(50 mg/kg, i.p.). Atropine sulfate and penicillin B were given at the i.p.). Horizontal locomotor activities traveled were recorded for 2 h.

time of surgery. All rats were implanted with chronically indwelling Total distance traveled was recorded and analyzed as the measure

i.v. catheters. A silicon catheter (3.5 cm in length, 0.58 mm in inner of locomotion using MED Associates SOF-811 open-ﬁeld activity

diameter, 0.91 mm in outer diameter; BPU-T30, Instech, Plymouth software.

Meeting, PA, USA) was inserted into the right external jugular vein

so that the tip reached the right atrium and was secured with 2.8. Statistical analysis

thread. The other end of the catheter (10 cm, PE20) was passed s.c.

through an incision on the back of the body, where it exited into a The data were expressed as the mean SEM. The differences in

custom-made ﬂuid-connector ﬁxed to a jacket. The catheters were total active responses, inactive responses and locomotor activity

ﬂushed daily with 0.2 ml saline–heparin solution (25 U/ml heparin) were analyzed by one-way analyses of variance (ANOVA) followed

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B. Ma et al. / Neuroscience Letters 559 (2014) 67–71 69

Fig. 1. The acquisition of heroin self-administration. (a) Active and inactive responses (nose pokes) during heroin self-administration over 12 consecutive days (mean ± S.E.M.).

(b) Extinction: nose pokes on the previously active and inactive responses over the 12 extinction sessions during which no heroin was available in the training chamber

(mean ± S.E.M.).

by the least signiﬁcant difference (LSD) post hoc test. All statistical of active responses over the last 3 days of self-administration

analyses were performed by with SPSS for Windows, version 11.5 training was equal among the groups (vehicle = 39.1 ± 1.8; l-

(SPSS Inc., Chicago, IL, USA). The level of signiﬁcance was set at SPD 2.5 mg/kg = 41.4 ± 3.0; l-SPD 5.0 mg/kg = 41.7 ± 1.2; l-SPD

p < 0.05. 10.0 mg/kg = 40.9 ± 0.9; mean ± SEM). The mean (±SEM) num-

ber of active responses across the last 3 days of the extinction

3. Results phase was 4.4 ± 0.1. In rats (n = 8) pretreatment with l-SPD at

2.5, 5 and 10.0 mg/kg reduced the heroin-induced reinstate-

3.1. The acquisition and extinction of heroin self-administration

ment of heroin-seeking behavior in a dose-dependent manner

(F3,28 = 46.94, p < 0.01). Fig. 2B illustrates the total number of inac-

Fig. 1A shows the average number of the active and inactive nose

tive responses observed during the last three days of heroin

pokes for all rats that were tested. The animals exhibited reliable

self-administration, the last three days of extinction, and the rein-

self-administration of heroin as indicated by the increase in the

statement test session in the four different treatment groups,

number of active nose-poke responses (p < 0.05). Fig. 1B shows the

indicating that l-SPD had no effect on inactive responses during

mean (±SEM) numbers of the active and inactive nose pokes over

reinstatement testing (F3,28 = 1.72, p > 0.05), suggesting that rats

the 12 days of extinction.

retained the ability to discriminate between the active and inactive

responses.

3.2. The effect of l-SPD on heroin-induced reinstatement of

heroin-seeking behavior

3.3. The effect of l-SPD on locomotor activity

Fig. 2A illustrates the total number of active responses observe

The results of the post hoc tests showed that l-SPD did not sig-

during the last three days of heroin self-administration, the

niﬁcantly alter the animals’ locomotion at any dose (F = 0.17,

last three days of extinction, and the reinstatement test session 3,28

p = 0.91) (Fig. 3).

in the four different l-SPD dose groups. The average number

Fig. 2. Systemic injection of l-SPD inhibits the reinstatement of heroin-seeking behavior induced by heroin priming. Panel A shows a statistically signiﬁcant reduction in

heroin-induced reinstatement after 2.5, 5.0 and 10.0 mg/kg l-SPD when compared with the vehicle treatment group. Panel B shows that l-SPD had no effect on inactive nose-

pokes. Active and inactive responses are shown (mean ± S.E.M.). **p < 0.01, compared with the vehicle group. @@p < 0.01, compared with the 2.5 mg/kg l-SPD pretreatment group.

