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The Journal of Neuroscience, May 1, 2002, 22(9):3326-3331
MINI REVIEW
Cannabinoid Addiction: Behavioral Models and Neural
Correlates
Rafael
Maldonado1 and
Fernando
Rodríguez de
Fonseca2
1 Laboratori de Neurofarmacologia, Facultat de
Cienciés de la Salut i de la Vida, Universitat Pompeu Fabra,
08003 Barcelona, Spain, and 2 Fundación Hospital
Carlos Haya, Unidad de Investigación, 29010 Málaga, Spain
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ABSTRACT |
The use of cannabis sativa preparations as
recreational drugs can be traced back to the earliest civilizations.
However, animal models of cannabinoid addiction allowing the
exploration of neural correlates of cannabinoid abuse have been
developed only recently. We review these models and the role of the
CB1 cannabinoid receptor, the main target of natural
cannabinoids, and its interaction with opioid and dopamine transmission
in reward circuits. Extensive reviews on the molecular basis of
cannabinoid action are available elsewhere (Piomelli et al., 2000 ;
Schlicker and Kathmann, 2001).
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ARTICLE |
Neuropsychopharmacological studies
have clarified the social controversy on the abuse liability of
cannabinoids by demonstrating that such drugs fulfill most of the
common features attributed to compounds with reinforcing properties
(Table 1). There were several reasons for
the delay of such models. (1) The structure and production of ethanol,
cocaine, opioids, and nicotine were identified early, whereas naturally
occurring psychoactive cannabinoids were not isolated and synthesized
until the late 1960s (Mechoulam, 1970). (2) Cannabinoids are
hydrophobic substances that redistribute to fat stores with a low rate
of excretion. This feature and additional pharmacokinetic properties
made it difficult to characterize a cannabinoid receptor and precluded
the identification of neuroadaptions associated with the onset
of dependence and withdrawal. (3) Initial studies of
cannabinoid-induced reinforcement used high doses unrelated to those
that induce subjective effects in humans. Most early findings pointed
to an aversive profile for cannabinoids (Elsmore and Fletcher,
1972).
After the identification of new synthetic cannabinoids, a cannabinoid
receptor was identified and cloned in the late 1980s (Matsuda et al.,
1990) (Fig. 1). By using a more rational approach, the subjective
effects of cannabinoids have been studied with classical paradigms in
animal models such as drug discrimination. Motivational properties and
indirect reinforcing measures were identified with intracranial
self-stimulation (ICSS) and conditioned place preference paradigms
(CPPs). The direct reinforcing properties of cannabinoids were
demonstrated recently with intravenous self-administration (ISA)
(Gardner and Vorel, 1998). Additionally, the induction of tolerance and
dependence and the identification of a cannabinoid withdrawal syndrome
have been verified. Biochemical and electrophysiological studies have
also clarified the effects of cannabinoids on brain circuits
responsible for the addictive properties of drugs. They include the
analysis of acute and chronic cannabinoid actions on mesolimbic
dopamine (DA) neurons, cannabinoid modulation of glutamate and GABA
transmission in reward circuits, and cannabinoid interactions with
neuropeptides relevant for processing motivation, such as the opioid
peptides and corticotropin-releasing factor (CRF). Most recently, CB1
cannabinoid receptor (CB1R) and other knock-out (KO) mice deficient in
different components of the endogenous opioid system were generated and
used to understand the contribution of these endogenous systems to
cannabinoid dependence (Ledent et al., 1999; Valverde et al., 2000;
Zimmer et al., 1999, 2001; Ghozland et al., 2002).
Behavioral models for studying cannabinoid motivational and
reinforcing properties
Drug discrimination
Early studies identified the discriminative stimulus properties of
 9-tetrahydrocannabinol (THC), the main
psychoactive constituent of cannabis. Because animals did
not easily self-administer cannabinoids, initial studies analyzed the
subjective properties of cannabinoids with this task. Animals easily
associate the pharmacological properties of low doses of THC (0.20 mg/kg) with a correct response for a reward (i.e., food) in a two-lever
drug discrimination task (Jarbe et al., 1976). The discriminative
stimulus effects of THC are pharmacologically selective.
