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Introduction
Drug addiction, a chronic brain disease, is characterized
by constant relapse that requires long-term
treatment[1]. Currently, the first line of treatment for chronic opioid
dependence is agonist maintenance treatment, such as
methadone and buprenorphine. The principle of maintenance
treatment is to suppress withdrawal symptoms and heroin craving,
reducing heroin abuse and the risks associated with drug
use behaviors[2,3]. Fundamentally, however, the maintenance
treatment is not an abstinence-oriented program. Once the
maintenance program is interrupted, the protracted
abstinence withdrawal syndrome (PAWS) will occur, resulting in
relapse.
New pharmacological strategies that target specific
elements of the addiction cycle are currently under intense
investigation. For example, naltrexone, an opioid receptor
antagonist, was initially developed to treat heroin
dependence by blocking euphoria and weakening the addiction
cycle. In clinical practice, however, naltrexone produced
adverse effects and did not ameliorate the PAWS of opiate
dependence, resulting in a lower retention rate and relapse
[4]. So far, pharmacological agents have shown limited efficacy
in the treatment of drug addiction[5]. There are no broadly
effective anti-relapse pharmacotherapies available for
human opiate dependence.
The major problem in the clinical treatment of drug
dependence is relapse. Many addicts respond very well to
inpatient treatment and yet their relapse occurs soon after
leaving the program. The addiction neurobiology, based on
decades of animal studies, suggests that the onset of heroin
withdrawal coupled with reward deficits could play a critical
role in provoking craving and relapse in human opiate
addicts[6]. We hypothesized that if a medication, without
reinforcing abuse potential, could effectively ameliorate the
PAWS of opiate dependence, especially the drug craving,
the medication could be effective in reducing the relapse
rate. To test this hypothesis, we employed rotundine, that
is, l-tetrahydropalmatine (l-THP), in this pilot study.
l-THP is a main active ingredient of a Chinese traditional
analgesic herb and has been safely prescribed in Chinese
clinical settings for more than 40 years.
l-THP significantly binds to dopamine
(D1, D2, and D3)
receptors[7_12] and antagonizes morphine abuse in animal
experiments[13_15]. Recent reports showed
D3 to be significantly involved in drug craving and
relapse processes[16_18]. Further,
l-THP has no abuse potential and its pharmacology and
neuropsychopharmacology have been extensively studied with animals and human
models. These results have been widely published,
particularly in Chinese literature[19]. Finally, since
l-THP is already listed in Chinese pharmacopeia, the associated costs and
time required to conduct clinical trials would be
substantially reduced.
We report our initial results in a randomized,
placebo-controlled, and double-blinded study with
l-THP treatment after 7_10 d of detoxification. We demonstrate that
l-THP treatment significantly ameliorates the PAWS, especially drug
craving, and increases abstinence rate among heroin users.
Materials and methods
l-THP l-THP is a purified compound isolated from
Chinese herbs by Best & Wide Pharmaceutical (Nanning, China).
It has been approved by the Chinese Government Agency
since 1964 (State Food and Drug Administration of China),
and listed in Pharmacopoeia of China (1977 edition) for
human use in relief of chronic pain, insomnia, and anxiety.
Human patients In total, 120 heroin-dependent patients
(27.57±5.76 years old, mean±SD, 89 males and 29 females)
were recruited during the study period between June 2000
and February 2001 from the inpatient population at the
Hengyang Detoxification Clinic (HDC), Hunan, China. Each
participant met the DSM-IV criteria for heroin
dependence and was tested as having a positive opiate in his or her urine
test before entering the HDC. The patients expressed their
willingness to participate in this trial. Exclusion criteria
included any drug dependence other than tobacco and opiates;
history of psychiatric and neurological diseases, such as
schizophrenia, psychosis, past seizure episode, or current
use of psychoactive medications; hepatic, cardiovascular,
and renal diseases; and pregnancy or breastfeeding.
