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Introduction
Drug dependence is a chronic, relapsing disorder in which
compulsive drug-seeking and drug-taking behavior persists
despite serious negative
consequences[1]. Addictive sub-stances, such as opioids, induce
pleasant states or relieve distress, effects that contribute to their recreational use. After
repeated exposure, adaptive changes occur in the central
nervous system that lead to drug
dependence[1_3]. Although the intrinsic rewarding properties of addictive drugs such as
heroin are important in the acquisition of drug
self-administration, compulsive drug-seeking and drug-taking by
addicts is not readily explained in terms of simple reward or
positive reinforcement processes
alone[4]. Abstinence from the drug in dependent subjects induces aversive withdrawal
symptoms that are thought to contribute to the compulsive
nature of drug self-administration in addiction.
The exact role of withdrawal in heroin addiction is
debatable. It has been proposed that a drug addict may
self-administer heroin to escape from abstinence symptoms
(avoidance theory)[5,6], but also that withdrawal from heroin
functions as a motivational state that enhances the
incentive value of the drug (incentive-motivational
theory)[4,7]. Other integrative reward theories of addiction, such as the
incentive salience-sensitization
theory[8], propose that drug-addicts are sensitized to some motivational effects of drugs
of abuse. Indeed, it has been shown that repeated morphine
administration produces hypersensitivity to subsequent
doses of morphine ("behavioral sensitization") and to other
drugs of abuse ("cross-sensitization"). Sensitization and
cross-sensitization have been extensively studied in
rodents[9_11], but there is little evidence for such phenomenon in primates.
Since drug priming effectively reinstates extinguished drug
self-administration behavior in
animals[12_14], it is likely that enhanced reactivity to the effects of drug of abuse may
facilitate relapse in drug addicts. The fact that low doses of
morphine or cocaine can cause hyperactivity or
drug-seeking in drug reinstatement rodent models supports this
notion[15,16]. Therefore, there is a great interest in developing
medications that may block sensitization processes in order
to reduce relapse in humans.
It is well established that noradrenergic pathways are
implicated in morphine withdrawal. Activity of central
adrenergic neurons is inhibited by
opiates[17] and increased firing of the noradrenergic neurons in the locus coeruleus has
been clearly demonstrated during opiate
withdrawal[18]. Clonidine, an
α2 adrenoreceptor agonist, reduces this
increased firing in morphine-dependent
rats[18], an effect that is thought to mediate the drug's ability to reduce morphine
withdrawal symptoms in animals and
humans19,20]. α2 adrenoceptor agonists, such as clonidine and lofexidine, are
used to reduce withdrawal syndromes during the initial phase
of opioid abstinence in humans[21_23]. Typically, these
α2 adrenoreceptor agonists are used to control opioid
withdrawal on a tapered dosing schedule for the first week of
drug abstinence. Most of the studies conducted in animals
have evaluated the effects of clonidine on opiate withdrawal
symptoms and little is known about the long-term effects of
α2 adrenoceptor agonists after their administration.
Recent evidence suggests that noradrenergic pathways
are involved not only in withdrawal states, but also in other
aspects of drug dependence such as drug-seeking
behavior[24] and behavioral
sensitization[25]. The α2 adrenoceptor
agonist lofexidine attenuates stress-induced reinstatement of
alcohol-seeking and also decreases alcohol
self-administration[26]. The
α2 adrenoceptor antagonist, yohimbine, induces
reinstatement in animal models of abuse of
alcohol[26],
methamphetamine[27],
cocaine[28], heroin[29], and a mixture of
cocaine and heroin (speedball)[30]. There is a strong
correlation between increases in cortical extracellular
norepinephrine levels and the expression of behavioral sensitization to
amphetamine[25]; cortical α1-adrenergic receptors are
critically involved in locomotor responses to amphetamine and
morphine[31,32]. In spite of the widespread use of clonidine
during the initial phase of opiate withdrawal in humans, the
long-term effects of clonidine on subsequent motivational
effects of drugs of abuse have not been explored.
The present study was designed to evaluate the
immediate and long-term effects of clonidine administered during
the initial phase of morphine withdrawal in rhesus monkeys.
First, to induce dependence, rhesus monkeys received an
escalading morphine dosage regimen over 90 d. To induce
morphine withdrawal, morphine treatment was abruptly
stopped. To evaluate the immediate and long-term effects of
clonidine on withdrawal signs, the monkeys received
clonidine for 1 week and the withdrawal signs were
measured daily during a period of 21 d. Finally, the effects of
clonidine on the challenge injection of morphine or cocaine
were evaluated after prolonged morphine abstinence.