Non-cannabinoid drugs generally do not substitute for THC, whereas
cannabinomimetic drugs fully substitute for THC in pigeons, rats, and
monkeys (Wiley et al., 1995). A GABAergic component may be involved in
cannabinoid drug discrimination, as revealed by the partial
substitution elicited by diazepam (Wiley and Martin, 1999). Cannabinoid
discriminative effects are prevented by pretreatment with the CB1R
antagonist SR141716A (Wiley et al., 1995). Anandamide and stable
analogs of this endocannabinoid do not fully substitute for THC,
indicating a different pharmacological profile for natural and
synthetic cannabinoids and endocannabinoids (Wiley, 1999).
Conditioned place preference paradigms and conditioned
taste aversion
Initial studies with THC showed that this cannabinoid elicits
aversive responses in both CPP and conditioned taste aversion (CTA)
procedures (Elsmore and Fletcher, 1972). The rationale of these
Pavlovian tests is to establish conditioned associations between
certain environments or a certain taste and the acute motivational
actions of the drug tested. Positive rewarding effects are associated
with place preference. However, several abused drugs produce CTA when
paired with a certain flavor. THC and other cannabinoid agonists induce
CTA and place aversion. These aversive effects are dependent on two
variables: high doses induce robust aversion, whereas low doses induce
aversion only when tested in naive animals (Gardner and Vorel, 1998).
In fact, preexposure to cannabinoids previous to conditioning
eliminates the aversive component of cannabinoid effects, resulting in
the development of CPP (Valjent and Maldonado, 2000). This aversive
effect appears to be mediated by CB1Rs (Chaperon et al., 1998) and to
be dependent on endogenous dynorphin transmission (Zimmer et al., 2001)
through the activation of  opioid receptors (KORs) (Ghozland et al., 2002). CPP induced by cannabinoid agonists can also be prevented by
CB1R blockade (Navarro et al., 2001), and the endogenous opioid system
participates in this response. In
agreement, THC-induced CPP was suppressed in KO mice deficient
in µ opioid receptors (MORs) (Fig. 2)
but was unaffected in mice lacking  opioid receptors (DORs) or KORs,
suggesting a selective involvement of MORs in this THC response
(Ghozland et al., 2002). This interaction between cannabinoid and
opioid systems seems to be bidirectional given that the rewarding
effects of morphine in the CPP paradigm are blocked in CB1R KO mice
(Martin et al., 2000). Furthermore, the CB1R antagonist SR141716A
blocks acquisition of morphine CPP, as well as the rewarding effects of
other drugs of abuse (Chaperon et al., 1998).
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Figure 1.
Molecular targets of major abused drugs.
Cannabinoids, like opiates, activate a G-protein-coupled receptor, in
this case the CB1R, which couples to transduction mechanisms, mainly
adenylyl cyclase (AC), and voltage-gated potassium, and
calcium channels through the small GTP-binding proteins
Gs/olf and Gi/o. CB1 receptors thereby modulate
the resting membrane potential and intracellular concentrations of
cAMP. Subsequent modification of the activity of specific
protein kinases, primarily PKA, but also mitogen-activated protein
kinases, leads to both acute responses (modulation of neurotransmitter
release or firing rates) and long-term adaptations associated with
dependence and withdrawal.
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Figure 2.