Written informed consent was obtained from each patient, and
the human protocol was approved by the IRB of Second
Xiangya Hospital (Changsha, China).
Study design A randomized, double-blinded,
placebo-controlled trial was designed. As shown in Figure 1,
participants had been detoxified in a ward at the HDC and were
abstinent for at least 7 d before entering the trial. The
participating patients remained in a ward during this trial. The
participants were randomly divided into 2 groups:
the l-THP treatment group (2 tablets [30 mg
l-THP] twice per day) and the placebo group (2 placebo tablets twice per day). The
treatment dose was selected based on the preclinical and
clinical studies in order to minimize its mild sedative effects,
which began to manifest at a higher dose (>100 mg/70 kg
body weight). The l-THP and the placebo tablets were
provided by Best & Wide Pharmaceutical (China). The
l-THP medication lasted for 1 month, while participants stayed in
the clinic as inpatients. After the cessation of
l-THP treatment for 1 month, the participants either stayed in the clinic
or decided to return home. Urine samples were collected to
test for heroin or morphine by 8 different intervals: day of
admission, d 7, 14, 21, and 28 during l-THP medication, and
on d 5, 14, and 28 after the cessation of the medication.
During the following 3 months after the patients were discharged,
the random urine tests were conducted to check their
abstinence-free status for the residual of heroin or morphine.
During the 5 month study period, participants could
discontinue the study at any time. No patient received psychotherapy.
The PAWS severity was determined by completing a
questionnaire at the 8 time intervals, as described earlier.
The questionnaire measuring the severity of the PAWS,
termed the Heroin Withdrawal Scale (HWC), was specifically
developed and validated for opiate
dependence[20]. As listed in Table 2, this self-rating scale consists of 30 symptoms in 4
categories: 9 symptoms in the mood category, 8 symptoms
in the craving category, 4 symptoms in the insomnia category,
and 9 symptoms in the somatic category. The intensity of
each symptom was rated with a 5 point scale of 0=not at all,
1=a little, 2=moderately, 3=quite a bit, and 4=extremely). The
rated scores for each symptom in the same category from
every patient were added up as the categorized score for the
patient. The categorized scores from individual patients in a
group were then averaged to obtain the mean±SD. The higher
the scores were, the more severe the PAWS.
End-points of the study Retention in treatment and
abstinence rates were employed as the end-points. No
information was collected from patients who left the trial program.
These patients were categorized as "relapsed" when
determining the abstinence rate. Other outcome measures
included changes in the PAWS severity scores (HWC-30) for
mood, craving, sleep, and somatic symptoms. The higher
the scores, the more severe the syndrome.
Data analysis The Kaplan_Meier method was employed
to estimate the event-free survival probability of patient
retention in the treatment program, and the log_rank test was
used to analyze the retention rate between the
l-THP-treated group and the placebo group. Considering the effects of
antagonistic mechanisms of l-THP treatment on the mood
syndrome, the estimations were conducted in 2 time periods:
the first was done in the initial 2 weeks, and the other was
accomplished during the rest of trial period. The differences
in severity among the PAWS scores and the individual PAWS
categorical ratings for "somatic", "mood", "sleeping", and
"craving" were analyzed with the following time-dependent
regression model:
Yk,i,j=mk(
ti,j)+εk,i,j, for
k=1, 2; i=1, …, nk;
j=1, 2, …, 8,
where tk,i,j= (0, 7, 14, 21, 28, 35, 42, and 56 d) are
observation times, Yk,i,j is the
jth measurement of the ith patient from
the kth treatment group, and
εk,i,j are the 0 mean error terms.
The testing null and alternative hypotheses are:
H0:
m1(tj)=m2
(tj) for all j=1, 2, …,
8 versus HA:
m1(tj)
≠ m2(tj) for
some j.
The differences in the severity scores of the PAWS
measurements between the treated and placebo groups were
assessed using the method of comparing cross-section
growth data[21,22]. This method compares the difference of
the areas under the regression curves (ie it examines whether
there is an overall difference between the 2 groups). When
a significant difference is detected, the student
t-test method can be used to identify differences at a given time point.
