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The Journal of Neuroscience, July 15, 2001, 21(14):5344-5350
Functional Interaction between Opioid and Cannabinoid Receptors
in Drug Self-Administration
M.
Navarro1,
M. R. A.
Carrera3,
W.
Fratta4,
O.
Valverde5,
G.
Cossu4,
L.
Fattore4,
J. A.
Chowen6,
R.
Gómez1,
I.
del
Arco1, 7,
M. A.
Villanúa2,
R.
Maldonado5,
G. F.
Koob3, and
F. Rodríguez
de Fonseca1, 7
Departamentos de 1 Psicobiología and
2 Fisiología, Universidad Complutense de Madrid,
28223 Madrid, Spain, 3 Department of Neuropharmacology, The
Scripps Research Institute, La Jolla, California 92037, 4 Department of Neuroscience, University of Cagliary,
Sardinia, 09124 Italy, 5 Departamento de
Farmacología, Universidad Pompeu Fabra de Barcelona, 08003 Spain, 6 Instituto Cajal, Consejo Superior de
Investigaciones Cientificas, Madrid, 28002 Spain, and
7 Fundación Hospital Carlos Haya, 29010 Málaga,
Spain
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ABSTRACT |
The present study was designed to explore the relationship between
the cannabinoid and opioid receptors in animal models of opioid-induced
reinforcement. The acute administration of SR141716A, a selective
central cannabinoid CB1 receptor antagonist, blocked heroin
self-administration in rats, as well as morphine-induced place
preference and morphine self-administration in mice. Morphine-dependent animals injected with SR141716A exhibited a partial opiate-like withdrawal syndrome that had limited consequences on operant responses for food and induced place aversion. These effects were associated with
morphine-induced changes in the expression of CB1 receptor mRNA in
specific nuclei of the reward circuit, including dorsal caudate
putamen, nucleus accumbens, and septum. Additionally, the opioid
antagonist naloxone precipitated a mild cannabinoid-like withdrawal
syndrome in cannabinoid-dependent rats and blocked cannabinoid
self-administration in mice. Neither SR141716A nor naloxone produced
any intrinsic effect on these behavioral models. The present results
show the existence of a cross-interaction between opioid and
cannabinoid systems in behavioral responses related to addiction and
open new strategies for the treatment of opiate dependence.
Key words:
addiction; cannabinoid; drug abuse; opioid; rat; mice; self-administration
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INTRODUCTION |
Converging research findings have
provided evidence for the existence of a functional interaction between
the endogenous brain cannabinoid system and the endogenous opioid
system (Hine et al., 1975 ; Vela et al., 1995; Pugh et al., 1997; Tanda
et al., 1997; Manzanares et al., 1999; Valverde et al., 2000). The
former is the pharmacological target of the psychoactive compounds of
marijuana (Felder and Glass, 1998). It is composed by the cannabinoid
CB1 receptor (Devane et al., 1988; Matsuda et al., 1993), several endogenous lipid transmitters, including anandamide (Devane et al.,
1992) and 2-archidonyl glycerol (Mechoulam et al., 1995; Stella
et al., 1997). The CB1 receptor has been proposed as the receptor
responsible for the reinforcing properties of cannabinoids (Martellota
et al., 1998; Ledent et al., 1999; Tanda et al., 1997, 2000). On the
other hand, the opioid system (which includes several families of
related neuropeptides and the opioid receptors) is activated by the
opiate morphine and several semisynthetic opioids (heroin, methadone)
that act through specific interactions with µ,  , and  opioid
receptors (Akil, 1984; Thompson et al., 1993; Mansour et al., 1995).
Among them, the µ receptor has been identified as the major
contributor to opiate dependence (Matthes et al., 1996; Kieffer, 1999).