Involvement of the endogenous opioid
system in cannabinoid motivational properties, tolerance, and
dependence. A, THC-induced CPP is abolished in MOR KO
mice. Scores are calculated as the difference between test and
preconditioning time spent in the drug-paired compartment (from
Ghozland et al., 2002). B, Tolerance to THC-induced
antinociception is reduced in KO mice deficient in the
pre-proenkephalin gene (from Valverde et al., 2000). C,
Severity of SR141716A-precipitated THC withdrawal syndrome is
attenuated in KO mice deficient in the pre-proenkephalin gene. A
global withdrawal score was calculated for each animal by giving each
individual sign (tremor, wet dog shakes, ptosis, front paw tremor,
ataxia, mastication, hunched posture, sniffing, piloerection, and
penile lick) a proportional weight (from Valverde et al., 2000). Values
are expressed as mean ± SEM;  p < 0.05, p < 0.01, comparison between
treatments;  p < 0.05, p < 0.01, comparison between
genotypes (one-way ANOVA).
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Intracranial self-stimulation
This behavioral paradigm allows direct in vivo
monitoring of drug effects on brain reward circuits by evaluating
self-delivery of rewarding electrical stimulation of the medial
forebrain bundle. Drugs capable of activating reward circuits
facilitate ICSS. Low doses of THC enhance ICSS by lowering reward
thresholds (Gardner et al., 1988). This effect varies in different rat
strains. Lewis rats, which are very sensitive to positive reinforcers,
exhibit the most robust effects (Gardner and Vorel, 1998). The CB1R
antagonist SR141716A decreases sensitivity to electrical stimulation,
an effect observed also after withdrawal from THC (1 mg/kg) treatment (Gardner and Vorel, 1998). These observations suggest that CB1R activation in reward circuits facilitates the effects of positive reinforcers, although the magnitude of this effect has been questioned (Arnold et al., 2001). Naloxone blocks the facilitatory effects of THC
on ICSS, suggesting an opioid component in these THC-induced rewarding
effects (Gardner and Vorel, 1998).
Intravenous self-administration
Since 1970, all attempts to obtain a robust procedure for THC
self-administration have failed. This failure has been fundamental to
claims of a differential status for cannabinoids with respect to major
abused drugs. The availability of new cannabimimetic compounds that
activate CB1Rs and have different pharmacokinetic properties than THC
led to the first observation of cannabinoid ISA in mice. Drug-naive
mice self-administer the aminoalkylindole WIN 55,212-2 (Martellotta et
al., 1998), the bicyclic cannabinoid CP 55,940, and the THC derivative
HU-210 (Navarro et al., 2001). These compounds cover the three major
types of cannabinoid-like chemicals. Rats also exhibit ISA (Fattore et
al., 2001) of synthetic cannabinoid agonists. In all cases, an inverted
U-shaped relationship between cannabinoid dose and injection frequency
is observed, as for most self-administered drugs. Although THC is
unable to sustain ISA in mice and rats, self-administration of
synthetic cannabinomimetic compounds was counteracted by the antagonist SR141716A, indicating a major role for CB1Rs. The fact that squirrel monkeys (Tanda et al., 2000) self-administer THC, an effect than can
also be precluded by CB1R antagonism, indicates species-specific differences in the pharmacokinetics and pharmacodynamics of THC between
primates and rodents that preclude the observation of THC
self-administration in murine models. In any case, both ISA paradigms
require manipulations of the motivational state of the animal to
achieve stable self-administration patterns. Rodents must be food
restricted, whereas THC self-administration in monkeys is achieved
after previous acquisition of cocaine self-administration. Cannabinoid
self-administration is dependent not only on CB1Rs, but an opioid
component is also observed; naloxone blocks this behavior in mice and
rats (Fattore et al., 2001; Navarro et al., 2001), whereas naltrexone
blocks THC ISA in monkeys (Tanda et al., 1997, 2000). This interaction
between cannabinoid and opioid systems is also bi-directional. Morphine
ISA is abolished in CB1R KO mice (Ledent et al., 1999).
