Rimonabant: The first therapeutically relevant cannabinoid antagonist

Life Sciences 77 (2005) 2339 – 2350 www.elsevier.com/locate/lifescie

Minireview

Rimonabant: The first therapeutically relevant cannabinoid antagonist Mauro A.M. Caraia,b,T, Giancarlo Colombob, Gian Luigi Gessaa,b a

Bernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz 182, I-09126 Cagliari (CA), Italy b C.N.R. Institute of Neuroscience, Viale Diaz 182, I-09126 Cagliari (CA), Italy Received 4 January 2005; accepted 1 April 2005

Abstract The present paper synthetically reviews the multiple experimental lines of evidence indicating the ability of the prototypic cannabinoid CB1 receptor antagonist, rimonabant (also known as SR 141716), to suppress the reinforcing/rewarding properties of different drugs of abuse, including cocaine, heroin, nicotine and alcohol, in laboratory rodents. This paper also reviews the data demonstrating that rimonabant reduces food intake and body weight in laboratory animals and humans. Taken together, the data reviewed here suggest that rimonabant may constitute a new and potentially effective medication for the treatment of drug addiction and obesity-related disorders. D 2005 Elsevier Inc. All rights reserved. Keywords: Rimonabant (SR 141716); Cannabinoid CB1 receptor; Drug addiction; Food intake; Body weight

Contents Introduction . . Rimonabant and Rimonabant and References . . .

. . . drugs food . . .

. . . . . . . of addiction . . . . . . . . . . . . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

T Corresponding author. Tel.: +39 070 302227; fax: +39 070 302076. E-mail address: [email protected] (M.A.M. Carai). 0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.04.017

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

2340 2340 2344 2347

2340

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

Introduction Over the last fifteen years, research in the cannabinoid field has been dramatically boosted, achieving a number of important findings including–among others–the discovery and subsequent cloning of specific receptors for cannabinoids, the identification of endogenous ligands and the synthesis of potent agonists and antagonists (see Drysdale and Platt, 2003; Iversen, 2003; Di Marzo et al., 2004). With regard to the latter, experimental and preliminary clinical data suggest that antagonists at the cannabinoid CB1 subtype receptors may constitute novel and effective pharmacotherapies for different pathologies (see Lange and Kruse, 2004). Accordingly, the present paper briefly reviews the data featuring rimonabant (also known as SR 141716), the prototypic cannabinoid CB1 receptor antagonist, as a novel and effective pharmacotherapy for drug addiction and obesity-related disorders. Rimonabant (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide) is a potent CB1-selective ligand (Rinaldi-Carmona et al., 1994). The ability of rimonabant to prevent the occurrence of different in vivo and in vitro CB1 receptor-mediated events has led it to be considered as a potent and effective cannabinoid CB1 receptor antagonist (Rinaldi-Carmona et al., 1994). However, results of in vitro studies, indicating that rimonabant has direct effects on CB1 receptormediated intracellular transduction signaling opposite to those produced by receptor agonists, suggest that rimonabant may also behave as an inverse agonist at the cannabinoid CB1 receptor (Bouaboula et al., 1997).

Rimonabant and drugs of addiction Accumulating lines of experimental evidence suggest the ability of rimonabant to reduce the rewarding and/or reinforcing properties of different natural stimuli and drugs of abuse, including heroin, morphine, cocaine, nicotine and alcohol. Research in this field has benefited from the use of validated experimental models of human drug seeking and taking behaviors, including a) intravenous or oral drug self-administration of the addicting drug (which models drug taking of human addicts), b) reinstatement– triggered by various factors–of drug seeking behavior (model of the relapse into drug taking and craving for the drug), and c) conditioned place preference (method for measuring the rewarding properties of psychoactive drugs). The acute administration of rimonabant has repeatedly been found to suppress the intravenous selfadministration of the opioids morphine and heroin, in laboratory rodents. In this experimental paradigm, the animal is trained to lever-press or nose-poke for the intravenous infusion of a given amount of the drug in daily sessions of temporarily limited access (see Katz, 1989; Caine et al., 1993). Relatively low doses of rimonabant (0.25–3 mg/kg, administered either intraperitoneally or subcutaneously) dosedependently reduced the number of lever-presses or nose-pokes in rats self-administering heroin (Braida et al., 2001; Navarro et al., 2001; De Vries et al., 2003) or mice self-administering morphine (Navarro et al., 2001). When a temporal analysis was performed, rimonabant administration was associated with an initial transient increase in heroin self-administration, suggestive of the induction of a decreased perception of the reinforcing properties of heroin (Navarro et al., 2001). Treatment with rimonabant was not associated with any decrease in the rate of pressing on an inactive lever, when available, suggesting that the action of rimonabant was specific on opioid self-administration (Braida et al., 2001; De Vries et al., 2003). Importantly, particularly in terms of their predictive validity for the human pathology, rats