When comparing µ, , , and CB1 receptors, clearly they exhibit
overlapping neuroanatomical distribution, convergent neurochemical
mechanisms, and comparable functional neurobiological properties: (1)
opioid peptides and receptors have a similar neuroanatomical presence
than cannabinoid receptors in the different structures of the reward
circuitry, including dorsal caudate putamen, ventral striatum, septal
nuclei, and the amygdaloid complex. (Herkenham et al., 1991; Matsuda et
al., 1993; Delfs et al., 1994; Mansour et al., 1995; Navarro et al.,
1998; Mason et al., 1999), (2) opioid and cannabinoid receptors are members of the G-protein-coupled family of receptors for
neurotransmitters (Matsuda et al., 1990; Kieffer, 1999), and they
modulate similar transduction systems, including the cAMP-protein
kinase A cascade, inward rectifier K+
channels, and voltage-dependent Ca2+
channels (Howlett, 1995; Reisine et al., 1996; Hutcheson et al., 1998),
(3) last, opioid and cannabinoid signaling systems are implicated in
the regulation of common physiological processes such as nociception,
motor behavior, or reward (Akil, 1984; Pugh et al., 1997;
Gardner and Vorel, 1998; Manzanares et al., 1999). The existence of a
functional cross-talk between both systems is supported also by
pharmacological analysis confirming the existence of a cooperation
between opioids and cannabinoids in analgesia and tolerance-dependence
phenomena (Hine et al., 1975; Welch et al., 1992; Vela et al., 1995;
Ledent et al., 1999; Navarro et al., 1998; Manzanares et al.,
1999; Mason et al., 1999; M. Martin et al., 2000). Theoretically, these
functional interactions might be potentially useful for the development
of therapeutic strategies for opiate and marijuana addiction, following
the rationale that led to the use of opioid antagonists (i.e.,
naltrexone) for the treatment of ethanol abuse (Volpicelli et al.,
1992). The present study was designed to test this hypothesis in animal
models (nongenetically-modified rodents) by (1) analyzing the effects
of the CB1 cannabinoid receptor antagonist SR 141716A in opiate
self-administration and opiate-induced place preference in rats and
mice and (2) evaluating the actions of the opiate antagonist naloxone
in both cannabinoid-dependent rats and in cannabinoid
self-administration in mice.
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MATERIALS AND METHODS |
Animals. Male Wistar rats obtained from Charles River
Laboratory (Hollister, CA) (La Jolla experiments), or through Panlab (Barcelona, Spain) (Madrid experiments) were used in the present studies. Body weights were 200-250 gm on arrival and reached
~300-400 gm at the time of testing. The rats were housed two per
cage with food and water available ad libitum (except for
limited access to either food or water as required). Lights were on a
12 hr light/dark cycle with lights on at 6:00 A.M. Naive CD1 mice
(Panlab; Harlan, Nossan, Italy) weighing 20-22 gm were used in all the
experiments. They were housed six per cage and acclimatized to
laboratory conditions for at least 1 week before use.
All animal procedures met the guidelines of the National Institutes of
Health detailed in the Guide for the Care and Use of Laboratory
Animals and the European Communities directive 86/609/EEC regulating animal research.
Opiate self-administration in rats and mice. Rats were
trained to lever press for food (one 0.45 mg food pellet; Bio-Serve, Frenchtown, NJ) on a fixed ratio 1 (FR1) schedule of reinforcement, while food was restricted to 20 gm of chow per rat per day. Once stable
responding was achieved, animals were divided into two groups. The
first group (n = 9) was trained to acquire an FR5, time-out 2 min schedule of food reinforcement and was given a limited
access to food for the rest of the experiment. When a stable baseline
was achieved, they were used for studying the effects of acute
administration of the CB1 receptor antagonist SR 141716A (a gift from
Sanofi, Montpellier, France). To this end, the animals received
intraperitoneal injections of either saline or the cannabinoid
antagonist (0, 0.03. 0.3, and 3 mg/kg) in a Latin square design manner,
either 60 min before or immediately before the testing session.
Baseline sessions were intercalated between testing sessions for
assessing carryover effects. The second group (n = 30)
was deeply anesthetized under halothane (1.0-1.5%) and implanted with
chronic indwelling catheters in the jugular vein, as previously
described (Caine et al., 1993). After a postoperative recovery period
of 7 d, animals were trained to self-administer heroin on a daily
basis (Carrera et al., 1999) using standard 240 min sessions on a
heroin dose of 0.06 mg/kg per infusion. In all self-administration
sessions a lever press resulted in an intravenous infusion of a 100 µl solution of heroin dissolved in saline. A white cue light above
the lever indicated delivery of a heroin infusion and remained lit for
a 20 sec time-out period, during which responses were recorded but not
reinforced. All operant sessions were conducted during the animals'
dark cycles. The daily sessions for all the studies continued until the
total number of heroin infusions per session stabilized to within
±10% for 3 consecutive days. Trained rats were used for evaluating the effects of SR 141716A (0, 0.03, 0.3, and 3 mg/kg, i.p.) on heroin
self-administration in a Latin square design. Each rat received one
dose per day. Heroin self-administration sessions included a
pretreatment of subcutaneous saline (1.0 ml/kg body weight) 25 min into a session, and an intraperitoneal dose of SR 141716A 30 min
after saline, 55 min into a session. Immediately after each injection
the lever was retracted for 5 min to avoid self-injections before the
onset of drug effect. Dose effects were evaluated 5 min after injection
for 180 min. Somatic signs of withdrawal after the administration of
SR141716A were rated for 10 min as described below. Data were analyzed
by one-way ANOVA using a within-subject design, with two-factor design
vehicle (saline injection) and SR 141716A dose (0, 0.03, 0.1, 0.3, 3 mg/kg). Subsequent individual mean comparisons were conducted with the Newman-Keuls a posteriori test.