Materials and methods
Drugs Morphine hydrochloride and cocaine phosphate
were purchased from Qinghai Pharmaceutical Factory Co Ltd
(Xi'ning, China). Solutions of morphine and cocaine were
prepared with saline (0.9% sodium chloride) and delivered
via sc injection. Clonidine is a commercial agent for human
use, given ig.
Animals Laboratory-reared, male rhesus monkeys
(Macaca mulatta), weight between 3.5 and 5.5 kg (2_3 years
old), were purchased from the Beijing Xierxing Institute of
Biological Resources (Beijing, China). The monkeys were
housed individually in 80 cm (height)×70 cm (width)×70 cm
(length) metal cages. The monkeys were allowed free access
to water, and restricted food and fresh fruit access was
available at 09:00 h and 15:00 h. The animals were maintained
according to the Guide for the Care and Use of Laboratory
Animals (National Institute of Health, 1996). The
experimental protocol was approved by Institutional Animal Care and
Use Committee of National Institute on Drug Dependence,
Peking University.
Morphine dependence induction The experiment
consisted of 3 phases: morphine dependence induction (90 d),
morphine withdrawal (21 d), and drug challenge (7 d). To
ensure consistent drug administration and to reduce stress
on and increase the cooperativeness of the monkeys, all
drug administrations were performed by the same
experi-menters, who were blind to the animals' group assignment.
During the 90 d period of morphine dependence induction,
the monkeys were housed in an environment similar to that
in which they were reared. Eighteen monkeys were randomly
divided into 3 groups of 6 monkeys per group (3 groups:
Sal-Sal, Mor-Sal, and Mor-Clo). Table 1 summarizes the
details of the experimental procedure. Morphine dependence
was induced by repeated administration of morphine at
increasing dosages for 90 d. Every day, the monkeys
received sc injections in their back legs (08:00 h, 13:00 h, and
20:00 h). The Sal-Sal group was given 0.5 mL/kg of saline.
The Mor-Sal and Mor-Clo groups were given morphine on a
dose schedule of 3 mg/kg (d 1_7), 6 mg/kg (d 8_14), 9 mg/kg
(d 15_21), 12 mg/kg (d 22_28), 15 mg/kg (d 29_90). Each
monkey in the Mor-Clo and Mor-Sal groups received a total
of 3420 mg/kg morphine over 90 d.
Morphine withdrawal and clonidine treatment
During the 21 d period of morphine withdrawal, none of the groups
were given morphine. In the first week of withdrawal, the
monkeys in the Mor-Clo group received 0.02 mg/kg (ig)
clonidine twice per day just prior to feeding (09:00 h, 15:00
h), while the monkeys in the Sal-Sal and Mor-Sal groups
received an equal volume of saline (ig). In the second and
third weeks of withdrawal, all the monkeys were given saline
injections twice per day just prior to feeding. Withdrawal
signs, including holding the abdomen, tremor, spasm,
grimacing, face flush, eye closing, dysphoric facial
expres-sions, and provoked screams, were assessed immediately
after each injection.
Drug challenge During the 7 d period of drug challenge,
all the monkeys received a saline injection daily in the first
3 d, a challenge injection of 5 mg/kg morphine (sc) on the
fourth day, a saline injection on the fifth and sixth days, and
a challenge injection of 5 mg/kg cocaine (sc) on the seventh
day. The monkeys' response activity, including locomotor
activity, irritability, vocalization and grooming, were
assessed immediately after the challenge injection.
Physiological recording and behavioral scoring
On the last day of the 90 d morphine induction period, the body
temperature, breath rate, heart rate, and body weight of each
monkey were recorded just before each feeding (09:00 h,
15: 00 h), and the average of the 2 values of each parameter
was recorded as the pretest value. This measure was
repeated on withdrawal day 1_21. While the measurements
were taken, the monkeys were limited to a small corner of the
cage by an apparatus designed by the experimenters. The
monkeys were allowed to rest for at least 10 min prior to the
recording. Withdrawal signs were observed from 08:30_
09:00 and 14:30_13:00. If symptoms of withdrawal appeared
in the 30 min observation, the monkey was given a score of
1, and observation periods in which symptoms were not
shown were given 0. The average score (0, 0.5, or 1) of the 2
daily observations of each monkey was taken as their
current day score value. On the challenge days (challenge d 4
and 7), the monkeys' behavioral changes were scored
according to the following scale: -3 (apparently reduced), 0
(no change), 3 (few observed), 6 (many observed), and 10
(extremely changed). The observation span was 6 h after the
challenge injection (09:00 h). All the recording of
physiological signs and behavioral scoring were carried out by
the same experimenters who were kept blind to the group
assignment in order to ensure consistency.