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

2341

40

active lever

35

inactive lever

30 25 20 15 10 5

in er o

nt

H

ab a R

im

on

ab

an

t+

R im on

H er oi n

Ve h

ic

le

e Sa lin

n ct io

Tr ai

Ex tin

ng

0

ni

Mean number of lever presses

made physically dependent upon morphine were more sensitive to the reducing effect of rimonabant on heroin self-administration (Navarro et al., 2004). The anti-relapse properties of rimonabant have been experimentally investigated using the breinstatementQ model. In this paradigm, rats are first trained to self-administer a given drug under a standard self-administration procedure. Subsequently, rats are subjected to extinction sessions during which the drug is no longer available. Once lever-pressing (or nose-poking, depending on the behavioral operandum chosen) has been virtually extinguished, administration of a low dose of a specific drug (including that self-administered by the rat before the extinction phase), presentation of environmental (olfactory or visual) stimuli previously associated to drug availability or exposure to stress have been found to reinstate the lever-pressing (or nose-poking) behavior. The magnitude of this behavior has been proposed to model the relapse to drug taking and craving for the drug in human addicts (see Katz and Higgins, 2003; Shaham et al., 2003). The predictive validity of the breinstatementQ model for the human pathology has been strengthened by the observation that the conditions which reinstate drug seeking behavior in laboratory animals (re-exposure to specific drug, drug-associated stimuli and stress) are similar to those reported to induce drug craving and relapse in humans. The acute administration of rimonabant (0.3–3 mg/kg, i.p. or s.c.) has been found to significantly attenuate the reinstatement of heroin seeking behavior induced by a priming injection of heroin or visual cues associated to heroin in rats (De Vries et al., 2003; Fattore et al., 2003) (Fig. 1). Pretreatment with rimonabant (0.3 mg/kg, i.p.) also attenuated the reinstatement of heroin seeking behavior triggered by the injection of the cannabinoid CB1 receptor agonists WIN 55,212-2 and CP 55,940 (Fattore et al., in press). Conversely, rimonabant did not reinstate any heroin seeking behavior when given alone, indicating that it is devoid of any intrinsic effect at these doses and in this model (Fattore et al., 2003, in press). Additional studies investigated the effect of rimonabant on the rewarding properties of morphine, measured by means of the conditioned place preference paradigm. In this paradigm, laboratory rodents are trained to associate the interoceptive cues produced by a drug with the external (neutral) stimuli of a

Fig. 1. Suppressing effect of rimonabant on reinstatement of heroin seeking behavior induced by a priming injection of heroin in rats. Bars indicate the mean F SEM of number of responses on the active (black) and inactive (white) levers during the last five training sessions, the last five extinction sessions, and sessions with acute primings. Adapted from Fattore et al., 2003.