Results
Demographics and clinical characteristics of
participating patients Table 1 lists the demographics and clinical
characteristics of the participants taken from the Selected
Structured Clinical Interview for the
DSM-IV diagnoses at intake. None of the variables differed in terms of sex, age,
education, the kind of treatment, the age of onset, and the
daily time of heroin administed between the
l-THP-treated group and the placebo group. No significant differences
were evident in these demographics between the 2 groups.
Comparison of the dropout rates and abstinence rates
after l-THP medication The results of the retention for the
l-THP-treated and placebo groups are shown in Figure 2 by
the Kaplan_Meier estimators. After medication for 2 weeks,
the survival probability of retention for the placebo group
was 100% (95% confidence interval [CI]:
100%_100%), while that of the
l-THP-treated group was 72% (95% CI: 60%_83%). The log_rank test showed that the dropout rate for
the l-THP-group was significantly higher than that of the
placebo group (Figure 2A; Table 3, P<0.0001). The placebo
group retained 59 patients in the trial program, whereas the
medication group decreased from 61 patients to 44 (Figure
2A; Table 3).
After the 3 month follow-up observation, it was noted
that participants who survived the 2 weeks of medication
and remained in the trial program had a high abstinence rate
of 47.7% (95% CI: 33%_67%) as opposed to the placebo
group of 15.2% (95% CI: 7%_25%). The log_rank test has a
P-value of 0.0005, indicating that the abstinence rate was
significantly higher in the treatment group than the placebo
group (Figure 2B).
Effects of l-THP medication on
total scores and the 4 categories of the PAWS
According to the regression analysis, 1 month of
l-THP medication significantly reduced the total
scores of the PAWS severity, as shown in Table 3 (Z=-9.73;
P<0.0001). The l-THP-treated group showed a significant
reduction in severity than the placebo group in the somatic
syndrome (Figure 3A; Z=-6.082; P<0.0001), insomnia (Figure
3C; Z=-6.399; P<0.0001), and craving (Figure 3D; Z=-22.42;
P<0.0001), but not in the mood state (Figure 3B; Z=0.2568;
P=0.7973).
The most intriguing result of the l-THP treatment was the
significant reduction in opiate craving (Figure 3D). After 1
week of treatment with l-THP, the craving scores were
substantially reduced compared to the placebo group, and
continued to decline thereafter. One month after the cessation
of treatment, the craving score was 3.5±2.6 (mean±SD) for the
treatment group versus 7.0±3.5 for the placebo group
(P<0.01; Figure 3D).
Discussion
l-THP has an antirelapse effect The present study
supported a clinical hypothesis that continued treatment is
necessary beyond detoxification, even when the body is
cleansed of the drug. Our experimental results demonstrated
that l-THP medication can significantly reduce the severity
of the PAWS, especially opiate craving, and increase the
abstinence rate after medication. Our preliminary results
demonstrated that proper medication, such as
l-THP, could be effective in decreasing opiate relapse.
The present study design has a unique feature in that
the administration of l-THP was given after 7_10 days of
drug abstinence. Since the main goal of this study is to test
if l-THP is effective as an antirelapse medication, it is
necessary for patients to achieve a drug-free state first, at least for
a period of time, then determine the relapse rate from the
drug-free state. There was difficulty in ascertaining the ideal
length of the drug-free state. It is noteworthy that in the
Kaplan_Meier curves in Figure 2A, the retention rate was
significantly lower after 2 weeks of l-THP treatment, as
opposed to the placebo group. The treatment retention rate
was improved after 14 d of l-THP medication, as shown in
Figure 2B. It is denoted that a period of drug-free state
requires at least a 2 week trial period of
l-THP. The detailed mechanisms underlying the lower retention rate in the first 2
weeks are not clear. Among these unscheduled early
termination cases, there were no reports of adverse effects or
acute hepatic toxicity due to the l-THP treatment. The
effects of the dopaminergic antagonisms of
l-THP could have played a role in early discharge. A previous study suggested
that chronic heroin users might produce a reduction in
dopaminergic activity in the human
brain[18]. The antagonisms of l-THP medication could reduce the post-synaptic
dopaminergic activities further, resulting in lower retention. After the 2
weeks, the dopaminergic activities may recover and the
retention rate may be improved significantly. This mechanism
may be similar to that evidenced in clinical practice whereby
naltrexone treatment may not be given to heroin users until
they have a negative reaction to naloxone. However, in
animal studies, l-THP could enhance the presynaptic
dopaminergic activity, including biosynthesis and release of
dopamine via the feedback
regulation[38-40]. This mechanism might
be involved in the early termination cases.