Statistical analysis The data are expressed as mean±
SEM. and were analyzed with SPSS 13 software (SPSS Inc,
Chicago, Illinois, USA). Physiological signs and withdrawal
score were analyzed using a repeated measure ANOVA followed by a mean comparison with the Bonferroni test.
Behavioral scores from the challenge tests were analyzed
with repeated measure ANOVA followed by a mean
comparison with the Bonferroni test.
Results
After the 90 d morphine treatment, the monkeys exposed
to morphine (Mor-Sal and Mor-Clo groups) showed body
weight loss (3.88±0.14 kg before morphine treatment
vs
3.61±0.11 kg thereafter, n=11) compared with the
morphine-naive monkeys (Sal-Sal group, 3.87±0.23 kg before
vs 4.08±
0.20 kg after, n=6, P<0.05). During the chronic morphine
treatment, 1 monkey in the Mor-Clo group died at d 69 after
receiving a total dosage of 2430 mg/kg morphine.
Effects of clonidine on morphine withdrawal signs
During the 21 d withdrawal period, different weight loss trends
was observed in the 3 groups (F[2,
11]=3.341 P=0.074; Figure 1A). Most withdrawal signs were observed in the first week
after cessation of morphine treatment; thus, the effects of
clonidine on body weight were analyzed in the first, second,
and third week separately. A significant difference was
observed in the weight loss in the first
(F[2, 11]=12.146, P<
0.01), but not the second or the third withdrawal weeks.
However, clonidine had no effect on the body weight in the
first week of morphine withdrawal (P>0.05).
During the 21 d withdrawal period, significant differences
were found in the body temperatures
(F[2, 11]=16.381, P<0.01;
Figure 1B) of the 3 groups. As compared with the Sal-Sal
group, morphine withdrawal (Mor-Sal) produced a
significant decrease in body temperature (P<0.01), but clonidine
treatment had no effect on these withdrawal-induced body
temperature decreases. Significant differences were found
between the 3 groups for body temperature during the first
(F[2, 11]=20.6, P<0.01), second
(F[2, 11]=11.8, P<0.005), and third
(F[2, 11]=4.8, P<0.05) weeks of the withdrawal period.
During the 21 d withdrawal period, a significant
difference in heart rate
(F[2,11]=4.722, P<0.05;
Figure 1C) was observed in the 3 groups. Clonidine was found to increase
the monkeys' heart rate in the first withdrawal week. No
significant difference was found for breath rate
(Figure 1D) in the 3 groups.
Cessation of morphine treatment produced obvious
withdrawal signs, including holding the abdomen, tremor, spasm,
grimacing, face flush, eye closing, dysphoric facial
expres-sions, and provoked screams. During the first week of
withdrawal, 1 monkey in the Mor-Sal group died at
withdrawal d 7. A significant difference was only observed for
the overall withdrawal score during the first 14 d withdrawal
period (F[2,13]=19.9, P<0.01); most withdrawal signs
disappeared after the fourteenth day (Figure 2). In the 14 d
obser-vation, clonidine reduced the symptoms of withdrawal only
during the first 4 withdrawal days (P<0.01, Mor-Sal
vs Mal-Clo). Clonidine had no further effects on withdrawal
symptoms after 4 d (P>0.05). The main behaviors that contributed
to the total withdrawal score were holding the abdomen,
tremor, spasm, grimacing, face flush, eye closing, dysphoric
facial expressions, and provoked screams (Figure 3).
Clonidine proved effective in controlling the withdrawal
signs of abdomen holding, tremor, eye closing, and provoked
screams in the first 7 withdrawal days, but not all the signs of
morphine withdrawal were eliminated by clonidine.
Effects of clonidine on the effect of cocaine and
morphine challenge injection Body weight, body temperature,
and heart and breath rate were also recorded 5 min before
and 1 and 5 h after the challenge injection of morphine or
cocaine. No apparent change was observed in the monkeys
receiving morphine priming. The response activities to
morphine or cocaine, including locomotor activity, vocalization,
grooming, and irritability were reliably observed and used to
discern the sensitization of the monkeys to the challenge of
morphine and cocaine.