Self-administration of morphine, naloxone, SR141716A, WIN 55,212-2,
HU-210, and CP 55,940 in CD1 mice was performed
as described (Martellota et al., 1998). Animals were tested in pairs in
identical test cages. Each test cage presented a frontal hole provided
with an infrared detector that activated a cumulative recorder and operated a syringe pump to deliver solution contingent on a nose poke
response. A rear vertical chink was made on the opposite wall through
which the tail was extended outside the box and secured to a horizontal
surface allowing access to tail veins with a 27 gm winged needle,
connected to a syringe through a Teflon tubing. Each nose poke of the
active mouse resulted in a contingent injection of 1.0 µl of either
vehicle or drug solution both to the active and yoked passive mouse.
Nose pokes of the yoked controls were counted but had no programmed
consequences. Pairs of animals were selected on the basis of
approximately equal levels of nose poking during pretest and randomly
allocated to the different experimental groups. Each mouse was used in
only one 60 min self-administration session.
Conditioned place preference in rats and mice.
Place-conditioning studies were performed using male Wistar rats,
tested in a Y-maze with three chambers of the same size interconnected
by a common central passage, as previously described (Rodríguez de Fonseca et al., 1995; Chaperon et al., 1998). Two groups of animals
were tested. The first experiment (n = 10-12per group) studied the effects of intraperitoneal injections of saline (unpaired compartment) or SR141716A (0, 0.1, 0.3 and 3 mg/kg, paired
compartment), administered immediately before placing the animal in the
conditioning chambers. A preconditioning session was performed on day 0 for establishing the initial preferences of the animals. Six
conditioning sessions (one per day) were performed thereon, on which
days 1, 3, and 5 were used for the injection of SR141716A, whereas days 2, 4, and 6 for used for saline pairings. Testing session was performed
on day seven and lasted 30 min. The second experiment was performed in
male rats implanted with either a placebo or a morphine pellet as
described above. Seventy-two hours after pellet implantation, animals
were used for analyzing the effects of vehicle or intraperitoneal SR
141716A injections during conditioning sessions on the establishment of
place aversion. Animals were exposed on day 0 to a preconditioning
session, followed on day 1 to a vehicle injection (unpaired
compartment) and on day 2 to SR141716A administration (paired
compartment). Testing session was performed on day 3 and lasted 30 min.
Place preference in mice was performed as previously described (Ledent
et al., 1999). Preconditioning and expression sessions lasted 18 min,
whereas alternative saline or morphine conditioning sessions were of 20 min each. The experimental protocol includes two studies. Experiment 1 was designed to test the effects of acute administration of vehicle, SR
141716, morphine, or the combination in the establishment of place
preference conditioning. Experiment 2 used the animals injected with
vehicle or morphine of experiment 1 to test the effects of SR 141716A
on the expression of an already acquired morphine-induced place
preference. Morphine hydrochloride (5 mg/ml) was dissolved in saline
and given subcutaneously before the mice was confined in the
corresponding compartment during experiment 1. Morphine pellets (75 mg
morphine base) or placebo pellets were implanted subcutaneously after
the first place preference test. Seventy-two hours after pellet
implantation, mice were tested again in the place preference paradigm
for the experiment 2. The CB1 antagonist SR
141716A was administered intraperitoneally at the dose of 3 mg/kg
dissolved in 5% chremophor, 5% ethanol, and 90% distilled
water. This compound was given 10 min before the mouse was confined in
the compartment in the conditioned period for the experiment 1 and 10 min before the testing phase in experiment 2. All compounds were given
at 0.1 ml/10 gm body weight, except SR141716A which was given at 0.2 ml/10 gm body weight.