Alternatively, we suggest that in the morphine users, the
brain function of endogenic opioid peptides, such as
endophine (μ agonist) and enkephalin (δ agonist), have not
dropped away from the substitutive inhibition of morphine
(an exogenic μ and δ agonist) during the 10 d period. Under
these in vivo circumstances in the brain, the
D2 antagonism of l-THP would aggravate the substitutive inhibition of
heroine users. The above-mentioned animal
results[38-40] would support this idea. However, in the animal experiments, the
D2 antagonism of l-THP was substantiated to be an
augmentation on the brain function of endophrine in the periaqueductal
gray (PAG), and enkphrine in the
brain[19,31,32,41]. Since the
main goal of this study was to test if l-THP is effective as an
anti-relapse medication, it is necessary that patients achieve
a long drug-free state first, followed by l-THP treatment
to prolong heroin abstinence. Based on this observation, it is
suggested that patients be tested 21_30 d before
l-THP medication, rather than the current 7-10 d. This should allow
a higher retention rate during the early treatment period.
Possible mechanism of l-THP treatment for heroin
abstinence First, l-THP is an antagonist of DA
receptors[7-11]. Its antagonistic effect on DA receptors, particularly
D2 and D3 receptors, would play an important role in reducing drug
craving. Many recent studies using animal models have
demonstrated that l-THP is a potential candidate for treating
heroin[12-15] and cocaine
addiction[23-25]. Other studies have shown that
D3 receptor antagonism significantly inhibits
cocaine-seeking behavior[26-28] and reduces nicotine-paired
environmental cue functions[29].
The D2 receptor, like DA (D2
and D3) receptors, display a presumed pharmacological similarity and homology in the
sequence of amino acids, which increased up to 75% in the 7
transmembrane domains. It has been shown that
D3 receptors are mainly located post-synaptically, and a subset of
D3 receptors is located presynaptically. The neuroanatomical
locations of D3 receptors are mainly restricted to expression
in distinct areas of the limbic system, such as the nucleus
accumbens and the islands of Calleja. The nucleus
accumbens is involved in the diverse neurological and psychiatric
disorders, such as Parkinson's disease, schizophrenia, and
drug abuse (heroin, morphine, cocaine etc), which have been
extensively reviewed[16,30].
Second, it has been shown that the antinociception of
l-THP is based on the antagonism on the
D2 and D3 DA receptors in the ventral tegmental area (VTA)_accumbens
nucleus_prefrontal cortex DA
pathway[19], and the D2 receptors in the
arcuate nucleus of the hypothalamus is also involved in
l-THP-induced, β-endorphin neuron-mediated analgesic
action[19,31], which projects to PAG, an important action site of
morphine. It has been observed that l-THP acts on the
arcuate nucleus and has a sequential enhancement of END
release, which modulates the physiological functions, such
as analgesia or anticraving resulting from long-time
exposure to morphine[32,33]. As well as this,
D2 and D3 antagonism of
l-THP would interrupt the DA transporter function in the
nucleus accumbens on the pre- and post-synaptic
sites[11,34,35].