2342

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

specific environment as well as the absence of those effects with the stimuli of a second, distinguishable environment. After a proper number of conditioning sessions, animals are given a choice between the two environments: if the animal increases the time spent in the drug-paired context, it is inferred that the drug possesses rewarding properties (see Carr et al., 1989; Tzcshentke, 1998). Rimonabant (0.1–0.3 mg/ kg, i.p.), given concomitantly to morphine (4 mg/kg, s.c.) during the conditioning phase, dosedependently prevented the development of conditioned place preference to morphine in rats (Chaperon et al., 1998; Singh et al., 2004). A similar result was collected in a mouse study, where 1–10 mg/kg rimonabant (i.p.)–administered together with 3 mg/kg morphine (s.c.)–dose-dependently prevented the development of conditioned place preference to morphine (Mas-Nieto et al., 2001). Rimonabant, given acutely at the dose of 3 mg/kg (i.p.), also counteracted an already established morphine (5 mg/kg, s.c.)induced conditioned place preference in mice made dependent upon morphine by the subcutaneus implantation of a morphine pellet (Navarro et al., 2001). Some studies also investigated the effect of rimonabant on cocaine seeking and taking behaviors in rats. Acutely administered rimonabant (1–9 mg/kg, i.p. or s.c.) failed to alter the intravenous selfadministration of cocaine in rats (Fattore et al., 1999; De Vries et al., 2001). Accordingly, a 5-day treatment with 0.3 mg/kg rimonabant (i.m.) did not affect the intravenous self-administration of cocaine in monkeys (Tanda et al., 2000). In contrast, rimonabant (a) prevented at the doses of 0.3–3 mg/kg (s.c.) the reinstatement of cocaine seeking behavior when it was triggered by a priming injection of cocaine itself or cocaine-associated visual and auditive stimuli, but not stress in rats (De Vries et al., 2001), and (b) reduced at the doses of 1 and 3 mg/kg (i.p.) the breakpoint for cocaine in mice self-administering cocaine intravenously (Soria et al., in press). The apparent discrepancy in the effect of rimonabant on cocaine self-administration (drug taking) and reinstatement of cocaine seeking behavior suggests that the cannabinoid CB1 receptor may be selectively involved in the neural pathway underlying craving for cocaine during abstinence rather than that mediating the reinforcing effects of the drug. Accordingly, it has been reported that acute treatment with rimonabant (0.3–3 mg/kg, i.p.) did not alter the locomotor stimulating effect of 4 mg/kg cocaine (s.c.) in rats [a possible animal model of the euphorigenic properties of the drug (see Wise and Bozarth, 1987)] (Chaperon et al., 1998). Rimonabant has been also tested on cocaine-induced conditioned place preference. When administered concomitantly to cocaine (2 mg/kg, s.c.) during the sessions of the conditioning phase, rimonabant (0.1–3 mg/kg, i.p.) suppressed the development of conditioned place preference to cocaine in rats (Chaperon et al., 1998). In contrast, its acute administration (0.3–10 mg/kg, i.p.) before the test (or post-conditioning) session failed to affect the expression of cocaine (2 mg/kg, s.c.)-induced conditioned place preference (Chaperon et al., 1998). These results suggest that only the acquisition stage of cocaine reward may require the activation of the cannabinoid CB1 receptor. Cohen et al. investigated the effect of rimonabant on nicotine seeking and taking behavior in rats. Using a standard procedure of intravenous self-administration, injection of rimonabant (0.3 and 1 mg/kg, i.p.) on two consecutive days resulted in a marked decrease in the number of nicotine infusions, with inconsistent changes in the number of responses on the inactive lever (Cohen et al., 2002). More recently, the same research group demonstrated that acute injection of rimonabant (1 mg/kg, i.p.) blocked the reinstatement of nicotine seeking behavior elicited by re-exposure to environmental stimuli previously associated to nicotine in rats (Cohen et al., 2005). The data reported by Cohen et al. (2002, 2005) have recently been generalized–to some extent–to humans. Indeed, a recently completed double-blind, placebo-controlled survey, enrolling 787 smokers