An injection of 5 mg/kg morphine caused a significant
increase in locomotor activity
(F[2,11]=29.9, P<0.01) and
irritability (F[2,11]=24.8,
P<0.01), but not in vocalization
(F[2,11]=
1.445, P>0.05) and grooming
(F[2,11]=1.445, P>0.05; Figure
4A). The monkeys naive to morphine (Sal-Sal) showed
deceased locomotor activity and irritability, which may reflect
the sedative effects of morphine[33_35]. Compared with the
Sal-Sal group, the monkeys with a history of morphine
treatment demonstrated increased locomotor activity and
irritability (P<0.01, Sal-Sal vs Mor-Sal), and these behavioral
responses were greatly attenuated in the monkeys that had
previously received clonidine during the first week of
morphine withdrawal (P<0.01, Mor-Clo
vs Mor-Sal).
An injection of 5 mg/kg cocaine increased all the
observed behaviors in the Mor-Sal group (Figure 4B):
locomotor activity (F[2,11]=8.941,
P<0.01), vocalization
(F[2,11]=7.364, P<0.01), grooming
(F[2,11]=5.535, P<0.05), and irritability
(F[2,11]=5.914, P<0.05). The monkeys that received clonidine
treatment during the first week of morphine withdrawal
showed significantly decreased vocalization compared with
no clonidine treatment after morphine withdrawal
(P<0.05, Mor-Clo vs Mor-Sal), and enhanced grooming performance
compared with saline control (P<0.05, Sal-Clo
vs Sal-Sal). One monkey in the Mor-Sal group demonstrated a dramatic
increase in locomotor activity (scored 10), irritability (scored
8), and vocalization (scored 6) 1 h after the cocaine injection.
After 4 h, all the above behaviors declined, and 1 monkey
died 13 h after the cocaine injection in the Mor-Sal group.
Discussion
In the present study, withdrawal symptoms were found
to persist for 14 d after cessation of the 90 d morphine
administration in the rhesus monkeys. Clonidine administration
reduced morphine withdrawal symptoms. However, the
effects of clonidine were not persistent and disappeared when
clonidine administration was stopped. After prolonged
abstinence from morphine, the morphine-dependent
monkeys displayed an enhanced response to a challenge
injection of morphine ("behavioral sensitization") and cocaine
("cross-sensitization"). Clonidine administration during the
initial week of the withdrawal phase produced attenuation of
subsequent behavioral sensitization and cross-sensitization.
After a period of chronic opiate administration, failure to
continue periodic administration of the drug to an animal
resulted in severe physiological and behavioral disturbances
several hours after the last dose of the drug. This complex of
signs and symptoms, termed opiate abstinence syndrome,
indicates that the organism has become physically
dependent on the opiate[36]. Here, the withdrawal symptoms were
measured daily for 21 d to determine precisely the time-course
of appearance and disappearance of the symptoms in rhesus
monkeys as compared with the symptoms previously
documented[37,38]. Few reports are available on the time-course of
the various opiate withdrawal symptoms following
spontaneous abstinence in rhesus monkeys. Here we found the
peak of withdrawal signs at day 2 and 3 following the
cessation of the morphine injections (Figure 2). Morphine
withdrawal was associated with significant weight loss and
decrease of body temperature (Figure 1A, 1B), but there was
no significant change in heart rate. Although breath rates
decreased in morphine-dependent monkeys compared to
control group, this difference was not significant (Figure
1D).
The various signs of morphine withdrawal that were
scored during the withdrawal phase were highly specific,
since control monkeys did not exhibit these signs (see
however Figure 3 the presence of face flush in some control
monkeys). After 14 d of withdrawal, nearly all of the
observ-ed withdrawal signs disappeared (Figures 2, 3). It should be
noted that withdrawal in this study was not induced by
injections of opiate antagonist, but with the cessation of
morphine treatment, a situation that mimics that of human
addicts that stop taking drugs. In contrast, many previous
investigators have used opioids antagonists, such as
naloxone or nalorphine, to induce morphine withdrawal syndrome
in monkeys[39] and
rodents[40_46] (see ref 47 for a comparison
of studies). The symptoms of withdrawal are often more
pronounced when provoked by an injection of an opioid
antagonist than provoked by cessation of morphine
injec-tions. Evidence suggests that the motivational signs of
withdrawal appear first in a situation of mild withdrawal, whereas
physical signs are seen in a situation of severe
withdrawal[46_48]. However, some physical signs of withdrawal were also
relatively severe during the spontaneous withdrawal. This
present finding was strengthened by the fact that 1 monkey
died during the period of morphine withdrawal (see Results).