Furthermore, brain DA neurons in heroin addicts may
become maladapted due to long-term exposure to morphine
and could be readapted by l-THP treatment. In the
experiment of morphine-dependent rats, the levels of glial fibrillary
acidic protein (GFAP) and tyrosine hydroxylase (TH) in the
DA neurons of the VTA were significantly
increased. l-THP treatment significantly decreased the levels of GFAP and
TH in the VTA to normal levels, indicating that the function of
the dopaminergic neurons is in
recovery[36]. Similarly, l-THP treatment can reverse the decreases of dopamine D1 and D2
receptor mRNA in morphine-dependent
rats[37]. These results suggest that
l-THP treatment can facilitate the recovery of dopaminergic functions and gene expression.
Recent studies have demonstrated that l-THP treatment
could produce a rightward and downward shift in the
dose_response curve for cocaine self-administration and
attenuate cocaine-induced
reinstatement[23,24]. It is presumed that
the cocaine-induced DA transporter-mediated effect is
reduced by the D2 and D3 antagonism of
l-THP on the post-synaptic site in the nucleus accumbens, which may be
potentially of use in treating human cocaine addiction.
Limitations of this pilot study This pilot study
demonstrated that l-THP significantly ameliorated the PAWS,
especially reducing drug craving and increasing the abstinence
rate among heroin users. These results support the
potential use of l-THP for the treatment of heroin addiction.
However, there are several methodological limitations to be
addressed. First, the study participants were mixed between
treatment seekers and non-treatment seekers, since they were
recruited from the compulsory detox institution. It is
possible that treatment seekers and non-treatment seekers may
have different responses to l-THP treatment. Second, the
present study employed only pharmacotherapy with
l-THP medication without cognitive behavioral treatment (CBT). It
is expected that the combination of CBT with
pharmacotherapy may produce a synergistic effect. Third, the present
study has been limited to employing only 1 dose of
l-THP with a short duration (1 month). Although the short
duration and the low dose of l-THP were initially chosen to
reduce the risk of possible hepatic
toxicity[42], a future study may examine the effects of the length of treatment time,
number of treatment sessions, and dose responses.
Acknowledgements
We thank Dr Gao-hong WU and Mr Douglas WARD for
statistical analysis, and Ms Carrie O'CONNOR for editorial
assistance.
Author contribution
Zheng YANG, Guo-zhang JIN and Wei HAO designed
research; Zheng YANG, Wei HAO performed research;
Mei-Jie ZHANG Yong-cong SHAO contributed new analytical
reagents and tools; Mei-jie ZHANG, Yong-cong SHAO and
Jian-lin QI analyzed data; Zheng YANG, Yong-cong SHAO
and Shi-jiang LI wrote the paper.
References
1 O'Brien CP. Anticraving medications for relapse prevention: a
possible new class of psychoactive medications. Am J Psychiatr 2005;
162: 1423_31.
2 Haasen C, van den Brink W. Innovations in agonist
maintenance treatment of opioid-dependent patients. Curr Opin
Psychiatr 2006; 19: 631_6.
3 Sung S, Conry JM. Role of buprenorphine in the management of
heroin addiction. Ann Pharmacother 2006; 40: 501_5.
4 Dackis C, O'Brien C. Neurobiology of addiction: treatment and
public policy ramifications. Nat Neurosci 2005; 8: 1431_6.
5 Heidbreder CA, Hagan JJ. Novel pharmacotherapeutic approaches
for the treatment of drug addiction and craving. Curr Opin
Pharmacol 2005; 5: 107_18.
6 Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF.
Conditioned withdrawal drives heroin consumption and decreases
reward sensitivity. J Neurosci 2006; 26: 5894_900.
7 Xu SX, Yu LP, Han YR, Chen Y, Jin GZ. Effects of
tetrahydrop-rotoberberines on dopamine receptor subtypes in brain. Acta
Pharmacol Sin 1989; 10: 104_10.
8 Jin GZ. (_)-Tetrahydropalmatine and its analogues as new
dopamine receptor antagonists. Trends Pharmacol Sci 1987; 8: 81_2.