Data on place preference studies were expressed as the change of
preference toward either the morphine-paired or the saline-paired compartment. This change of preference was calculated as the difference between the time spent in a compartment the day of expression and the
time spent in that compartment on the day of preconditioning.
Opiate and cannabinoid withdrawal. Opiate withdrawal-related
signs during self-administration sessions were rated according to the
Gellert and Holtzman (1978) rating scale. This scale consists of graded
signs (weight loss, escape attempts, and wet-dog shakes) and checked
signs (diarrhea, fasciculations, teeth chattering, swallowing
movements, salivation, chromodacryorrhea, ptosis, abnormal posture,
erection and/or ejaculation, and irritability on handling). Cannabinoid
withdrawal was rated as previously described (Rodríguez de
Fonseca et al., 1997). The cannabinoid withdrawal rating scale was
composed of counted signs (wet-dog shakes, compulsive facial rubbings,
grooming activity, and scratching sequences) and observed signs
(including ptosis, piloerection, swallowing movements, salivation, penile grooming, or abnormal posture). The cannabinoid withdrawal rating scale does not include opiate withdrawal-associated signs like
weight loss, teeth chattering, diarrhea, vocalization, or eye blinking.
Counted signs (total number of events) were summed with observed
signs (events observed over a specific observation time) and subjected
to parametric statistics.
In situ hybridization. In situ hybridization for analyzing
the CB1 receptor mRNA level in neurons of reward-relevant brain areas
was performed as previously described (Navarro et al., 1998) using
emulsion-coated paraformaldehyde-fixed tissue sections (20 µm)
stained with methylene blue. They were obtained from: (1) animals
treated with either saline (vehicle group) or morphine (acute
morphine group; 10 mg/kg, i.p.) and killed 6 hr after the injection, (2) animals implanted under anesthesia with either two
lactose pellets (placebo group) or two morphine (75 mg morphine base
each) pellets (chronic morphine group) pellets and killed 48 hr after
surgical implantation, or (3) animals killed 6 hr after removing the
two morphine pellets that were implanted under anesthesia 48 hr before
(abstinence group). Antisense- or sense-labeled cRNA probes were
generated with T3 and T7 polymerases in the pBSK (+). The sense cRNA
probe was used as a specific control and under identical conditions
showed no detectable labeling. CB1 riboprobes were synthesized by using
T3 polymerase plasmid generously provided by Dr. M. Parmentier (Université Libre de Bruxelles, Belgium), in a
standard transcription reaction containing
33P[UTP]. This resulted in probes with
specific activities of ~1.8 × 109
dpm/µg. The probes were hydrolyzed in bicarbonate buffer to an average length of 150 bases and used for the hybridization studies. After hybridization overnight at 48°C, the slides were washed to
reduce background, counterstained with cresyl violet, placed in 70%
ethanol for 1 min, air-dried, and dipped in LM-1 photographic emulsion
(Amersham Pharmacia Biotech, Arlington Heights, IL), and left exposed
for 3 weeks. The slides were then developed and coverslipped. For
quantitative analysis of CB1 mRNA expression, a computer-aided
quantitation of silver grains of positive-labeled cells was performed
as previously described (Busiguina et al., 2000). For each CB1 receptor
mRNA-labeled neuron examined, a circular field of constant surface area
was delimited over the soma whose boundaries were defined by methylene
blue staining. Grain density was taken as an estimate of the level of
hybridization signals, an index of the CB1 receptor mRNA expression per
neuron. For each section, background grain density was measured
over the neuropil of at least 40 neurons in randomly chosen fields and
subtracted from the grain counts.
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RESULTS |
Effects of the cannabinoid receptor antagonist SR141716A on heroin
self-administration in rats
The acute administration of a cannabinoid receptor antagonist
SR141716A (Rinaldi-Carmona et al., 1994) at a dose of 3 mg/kg resulted
in a reduction of heroin self-administration (0.06 mg/kg per infusion)
during the first hour after the injection (Fig. 1A). A time analysis
(Fig. 1B) showed that the dose of 0.3 mg/kg resulted
in a transient increase of heroin self-administration in the first 30 min after the injection, whereas the 3 mg/kg dose profoundly decreased
heroin infusions up to the end of the session (Fig.
