Cannabinoid Addiction: Behavioral Models and Neural Correlates
Rafael Maldonado and Fernando Rodriguez de Fonseca
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).
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 (Table1).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).
Table 1.
Effects of psychoactive cannabinoids on behavioral and neurochemical paradigms of drug addiction
| Effect | Reference |
|---|---|
| Behavioral studies | |
| Discriminative stimulus in pigeons, rodents, and monkeys | Jarbe et al., 1976; Wiley et al., 1995 |
| Intracranial self-stimulation | Gardner et al., 1988 |
| Induction of conditioned place preference | Valjent and Maldonado, 2000; Navarro et al., 2001 |
| Self-administration in rodents and monkeys | Martellota et al., 1998; Tanda et al., 2000;Fattore et al., 2001 |
| Behavioral sensitization and cross-sensitization with psychostimulants and opiates | Gorriti et al., 1999; Cadoni et al., 2001; Pontieri et al., 2001 |
| Induction of dependence and cannabinoid withdrawal | Pertwee et al., 1993; Aceto et al., 1996; Rodriguez de Fonseca et al., 1997; Hutcheson et al., 1998 |
| Loss of cannabinoid actions in cannabinoid CB1 receptor knock-out mice | Ledent et al., 1999; Zimmer et al., 1999 |
| Neural correlates | |
| General role for CB1 receptors in reinforcement and relapse | Martin et al., 2000; De Vries et al., 2001; Navarro et al., 2001 |
| Acute activation of mesolimbic dopaminergic neurons | French et al., 1997 |
| Decline of dopaminergic activity after withdrawal | Diana et al., 1998 |
| Cooperation with endogenous opioids | Tanda et al., 1997; Valverde et al., 2000; Navarro et al., 2001 |
| Modulation of corticotropin-releasing factor and recruitment of stress systems during withdrawal | Rodriguez de Fonseca et al., 1997 |
After the identification of new synthetic cannabinoids, a cannabinoid receptor was identified and cloned in the late 1980s (Matsuda et al., 1990) (Fig. (Fig.1).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).
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.
Behavioral models for studying cannabinoid motivational and reinforcing properties
Drug discrimination
Early studies identified the discriminative stimulus properties of Δ9-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 κ 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. (Fig.2)2) but was unaffected in mice lacking δ 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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