Neural correlates of cannabinoid positive reinforcement
Ascending mesocorticolimbic projections of the ventral tegmental
area (VTA) DA neurons display a consistent response to major abused
drugs and appear to be a common substrate for the rewarding properties
of drugs of abuse. Most drugs of abuse activate VTA DA neurons, as
monitored by DA release in terminal areas [especially the nucleus
accumbens (NAc) and prefrontal cortex (PFC)] or by firing rates
of VTA DA neurons. THC and other cannabimimetic drugs increase DA
efflux in the NAc and PFC and increase DA cell firing in the VTA
(French et al., 1997). This effect is not caused by direct activation
of DA neurons because they do not express CB1Rs. Although the effects
on DA release can be blocked by the opioid antagonist naloxone (Tanda
et al., 1997), the increase in VTA DA cell firing cannot (French et
al., 1997), suggesting a differential role for endogenous opioid
systems as a modulator of cannabinoid actions in DA cell bodies and
terminal fields. Cannabinoid effects might also involve glutamatergic
and GABAergic inputs to the NAc and VTA, because presynaptic CB1Rs
regulate glutamate and GABA release in these areas (Schlicker and
Kathmann, 2001). Additional postsynaptic mechanisms involving direct
interactions between DA D2 receptors and CB1Rs have been proposed
(Giuffrida et al., 1999). In agreement with these actions of
cannabinoids in brain rewarding circuits, repeated cannabinoid exposure
can induce behavioral sensitization (Cadoni et al., 2001), similar to
other drugs of abuse. Chronic cannabinoid administration also produces
cross-sensitization to the locomotor effects of psychostimulants
(Gorriti et al., 1999) and opioids (Pontieri et al., 2001).
Behavioral models for studying cannabinoid tolerance, dependence,
and withdrawal
Tolerance
Chronic administration of CB1R agonists leads to tolerance to most
responses. Indeed, several studies have shown tolerance to cannabinoid
effects on antinociception, locomotion, hypothermia, catalepsy,
suppression of operant behavior, gastrointestinal transit, body weight,
cardiovascular actions, anticonvulsant activity, ataxia, and
corticosterone release. This tolerance occurs in rodents, pigeons,
dogs, and monkeys (Abood and Martin, 1992). The development of
cannabinoid tolerance is rapid, often occurring on the second administration (Abood and Martin, 1992). Tolerance is maximal after
short-term cannabinoid treatment (Bass and Martin, 2000).
Different pharmacokinetic mechanisms are involved in cannabinoid
tolerance, including changes in drug absorption, distribution, biotransformation, and excretion. However, the role of such
pharmacokinetic mechanisms seems minor (Dewey et al., 1972).
In contrast, pharmacodynamic events play a crucial role in
cannabinoid tolerance. Indeed, a significant decrease in the total
number of CB1Rs (Rodriguez de Fonseca et al., 1994) and levels of CB1R
mRNA occurs in several brain areas during chronic cannabinoid
administration (Romero et al., 1998). A widespread decrease in
mRNA levels of G i- and Gs-proteins
accompanies chronic treatment with cannabinoids (Rubino et al., 1997).
Changes in G-protein expression are related to desensitization of
CB1Rs. Reductions of cannabinoid agonist-stimulated
[35S]GTP S binding are seen in most
brain regions of rats chronically treated with cannabinoids (Sim et
al., 1996).
Cross-tolerance exists between different exogenous CB1R agonists with
respect to antinociception, hypolocomotion, catalepsy, and hypothermia
(Pertwee et al., 1993). Cross-tolerance between opioid and cannabinoid
compounds is also common. THC and morphine elicit cross-tolerance in
mice for nociception and cardiac rhythm (Hine 1985). However, no
modification (Martin, 1985) or even a potentiation (Melvin et al.,
1993) of cannabinoid antinociception has been reported in
morphine-dependent rats. Cross-tolerance between CB1R agonists and KOR
agonists on antinociception has also been reported (Rowen et al.,
1998). Similarly, administration of antisense oligodeoxynucleotides to
block KOR expression increases development of tolerance to THC (Rowen
et al., 1998). The development of THC tolerance is slightly modified in
KOR KO mice but is unaltered in either MOR or DOR KO mice (Ghozland et
al., 2002). These results agree with increased release of the
endogenous KOR agonist dynorphin induced by acute THC. However, there
appears to be no correlation between THC-induced dynorphin A release
and development of tolerance to THC antinociception (Mason et al.,
1999), and this THC tolerance is not modified in prodynorphin gene KO
mice (Zimmer et al., 2001). Interestingly, KO mice lacking the
pre-proenkephalin gene show a decrease in the development of tolerance
to THC antinociception and a slight attenuation of tolerance to THC
hypolocomotion (Fig. 2), suggesting the involvement of endogenous
opioid peptides derived from this precursor (Valverde et al.,
2000).