2B). This effect was
selective and not associated to motor disturbances because at any of
the doses selected for the present experiment the
CB1 antagonist affected operant responses for
food (Fig. 3B). Using the
place conditioning paradigm, SR 141716A was found to be ineffective on
inducing place preference, although the higher dose used (3 mg/kg)
shifted the preference of the animal toward the compartment paired with
this dose. This shift in the preference was not statistically
significant. Testing day values for absolute time spent in the SR
141716A-paired compartment in seconds were (mean ± SEM): vehicle,
493.8 ± 68; SR 0.1 mg/kg, 450 ± 92; SR 0.3 mg/kg,
434.3 ± 82.7; and SR 3 mg/kg, 673.6 ± 123.2. These results
indicate an absence of intrinsic rewarding properties of SR141716A in
the range of doses used.
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Figure 1.
Effects of the CB1 receptor antagonist on heroin
self-administration in Wistar male rats. A, Acute
injection of SR 141716A (3 mg/kg) reduced heroin self-administration
(0.06 mg/injection) in the next 60 min. B, Time analysis
along the 210 min session revealed that the effect of 3 mg/kg SR
141716A was still present 150 min after its administration. At the dose
of 0.3 mg/kg, the CB1 antagonist induced a temporary increase in heroin
self-administration. The CB1 receptor antagonist failed to modify
operant responses for food and did not induce place preference (see
Results). *p < 0.01 versus saline-treated group;
Newman-Keuls.
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Figure 2.
Effects of the CB1 receptor antagonist SR 141716A
on opiate reinforcement in mice. A, Mice
self-administered morphine following a bell-shaped dose-response
curve. Injection of morphine or vehicle to active (open
bars) and passive (hatched bars) mice was
controlled by nose pokes of the active mouse. The number of nose pokes
was recorded in n = 6-18 animals per group.
B, The CB1 receptor antagonist SR141716A failed to
induce self-administration. C, Pretreatment with SR
141716A (0.25 mg/kg, i.p.) 30 min before the onset of the session
prevented morphine (2 µg/kg) self-administration.
**p < 0.01; *p < 0.05, active
versus passive; Newman-Keuls test.
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Figure 3.
Effects of the administration of the CB1 receptor
antagonist SR 141716A in morphine-dependent rats. A,
Acute administration of SR 141716A (3 mg/kg) resulted in place aversion
as reflected by the significant negative change of preference in
morphine-dependent animals. n = 8-12 animals per
group; *p < 0.05 SR141716A versus saline
treatment; Newman-Keuls. B, CB1 cannabinoid receptor
blockade affected operant responding for food (60 min sessions, FR 5, time out 2 min) in food-deprived animals (n = 9),
only in morphine-dependent rats. *p < 0.05 SR141716A versus saline treatment; Newman-Keuls.
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Effects of cannabinoid receptor blockade on morphine
self-administration and morphine-induced place preference in mice
The above-described effects of the cannabinoid antagonist SR
141716A on opiate self-administration were replicated in mice (Fig. 2).
Mice self-administered morphine (Fig. 2A) but they
did not self-inject SR 141716A (Fig. 2B). However, SR
141716A administration blocked morphine self-administration (Fig.
2C). Also, mice did not exhibit the transient increase in
heroin self-administration observed in rats. Further research is needed
to clarify whether this difference is based on species-specific
responses or on the doses of SR141716A used in the present study in
mice. However, cannabinoid receptor blockade profoundly disturbed the
acquisition of morphine-induced place preference, a different
model for evaluating the reinforcing properties of this opiate. These
results clearly support the proposed mediation of the endogenous
cannabinoid system on opiate reinforcement. Testing day values for the
change of preference toward the different drug-paired compartments were (in seconds, mean ± SEM): vehicle-paired,  44 ± 41; SR
141716A-paired, 78 ± 80; morphine-paired, 166 ± 16 (p < 0.01 versus vehicle); and morphine + SR141716A-paired, 28 ± 61. In this model, the cannabinoid antagonist was not capable of inducing positive place preference conditioning, indicating again a lack of intrinsic rewarding properties.
Effects of cannabinoid receptor blockade on
opiate-dependent rodents
In an effort to further investigate the interactions between
cannabinoid and opioid systems we studied the effects of cannabinoid receptor blockade in opiate-dependent animals. First we tested the
potential aversive effects of cannabinoid receptor blockade in
opiate-dependent rodents. Acute SR141716A (3 mg/kg) administration resulted in place aversion (Fig. 3A) and produced a decrease
in the number of operant responses for food (Fig. 3B). These
negative reinforcing properties of SR 141716A in opiate-dependent rats were also observed in morphine-dependent mice, on which the
administration of the CB1 receptor antagonist
blocked the expression of an already acquired morphine-induced place
preference (Fig. 4).