Interestingly, the withdrawal syndrome created upon the
cessation of access to opioids in rats previously trained to
self-administer morphine caused many of the signs we
reported here in monkeys, such as weight loss, tremor,
hypersensitivity, agitation, soft stools, and increased
respiration[49].
Administration of clonidine, an α2 adrenoceptor agonist,
significantly decreased morphine withdrawal symptoms
during the first week of withdrawal. This finding is in agreement
with previous reports on rhesus
monkeys[38],
rodents[47,50_58], and
humans[21,22,59] that clearly demonstrate that clonidine
effectively attenuates some opiate withdrawal signs and
symptoms. Here, clonidine was able to reduce some, but not
all, symptoms of morphine withdrawal (Figure 3). Notably,
clonidine significantly reduced the overall withdrawal signs
during the first week of withdrawal (Figure 2). Some signs,
such as the provoked screams and holding of the abdomen
in the monkeys, were totally abolished by clonidine
administration. In contrast, clonidine had no or limited
effects on other symptoms such as face flush or grimacing.
Previous reports had shown that clonidine only affected a
subset of symptoms in monkeys[38],
rats[47], and
humans[21,22,59]. The effects of clonidine on withdrawal symptoms were
short-lasting, since the intensity of the morphine withdrawal signs
were even higher at the cessation of the clonidine treatment
(at week 2), suggesting a rebound phenomenon (Figure 2).
It should be noted, that clonidine produced a significant
effect on weight loss induced by withdrawal that was noted
at the third week of morphine withdrawal. However, most of
the withdrawal symptoms disappeared at d 14, regardless of
the presence or absence of clonidine treatment during the
first week of withdrawal, indicating that clonidine did not
dramatically alter the time-course of the abstinence
symptoms and is only able to attenuate its acute manifestations.
Hypotension or sedation are 2 frequent side-effects induced
by clonidine treatment in opiate
addicts[60,61]. The increase of heart rate found in the group of monkeys receiving
clonidine treatment may reflect a compensatory mechanism
to a hypotensive effect of clonidine. No particular sedation
was noticed in the monkeys receiving clonidine treatment.
We have also investigated the effects of priming
injections of morphine and cocaine after prolonged abstinence of
morphine. The monkeys with a history of morphine
treatment displayed enhanced locomotor responses to 5 mg/kg
cocaine and to 5 mg/kg morphine, as compared with naive
control monkeys (Figure 4). These enhanced responses
likely reflect "behavioral sensitization" to morphine and
"cross-sensitization" to cocaine. It is also possible that this
behavioral sensitization to morphine may have been
facilitated by the development of tolerance to the sedative or
depressing effect of morphine, since morphine
administration decreased locomotor activity in naive monkeys.
However, since these experiments have been performed
following prolonged withdrawal from morphine and it is well
known that extended abstinence strongly decreases the
tolerance to the effects of opiate, it is likely that the increased
response to morphine in the monkey with a history of
morphine administration reflects the development of behavioral
sensitization.
Although many investigators have demonstrated that
repeated administration of morphine can produce
long-lasting behavioral sensitization in
rodents[62], very limited evidence has been published so far that this phenomenon is
also observed in humans or monkeys. Therefore, this is (to
our knowledge) the first evidence that monkeys with history
of morphine treatment displayed both sensitized responses
to morphine and cross-sensitization to psychostimulants.
These findings were in agreement with previous experiments
performed on rodents which showed that heroin exposure
facilitates subsequent locomotor and drug-seeking
responses to cocaine in rats[10,63], and enhanced locomotion to ethanol
in mice[64]. In addition, animals with a history of heroin
self-administration displayed locomotor sensitization to
amphetamine[15].
It may seem surprising that a sensitized response to
cocaine administration has been observed on the locomotor
activity, but not grooming behavior following cocaine
admini-stration, since grooming is also a behavior mediated by
dopamine transmission and notably by the stimulation of
the dopamine D1 receptor in
rodents[65_68]. Since locomotor activity is mediated by both the
D1 and D2 receptor stimula-tion, this dissociation may reflect a preferential activation of
the D1 receptor. However, the fact that morphine
administration does not produce vocalization or grooming behavior,
that are known to reflect stress in
monkeys[28], strongly suggests that cocaine may have produced some aversive
effects in these monkeys that morphine dose not produce. It
is well known that cocaine, like other drugs of
abuse[69], produces both positive and aversive
effects[70,71]. It appears that opiates produce less aversive effects compared to
cocaine[70,71], which may explain the absence of grooming and
vocalization induced by the morphine challenge in these
monkeys. This hypothesis can be tested in subsequent
studies using doses of hormones that approximate the level of
stress in these monkeys following drug administration.