Cannabinoid dependence and withdrawal
Several studies have reported the absence of somatic signs of
spontaneous withdrawal after chronic THC treatment in rodents, pigeons,
dogs, and monkeys, even at extremely high doses (Diana et al., 1998;
Aceto et al., 2001). However, a recent study has reported somatic signs
of spontaneous abstinence after abrupt interruption of chronic
treatment with the cannabinoid agonist WIN 55,212-2 (Aceto et al.,
2001), perhaps because of different pharmacokinetic properties of THC
and WIN 55,212-2. In contrast, administration of the CB1R antagonist
SR141716A in animals chronically treated with THC can precipitate
somatic manifestations of withdrawal. In rodents, a large number of
somatic signs and an absence of vegetative manifestations characterize
cannabinoid withdrawal. The most characteristic somatic manifestations
in rodents are wet dog shakes, head shakes, facial rubbing, front paw
tremor, ataxia, hunched posture, body tremor, ptosis, piloerection,
hypolocomotion, mastication, licking, rubbing, and scratching (Aceto et
al., 1996, 2001; Hutcheson et al., 1998; Ledent et al., 1999). Dramatic
motor impairments also occur during cannabinoid withdrawal (Hutcheson et al., 1998; Tzavara et al., 2000). Doses of THC required to induce
dependence in rodents are very high, and SR141716A-precipitated withdrawal is seen after chronic administration of THC at doses of
10-100 mg/kg daily (Aceto et al., 1996, 2001; Hutcheson et al., 1998;
Ledent et al., 1999; Tzavara et al., 2000). CB1Rs mediate somatic
manifestations of cannabinoid withdrawal. Thus, SR141716A administration in CB1R KO mice receiving chronic THC treatment fails to
precipitate any manifestation of cannabinoid abstinence (Ledent et al.,
1999).
Bi-directional interactions between cannabinoid and opioid
dependence have been reported. Administration of the CB1R antagonist SR141716A precipitates withdrawal in morphine-dependent rats (Navarro et al., 1998), whereas naloxone precipitated withdrawal in
cannabinoid-dependent rats (Navarro et al., 1998). However, these
interactions are not observed in cannabinoid- and opioid-dependent mice
after naloxone and SR141716A challenge (Litchtman et al., 2001).
Furthermore, the severity of cannabinoid abstinence is not modified in
MOR, DOR, or KOR KO mice (Ghozland et al., 2002) or in prodynorphin KO
mice (Zimmer et al., 2001) chronically treated with THC. However, the
severity of cannabinoid withdrawal is decreased in THC-dependent KO
mice lacking the pre-proenkephalin gene (Fig. 2) (Valverde et al.,
2000) and in MOR KO mice chronically treated with higher doses of THC
(Litchtman et al., 2001). Therefore, endogenous opioid peptides
derived from pre-proenkephalin are important for the somatic expression
of cannabinoid abstinence by acting on MOR and other opioid receptors.
In contrast, the severity of morphine withdrawal is attenuated in CB1R
KO mice (Ledent et al., 1999). The use of combinatorial opioid receptor
KO mice lacking two or three opioid receptors will clarify these findings.