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Figure 4.
Acute administration of SR 141716A (3 mg/kg)
blocked the expression of an already established morphine-induced place
preference in morphine-dependent mice. SL, Saline;
MP, morphine, SR, SR141716A.
**p < 0.01, morphine-dependent versus
saline-treated group; Scheffé F test.
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Effects of opioid receptor blockade on rodent models of
cannabinoid dependence
The above-described experiments suggest the existence of a
functional interaction between opioid and cannabinoid receptors in
opiate addiction. The interaction is bidirectional because naloxone
administration induced a partial cannabinoid withdrawal syndrome in
rats chronically treated with the cannabinoid agonist HU-210 (100 µg · kg 1 · d1
for 14 d) (Fig. 5). Additionally,
both SR141716A and naloxone precipitated a partial cannabinoid
withdrawal syndrome in rats implanted with morphine pellets. The main
differences between the withdrawal syndromes induced by naloxone and SR
141716A in HU-210-dependent animals were in the repetitive and abruptly
interrupted motor sequences that characterize cannabinoid withdrawal
(facial rubbings, paw fluttering, scratching, and grooming sequences). These behaviors did not appear after naloxone treatment. As described before (Navarro et al., 1998), neither diarrhea, weight loss, teeth
chattering, nor chromodacryorrhoea were observed after SR141716A administration in opiate-dependent or cannabinoid-dependent animals. The opioid contribution to cannabinoid withdrawal also appeared in
mice. Naloxone (0.1 and 1 mg/kg) was found to block the
self-administration of the cannabinoid receptor agonists WIN 55,212-2
(0.1 mg/kg per infusion) (Fig.
6A) and HU-210 (5 µg/kg per infusion) (Fig. 6B). Naloxone, however,
was not self-administered by the rodents (Fig. 6A).
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Figure 5.
Naloxone administration (1 mg/kg, i.p.) induced a
partial cannabinoid withdrawal syndrome in male rats chronically
exposed to either the cannabinoid receptor agonist HU-210 (100 µg/kg
for 14 d) or to the opiate morphine (2 pellets of 75 mg of
morphine base implanted subcutaneously for 72 hr). The cannabinoid
antagonist SR 141716A (3 mg/kg) induced a partial cannabinoid
withdrawal syndrome in morphine-dependent animals.
n = 9-15 animals per group;
**p < 0.01; *p < 0.05, versus
saline-treated animals; Newman-Keuls test.
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Figure 6.
Opioid involvement in cannabinoid
self-administration. A, Mice did self-inject the CB1
receptor agonist WIN 55,212-2 (50 and 100 µg/kg per injection),
although they did not self-inject the opioid receptor antagonist
naloxone (NX). However, naloxone
(B) (100 µg/kg) decreased the
self-administration of the cannabinoid receptor agonists WIN 55,212-2
(WIN; 100 µg/kg per injection) and HU-210
(HU; 100 µg/kg per injection). n = 10-12 animals per group; **p < 0.01, active
versus passive; Newman-Keuls test.
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Effects of morphine on the expression of CB1 receptor mRNA in the
rat brain
Acute administration of morphine resulted in specific changes in
the expression of the CB1 cannabinoid receptor mRNA, as revealed by the
analysis of grain density in the labeled neurons from the in
situ hybridization. Morphine decreased the expression of the CB1
mRNA in the dorsal caudate putamen, the medial septum shell of the
accumbens, and the vertical arm of the diagonal band of Broca (Fig.
7A).These effects were
reversed in both morphine-dependent and morphine-withdrawing animals
(Fig. 7B). Morphine-dependent animals exhibited increased
levels of the CB1 mRNA in the diagonal band of Broca and normal levels
in the caudate putamen and septo-accumbens area. Withdrawal induced by
removing morphine pellets increased the cell labeling in the caudate
putamen and the vertical arm of the diagonal band.
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Figure 7.