Interestingly, some responses to a challenge injection of
cocaine and morphine were not affected by the previous
exposure to morphine (see Results). Notably, the
cardiovascular response to 5 mg/kg cocaine and 5 mg/kg morphine
was identical in all groups. Unfortunately, despite a
considerable research effort in the last 2 decades, the causes of
cardiovascular response to cocaine are still poorly
understood[72]. Many investigators are convinced that the
cardiovascular changes are mediated by changes in catecholamines
levels at the periphery[72], but this interpretation is debatable.
Opiates are mainly known to reduce heart rate and blood
pressure[73]. However, an initial cardiovascular stimulating
effect of opiate has been noted in
cats[74], dogs[75], and
humans[76]. These effects may also involve catecholamine and
histamine release[73]. Here, we extended these findings to
rhesus monkeys, since we had found significant
cardiovascular activation 1 h following morphine and cocaine
administration. It was noteworthy that the monkeys were
sensitized only to response mediated by the dopaminergic
system, whereas other responses that were likely to reflect
peripheral effects of drugs of abuse were not affected.
Early clonidine intervention during the first week of
withdrawal reduced sensitized behavior responses. This effect
was significant for locomotor activity and the irritation score
for morphine and for the vocalization score for cocaine. A
trend downward (a non-significant decrease) was also noted
for the locomotor activity and irritation behavior in the
monkeys. These findings suggest that clonidine treatment
during the first week of withdrawal serves not only to reduce
the acute withdrawal symptoms, but also to affect the
subsequent effects of drug challenge. Drug priming is able to
reinstate drug-seeking behavior in animals in a
reinstatement paradigm and can produce relapses in humans. It is
possible that clonidine administration has blocked some
neurobiological adaptations that are involved in behavioral
sensitization processes ("incentive salience-sensitization
theory") or that the reduction of the intensity of the
withdrawal symptoms accounts for the subsequent behavioral
response to a drug priming injection ("incentive-motivational
theory"). Further experiments are needed to delineate which
of these hypotheses underlie the effects of clonidine. Since
the noradrenergic structure mediates the expression of opioid
abstinence, one possibility is that clonidine normalizes the
firing of locus coeruleus neurons during withdrawal to
produce its effects[53,77]. However, the recent and surprising
finding that total neurochemical lesion of noradrenergic
neurons of the locus coeruleus does not alter either
naloxone-precipitated or spontaneous opiate withdrawal, nor
influence ability of clonidine to reverse opiate
withdrawal[78] suggests that other brain sites may be involved. It is
noteworthy that a noradrenaline-rich subdivision has been recently
identified in the human nucleus
accumbens[79] and that
behavioral sensitization processes to psychostimulants and
opiates may involve sensitized responses of noradrenaline
in frontal areas that project to the nucleus
accumbens[25]. Recent evidence suggests that the blockade of
noradrenaline release induced by clonidine during opiate
withdrawal[57] may involve brain areas other than the locus coeruleus, and
may implicate brain areas involved in the motivational
control of drug-seeking behavior.
In conclusion, the present study demonstrates that
morphine-dependent monkeys will not only present typical
morphine withdrawal symptoms at the cessation of morphine
administration, but will also display enhanced behavioral
responses to challenge injections of both morphine and
cocaine, providing evidence for both "behavioral
sensitization" and "cross-sensitization" processes in non-human
primates. In agreement with previous findings in humans
and laboratory animals, clonidine served to decrease
morphine withdrawal symptoms. However, these effects were
short-lasting. Clonidine produces long-lasting effects on
subsequent morphine and cocaine challenge after prolonged
abstinence. While these experiments do not allow us to
determine if the effects of clonidine are mediated by an
interaction with behavioral sensitization processes or with the
possible link between morphine withdrawal and subsequent
effects of drugs, these experiments indicate that active
intervention in the first stage of withdrawal using an
α2 adreno-ceptor agonist has a positive effect on reducing drug
relapse in the overall therapeutic strategy.
Acknowledgements
We would like to thank Dr Yavin SHAHAM (National
Institute on Drug Abuse, NIH, USA) for helpful comments
on an early version of this manuscript and Dr Ying WANG
(School of Medicine, Xi'An Jiaotong University, China) for
assistance in data analysis.
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