9 Jin GZ, Wang XL, Shi WX. Tetrahydroprotoberberine _ a new
chemical type of antagonist of dopamine receptors. Sci Sin [B]
1986; 29: 527_34.
10 Jin GZ, Xu SX, Yu LP. Different effects of enantiomers of
tetrahydropalmatine on dopaminergic system. Sci Sin [B] 1986;
29; 1054_64.
11 He Y. The pharmacological properties of
l-stepholidine on different dopamine receptor subtypes [PhD Dissertation]. Shanghai:
Shanghai Institute of Materia Medica, 2005.
12 Hong Z, Fan G, Le J, Chai Y, Yin X, Wu Y. Brain
pharmacokinetics and tissue distribution of tetrahydropalmatin enantiomers
in rats after oral administration of the recemate. Biopharm Drug
Dispos 2006; 27: 111_7.
13 Wang YB, RenYH, Zheng JW, Zeng I. Influence
of l-tetrahydropalmatine on morphine-induced conditioned place preference. Chin
Pharmacol Bull 2005; 21: 1442_5
14 Wang YB, Ren YH, Zheng JW. The effects of
l-THP on morphine-induced discrimination. Chin J Drug Dependence 2005;
14: 27_9.
15 Liu YL, Liang JH, Yan LD, Su RB, Wu CF, Gong ZH. Effect
of l-tetrahydropalmatine on locomotor sensitization to oxycodone
in mice. Acta Pharmacol Sin 2005; 26: 533_8.
16 Heidbreder CA, Gardner EL, Xi ZX, Thanos PK, Mugnaini M,
Hagan JJ, et al. The role of central dopamine D3 receptors in
drug addiction: a review of pharmacological evidence. Brain Res
Rev 2005; 49; 77_105.
17 Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG,
et al. Selective inhibition of cocaine-seeking behaviour by a
partial dopamine D-3 receptor agonist. Nature 1999; 400:
371_5.
18 Kish SJ, Kalasinsky KS, Derkach P, Schmunk GA, Guttman M,
Ang L, et al. Striatal dopaminergic and serotonergic markers in
human heroin users. Neuropsychopharmacology 2001; 24:
561_7.
19 Jin GZ. Discoveries in the voyage of corydalis research. Shanghai:
Shanghai Scientific & Technical Publishers; 2001.
20 Chen HX, Hao W, Yang DS. The development of subjective
protracted withdrawal scales for opiate dependence. Chin J
Mental Health 2003; 17; 294_7.
21 Scheike TH, Zhang MJ. Cumulative regression function tests for
regression models for longitudinal data. Ann Statistics 1999; 26;
1328_55.
22 Scheike TH, Zhang MJ, Juul A. Comparing reference charts.
Biometrical J 1999; 41; 679_787.
23 Luo JS, Ren YH, Zhu R. The effect of
l-THP on cocaine-induced conditioned position preference. Chin J Drug Depend 2003; 12:
177_9.
24 Mantsch JR, Li SJ, Risinger R, Awad S, Katz E, Baker DA,
et al. Levo-tetrahydropalmatine attenuates cocaine self-administration
and cocaine-induced reinstatement in rats.
Psychopharmacology 2007; 192: 581_91.
25 Xi ZX, Yang Z, Li SS, Li X, Dillon C, Pang XQ,
et al. Levo-tetrahydropalmatine inhibits cocaine's rewarding effects:
Experiments with self administration and brain-stimulation reward
in rats. Neuropharmacology 2007; 53: 771_82.
26 Vorel SR, Ashby CR Jr, Paul M, Liu X, Hayes R, Hagan JJ,
et al. Dopamine D3 receptor antagonism inhibits cocaine-seeking and
cocaine-enhanced brain reward in rats. J Neurosci 2002; 22:
9595_603.