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70 B. Ma et al. / Neuroscience Letters 559 (2014) 67–71

in this study are typically lower than those that produce compa-

rable reductions in other operant behaviors or that induce motor

side-effects that might impair responding.

In the locomotor activity test, we found that l-SPD had no inﬂu-

ence on the locomotor activities of rats, which indicates that the

attenuation of drug-seeking behaviors was not correlated with

locomotor activity in the present study. We also observed that

the inhibitory effect of l-SPD on heroin self-administration and

cue-induced reinstatement of heroin-seeking behavior was not

caused by an impairment of coordinated motor ability, which is

in agreement with previous ﬁndings that the effects of l-SPD do

not result from an inhibition of general motor ability [9]. A recent

study reported that l-SPD attenuates l-DOPA-induced dyskinesia

in Parkinson’s disease [18]. Furthermore, it has been reported that

l-SPD does not affect food-induced condition place preference [30],

likely because the neuronal circuits that subserve drug reward- and

natural reward-related behaviors (i.e., food seeking) are partially

segregated. Others studies indicate that the analog of l-SPD, l-THP,

had no effects on food reinforcement [17]. Thus, l-SPD is a rela-

Fig. 3. Examination of locomotor activity performed over 2 h immediately after

the heroin-induced reinstatement test. There were no statistically signiﬁcant dif- tively safe and effective therapeutic option that is associated with

ferences between groups (p > 0.05). Data are given as the mean ± S.E.M. (n = 8 per few complications.

group).

A recent study demonstrated that l-SPD functions as a partial

agonist of the 5-HT1A receptor [7]. It has been reported that the

4. Discussion 5-HT1A agonist 8-OH-DPAT attenuates the acquisition of heroin

self-administration [20]. These studies indicate that the interaction

The main ﬁndings of the present study are that the systemic between l-SPD and serotonin receptors might contribute to the

administration of l-SPD blocked the reinstatement of heroin- attenuation of heroin-induced reinstatement that is mediated by

seeking behavior, and the minimum effective dose of l-SPD for pretreatment with l-SPD. Thus, the effects of l-SPD on the reinstate-

inhibition was approximately 2.5 mg/kg, which suggests that l- ment of heroin-seeking behavior warrant further investigation.

SPD can antagonize heroin’s ability to induce relapse. Moreover,

the effective doses of -SPD failed to produce any signiﬁcant effects 5. Conclusion

on locomotion activity, inactive responding, suggesting that block-

age of heroin-induced reinstatement of heroin seeking by -SPD did In summary, the present results suggest that l-SPD may have

not result from sedative or motor inhibitory effects of the drug. beneﬁcial effects on inhibiting heroin-seeking behavior. In addi-

The effects of -SPD on heroin-induced reinstatement most tion, l-SPD did no affect on locomotor activity. These data,

likely stem from its actions at DA receptors [39]. Taken together combined with the positive data described above [30], suggest that

with other reports showing that either selective dopamine D1 l-SPD may have pharmacological utility as a modulator of heroin

agonists or D2 antagonists attenuated cocaine priming in rein- relapse.

statement models [11,25]. l-SPD may exert its effects through

direct dopamine D1 receptor agonism, D2 receptor antagonism or Acknowledgements

both, as both D1 agonism and D2 antagonism have been shown to

interact with opiate receptor signaling. The D1-like receptor antag- This work was supported by the Wuhan Science and Technology

onist SCH 23390, the D2-like receptor antagonist raclopride and Foundation (201150699189-23), the Hubei Education Founda-

the mixed dopamine antagonist ﬂupenthixol decanoate attenuate tion (Q20123405), the Natural Science Foundation of Hubei

heroin-induced relapse [26]. These ﬁndings indicate that acute - (2012FFB03402) and the National Natural Science Foundation of

SPD treatment may block heroin-induced reinstatement following China (81302762). No potential conﬂicts of interest were disclosed.

extinction both by blocking D2 receptors and stimulating D1 recep-

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