Neural correlates of cannabinoid withdrawal
Common features of withdrawal syndromes produced by several drugs
of abuse include elevations in extracellular CRF levels in the
mesolimbic system and a marked inhibition of mesolimbic DA activity
(Koob, 1996). Such changes have been reported during cannabinoid
withdrawal. Increased CRF release and enhancement of Fos
immunoreactivity occur in the central amygdala during
SR141716A-precipitated cannabinoid withdrawal (Rodriguez de Fonseca et
al., 1997). This alteration of limbic system CRF function may mediate
the stress-like symptoms and negative affect that accompany cannabinoid
withdrawal. In agreement with this hypothesis, the spontaneous firing
rate of VTA DA neurons is reduced during cannabinoid abstinence (Diana et al., 1998), which is likely related to the aversive and dysphoric consequences of cannabinoid withdrawal.
Similar to opioids, cannabinoid withdrawal is associated with
compensatory changes in the cAMP pathway. Initially, acute activation of CB1Rs inhibits adenylyl cyclase activity (Fig. 1). In contrast, SR141716A-precipitated THC withdrawal increases adenylyl cyclase activity in vivo (Hutcheson et al., 1998). Despite common
biochemical mechanisms, different brain structures are involved in the
physical manifestations of opioid and cannabinoid withdrawal. Brainstem structures, such as the locus coeruleus, are responsible for the somatic signs of opioid withdrawal (Maldonado et al., 1992), but the
cerebellum plays a crucial role in the somatic expression of THC
withdrawal (Hutcheson et al., 1998; Tzavara et al., 2000). Basal,
forskolin-, and calcium/calmodulin-stimulated adenylyl cyclase
activities were selectively increased in the cerebellum but not in
other brain structures (PFC, hippocampus, striatum, and periaqueductal
gray matter) during cannabinoid withdrawal (Hutcheson et al., 1998).
Furthermore, cannabinoid abstinence is markedly reduced when
cAMP-dependent protein kinase is activated in the cerebellum (Tzavara
et al., 2000).
Concluding remarks
Different animal models are now available to evaluate cannabinoid
dependence and abuse liability. These cannabinoid properties are
revealed in paradigms similar to those used for other drugs of abuse.
However, particular experimental conditions are required to show
cannabinoid rewarding properties in CPP and ISA paradigms. Similarly,
cannabinoid dependence typically requires high agonist doses and
antagonist challenge. These models have provided a better understanding
of the neurobiological mechanisms involved in THC actions and have
revealed commonalities between cannabinoids and other drugs of abuse
with respect to the addictive processes. Thus, the mesolimbic DA system
is clearly involved in the rewarding properties of cannabinoids as well
as in the motivational consequences of cannabinoid withdrawal. An
alteration in mesolimbic CRF function is also related to the dysphoric
effects of cannabinoid abstinence. Bi-directional interactions between
the endogenous cannabinoid and opioid systems are crucial for
cannabinoid motivational properties and the development of cannabinoid
tolerance and dependence.
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FOOTNOTES |
This work has been supported by grants from Plan Nacional Sobre
Drogas, European Communities BIOMED2 Grant PL 982267 and Fifth Framework Programme, Grant QLRT-2000-01691, Generalitat de Catalunya (Research Distinction), Human Frontier Science Program Organization (RG0077/2000-B), Ministerio de Ciencia y Tecnología (SAF
2000-0101), Fondo de Investigación Sanitaria (FIS 2001-00654),
and Laboratorios Dr. Esteve.
Correspondence should be addressed to Rafael Maldonado,
Laboratori de Neurofarmacologia, Facultat de Cienciès de la Salut i de la Vida, Universitat Pompeu Fabra, C/Dr. Aiguader 08003 Barcelona, Spain, E-mail: rafael.maldonado{at}cexs.upf.es, or
Fernando Rodríguez de Fonseca, Unidad de
Investigación, Fundación Hospital Carlos Haya, Avda Carlos
Haya s/n 7 Planta, Pabellón A, 29010 Malaga, Spain,
E-mail: frfonseca{at}hch.sas.junta-andalucia.es.
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