27 Xi ZX, Gilbert J, Campos AC, Kline N, Ashby CR Jr, Hagan JJ,
et al. Blockade of mesolimbic dopamine D3 receptors inhibits
stress-induced reinstatement of cocaine-seeking in rats,
Psychopharmacology (Berlin) 2004; 176; 57_65.
28 Xi ZX, Newman AH, Gilbert JG, Pak AC, Peng XQ, Ashby CR Jr,
et al. The novel dopamine D3 receptor antagonist NGB 2904
inhibits cocaine's rewarding effects and cocaine-induced reinstatement
of drug-seeking behavior in rats. Neuropsychopharmacology 2006;
31: 1393_405.
29 Pak AC, Ashby CR Jr, Heidbreder CA, Pilla M, Gilbert J, Xi ZX,
et al. The selective dopamine D3 receptor antagonist
SB-277011A reduces nicotine-enhanced brain reward and
nicotine-paired environmental cue functions. Int J Neuropsychopharmacol
2006; 9: 585_602.
30 Joyce JN, Millan MJ. Dopamine D3 receptor antagonists as
therapeutic agonists. Drug Dis Today 2005; 10: 917_25.
31 Hu JY, Jin GZ. Supraspinal D2 receptor involved in
antinociception induced by l-tetrahydropalmatine. Acta Pharmacol Sin 1999;
20: 715_9.
32 Hu JY, Jin GZ. Arcuate nucleus of hypothalamus involved in
analgesic action of l-THP. Acta Pharmacol Sin 2000; 21:
439_44.
33 Ge XQ, Lin AP, Sun Y, Zhou HZ, Zhang HQ,
et al. Effects of l-tetrahydropalmatine on opioid peptides contents in morphine
dependent rats. Chin Pharmacol Bull 2001; 17: 264_6.
34 Liu YL, Liang JH, Yan LD, Su RB, Wu CF, Gong ZH. Effects of
l-tetrahydropalmatine on locomotor sensitization to oxycodone
in mice. Acta Pharmacol Sin 2005; 26: 533_8.
35 Wang W, Zhou Y, Sun J, Pan L, Kang L, Dai Z,
et al. The effect of l-stepholidine, a novel extract of Chinese herb, on the
acquisition, expression, maintenance, and re-acquisition of
morphine conditioned place preference in rats. Neuropharmacology
2007; 52: 356_61.
36 Yang Z, Li CO, Fan M. Effect of tetrahydroprotoberberines on
contents of glial fibrillary acidic protein and tyrosine
hydroxylase in ventral tegmental area of morphine dependent rats. Chin
J Pharmacol Toxicol 2003; 17: 246_50.
37 Yang Z, Li CQ, Fan M. Effects of tetrahydroprotoberberines on
expression of dopamine system related genes in morphine
dependent rats. Chin J Psychiatr 2004; 37: 111_5.
38 Marcenac F, Jin GZ, Gonon F. Effect of
l-tetrahydropalmative on dopamine release and metabolism in the ret striatums.
Psychopharmcology 1986; 89: 89_93.
39 Huang KX, Sun BC, Gonon F, Jin GZ. Effects of
tetrahydroproto-berberines on dopamine release and 3,4-dihydroxyphenylacetio
acid level in corpus striatums measured by in
vivo voltammetry. Acta Pharmacol Sin 1991; 12: 32_6.
40 Chen LJ, Guo X. Wang QM, Jin GZ. Feed-back regulation of
presynaptic D2 receptors blockaded by l-stepholidine
and l-tetrahydropalmatine. Acta Pharmacol Sin 1992; 13: 442_5.
41 Hu JY, Jin GZ. Effect of tetrahydropalmatine analogs on Fos
expression. Acta Pharmacol Sin 1999; 20:193_200.
42 Lai CK, Chan A YW. Tetrahydropalmatine poisoning: diagnoses
of nine adult overdoses based on toxicology screens by HPLC
with diode-array detection and Gas chromatography-mass
spectrometry. Clin Chem 1999; 45: 229_36.
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