Opioid involvement in cannabinoid CB1 receptor
mRNA expression in the rat brain, measured by quantitative in
situ hybridization histochemistry. A, Acute
morphine (5 mg/kg) decreased the expression of the CB1 receptor mRNA in
specific brain areas. B, Chronic morphine (2 pellets of
75 mg of morphine base implanted subcutaneously for 72 hr) or opiate
withdrawal (removal of morphine pellets for 6 hr) reversed these
effects. n = 3-4 animals per group;
*p < 0.01, versus vehicle or placebo groups;
Newman-Keuls test. CP, Caudate putamen;
SPT-ACC, septum shell of accumbens; HDB,
horizontal arm of the diagonal band of Broca; VDB,
vertical arm of the diagonal band; ACA, anterior
amygdaloid nuclei; HBC, habenular complex.
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DISCUSSION |
The present study supports the existence of converging opioid and
cannabinoid mechanisms implicated in the acute positive reinforcing
actions of opioids and cannabinoids in rodents. The finding of an
association of a particular genetic variant of the human CB1 receptor
to intravenous drug use, including opiates, further supports this
hypothesis (Comings et al., 1997). The results also indicate the
existence of parallel neuroadaptions in both the endogenous opioid and
the endogenous cannabinoid systems that occur during both chronic
opiate or chronic cannabinoid exposure. The demonstration of the
pharmacological activity of SR 141716A as a blocker of the acute
reinforcing properties of morphine and/or heroin in intact animals
suggests that drugs acting as cannabinoid CB1 receptor antagonists may
be considered as a new therapeutic approach for the treatment of opiate
addiction (Navarro et al., 1998; Rubino et al., 2000). These properties
can be extended to ethanol abuse because SR141716A has been reported to
suppress ethanol self-administration in rodents (Colombo et al., 1998; Gallate et al., 1999; Rodríguez de Fonseca et al., 1999),
probably through the recently described ethanol-induced changes in both endocannabinoid synthesis and CB1 receptor function (Basavarajappa and
Hungund, 1999). Although the present data may suggest that the CB1
antagonist SR 141716A has an opiate receptor antagonist-like profile,
SR141716A cannot interact directly with µ-opioid receptors. Previous
studies reported that this compound exhibited no affinity for any of
the cloned opioid receptor subtypes (Rinaldi-Carmona et al., 1994).
The profile of these functional interactions suggests that the CB1
receptor seems to be necessary for the expression of the rewarding
properties of morphine and heroin in intact rats and mice, as
demonstrated using place preference and self-administration paradigms
(Figs. 1, 2) (see Results). These present data confirm the findings
described in CB1 receptor knock-out mice (Ledent et al., 1999; M. Martin et al., 2000), indicating that potential developmental
alterations in reward circuits are not the neural basis of the lack of
reinforcing effects of morphine in these animals. These results
extended to the reward system the convergent mechanisms described for
opioids and cannabinoids in analgesia, confirming the cooperation of
cannabinoid CB1 receptors with opioid µ, , and receptors in
multiple physiological roles (Welch and Stevens, 1992; Pugh et al.,
1997; Mason et al., 1999; Manzanares et al., 1999; T. J. Martin et al.,
2000).
Acute mechanisms contributing to the common effects of cannabinoids and
opiates may include the already described convergent activatory actions
of both types of psychoactive substances in ascending mesolimbic
dopaminergic projections, resulting in an enhancement of dopamine
release in the nucleus accumbens (Chen et al., 1990; Tanda et al.,
1997; Gardner and Vorel, 1998). Supporting this hypothesis, we have
recently found that morphine-induced increase in extracellular dopamine
levels in the nucleus accumbens is dramatically attenuated in CB1
knock-out (Mascia et al., 1999). The ability of cannabinoid CB1
receptor-acting drugs to reduce heroin self-administration is also
consistent with the recently described role of the anandamide-CB1
receptor system as a modulator of dopamine D2 receptor-mediated
responses (Giuffrida et al., 1999). Dopamine D2 receptors are
considered one of the major contributors to opiate-induced positive
reinforcement (Maldonado et al., 1997), and the capacity of the
cannabinoid receptor antagonist to interfere with the acquisition and
expression of morphine-induced place preference resembles that
described for dopamine D2-D3 receptor agonists such as
7-hydroxy-2(di-n-propylamino)tetralin
(Rodríguez de Fonseca et al., 1995). However, the finding of
cocaine-induced place preference and sensitization in CB1 receptor
knock-out mice suggests a secondary role for cannabinoid CB1
receptor-dopamine receptor interaction in the molecular events
responsible for the effects described on morphine reinforcement in the
present study.
The blocking of heroin self-administration responses found with high
doses of the CB1 antagonist SR 141716A (i.e., 3 mg/kg) may suggest the
induction of a negative affective state, which was exacerbated by the
induction of dependence (morphine pellet implantation) as reflected by
the suppression of operant responses for food and the place aversion
induced by SR141716A in the opiate-dependent animals. The finding of a
naloxone-induced cannabinoid withdrawal in cannabinoid-dependent
animals supports the bidirectional nature of these neuroadaptions. The
underlying effects of chronic administration of opiates and
cannabinoids may involve not only the direct actions on their
homologous receptor system, but also the common intracellular signaling
mechanisms. Thus, it has been described that both chronic cannabinoid
and opiate exposure not only induces parallel desensitization in
Gi-protein coupling to the adenylate cyclase (Sim
et al., 1996a,b; Nestler and Aghajanian, 1997), but also a
profound upregulation of the cAMP-dependent protein kinase activity to
counteract the inhibition of the cAMP-dependent cascade of signaling
events induced by both types of drugs (Blendy and Maldonado, 1998;
Hutcheson et al., 1998; Koob et al., 1998). Additionally, chronic
exposure to opiates or cannabinoids induce comparable neuroadaptions in specific transmitter systems, including dopamine (Diana et al., 1995,
1998) and corticotropin-releasing factor (Heinrichs et al., 1995;
Rodríguez de Fonseca et al., 1997). These adaptations
contribute to the onset of the aversive state that characterize
repeated drug exposure (Koob et al., 1998). Because both µ-opioid and
CB1 cannabinoid receptors are located in the same neuronal cells of reward-relevant telencephalic nuclei (Navarro et al., 1998), it is
possible that the effects of either the CB1 antagonist in
opiate-dependent animals or the opioid receptor antagonist in
cannabinoid-dependent rodents may reflect the convergence of both
heterologous receptors to a common functional response in processing
negative reinforcement, leading to a blockade of drug
self-administration. In this regard, the experiments with in
situ hybridization indicate that acute opiate exposure upregulated
the CB1 signaling pathway in dorsal striatum, septo-accumbens, and
diagonal band of Broca areas. Similar results have been reported in
opiate-dependent mice (Rubino et al., 1997). Additionally subchronic
cannabinoid administration upregulated the opioid signaling system in
the CNS (Mailleux and Vanderhaeghen, 1994; Manzanares et al.,
1999; Mason et al., 1999).
The present study provides solid evidence for the existence of a
potential cross-talk between opioids and cannabinoids in brain
motivational systems involved in drug dependence. As the identification
of opioid-ethanol interactions leads to the clinical evaluation of
opioid antagonists as a therapy in alcoholism, the existence of
functional interactions between the endogenous cannabinoid system and
the endogenous opioid signaling system may have a place as a new target
for the pharmacotherapy of addiction.
| |
FOOTNOTES |
Received Dec. 8, 2000; revised April 17, 2001; accepted May 1, 2001.
This work has been supported by Dirección General de
Investigación Cientifica y Técnica Grant PM 96/0047,
Comisión Interministerial de Ciencia y Tecnología, Spain
Grant SAF 2000-0101, Comunidad de Madrid (Grant 08.5/0013/98), and Plan
Nacional Sobre Drogas (M.N., F.R.F., J.A.C., I.A., M.A.V.); National
Institutes of Health Grant DK 26741 (G.F.K., M. R.C.); Ministero
dell'Università della Riecrea Scientifica e Technologica
and Consiglio Nazionale delle Ricerche (W.F., G.C., L.F.), BIOMED2
Grant PL982267, and Laboratorios Dr. Esteve (O.V., R.M.). M.N and F.R.F
are research fellows of the Del Amo Program, Universidad Complutense de
Madrid. We are grateful to Dr. M. Mossé (Sanofi Research) for
generously providing SR141716A. This is publication number 12558-NP
from The Scripps Research Institution.
Correspondence should be addressed to Miguel Navarro or Fernando
Rodríguez de Fonseca, Departamento de Psicobiología,
Facultad de Psicología, Universidad Complutense de Madrid,
28223 Madrid, Spain. E-mail: pspsc10{at}sis.ucm.es.
| |
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J. Neurosci.,
December 1, 2001;
21(23):
9499 - 9505.
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ABSTRACT
INTRODUCTION
Compound via MeSH