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

2343

(mean smoked cigarettes/day: 23), found that the daily administration of 20 mg rimonabant (per os) for 10 consecutive weeks resulted in a significantly higher, in comparison to placebo, percentage of patients having stopped smoking at the end of the study (36.2% vs 20.6%) (www.sanofi-synthelabo.us). Remarkably, rimonabant was well tolerated and produced a few, mild and transient side effects. These results, despite their preliminary nature and the need to be confirmed in subsequent studies, suggest that rimonabant may be effective for smoking cessation and maintenance of abstinence. Rimonabant has been repeatedly reported to suppress several alcohol-related behaviors in different animal models of excessive alcohol consumption. Specifically, rimonabant–given twice daily at the doses of 0.3–3 mg/kg (i.p.)–has been found to suppress the acquisition of alcohol drinking behavior in alcohol-naive Sardinian alcohol-preferring (sP) and Indiana alcohol-preferring (P) rats (two of the few rat lines selectively bred worldwide for alcohol preference and consumption) offered alcohol under the standard, homecage 2-bottle balcohol vs waterQ choice regimen (Serra et al., 2001; Bell et al., 2004). When tested in alcohol-experienced individuals (i.e., rats or mice which had already achieved a voluntary consumption of pharmacologically relevant amounts of alcohol before the start of the experiment with rimonabant; these animals constitute a validated model of the bmaintenanceQ or bactive drinkingQ phase of human alcoholism), acutely injected rimonabant (0.3–10 mg/kg, i.p.) reduced voluntary alcohol intake in C57BL/6J mice (Arnone et al., 1997), sP rats (Colombo et al., 1998b), P rats (Bell et al., 2004) and Wistar rats (Lallemand et al., 2001) exposed to the 2-bottle choice regimen. A further series of experiments demonstrated that the acute administration of rimonabant (0.3–3 mg/kg, i.p.) suppressed the temporary increase in voluntary alcohol intake occurring in sP and P rats after a period of deprivation from alcohol (a phenomenon named balcohol deprivation effectQ, which has been proposed to model the relapse episodes occurring in human alcoholics) (Serra et al., 2002; Bell et al., 2004). Finally, when operant procedures were employed, rimonabant (0.3–3 mg/kg, i.p.) decreased the oral self-administration of alcohol in unselected rats (Freedland et al., 2001), and reduced the appetitive properties of alcohol, as revealed by a reduction in a) the probability of completion of response requirement for alcohol in unselected rats (Gallate and McGregor, 1999; Freedland et al., 2001) and b) extinction responding for alcohol in sP rats (Colombo et al., 2004). Taken together, the above results indicate that rimonabant administration resulted in a marked reduction in alcohol intake, alcohol preference and alcohol’s motivational properties. Interestingly, the ability of rimonabant to reduce alcohol intake in alcohol-consuming rats has been recently found to a) extend to the newly synthesized cannabinoid CB1 receptor antagonist, SR 147778 (Gessa et al., 2005) and b) be significantly potentiated by the concomitant administration of the opioid receptor antagonist, naltrexone (Stromberg, 2004; Colombo et al., 2005). Rimonabant was effective in reducing the reinforcing properties of cannabinoids. Indeed, acutely administered rimonabant (0.5–3 mg/kg, i.p.) decreased the reinforcing properties of synthetic cannabinoid receptor agonists, CP 55,940 and WIN 55,212-2, in rats (Braida et al., 2001; Fattore et al., 2001). Consistently, 5-day treatment with 0.3 mg/kg rimonabant (i.m.) suppressed the intravenous self-administration of D9-tetrahydrocannabinol (D9-THC), the addictive ingredient of marijuana, in monkeys (Tanda et al., 2000). Rimonabant (0.3 mg/kg, i.p.) also blocked the reinstatement of WIN 55,212-2 seeking behavior triggered by the administration of WIN 55,212-2 itself or heroin (Spano et al., 2004). In terms of the cellular mechanism of action by which rimonabant exerts its anti-addictive effects, it should first be considered that the above-mentioned addicting drugs share the common property of activating the mesolimbic dopamine brewardQ system, and specifically, elevating the extracellular levels

2344

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

of dopamine in the nucleus accumbens (NAc) [the brain area where dopaminergic neurons originating in the ventral tegmental area (VTA) project their terminals] (see Spanagel and Weiss, 1999; Carnı´ and Farre´, 2003). Cannabinoid CB1 receptors located on afferent pathways to the VTA (specifically, on GABAergic and glutamatergic neurons) (see Schlicker and Kathmann, 2001; Wilson and Nicoll, 2002) have been proposed to contribute to controlling the activity of mesolimbic dopamine neurons and, ultimately, dopamine-mediated reward-related behaviors (Cohen et al., 2002). Accordingly, pharmacological activation of cannabinoid CB1 receptor at the level of the VTA has been found to stimulate dopamine release in the rat NAc (Tanda et al., 1997; Cheer et al., 2004). Vice versa, it has been reported that doses of rimonabant comparable to those that reduce the reinforcing and rewarding properties of addicting drugs suppressed the release of dopamine induced by D9-THC (Tanda et al., 1997), WIN 55,212-2 (Cheer et al., 2004), alcohol (Cohen et al., 2002) and nicotine (Cohen et al., 2002) in the NAc of rats. It has been hypothesized that rimonabant may remove an inhibitory cannabinoidergic tone on the GABA interneurons of the VTA, resulting in an enhancement of GABA release and a subsequent inhibition of dopamine neurons (Cohen et al., 2002). This inhibition would lead to the observed suppression of dopamine release in the NAc stimulated by the drugs of abuse and, in turn, to the suppression of dopamine-mediated reinforcing and motivational properties of the drugs of abuse. This mechanism may explain the apparent discrepancy on the effect of rimonabant on cocaine taking (self-administration) and seeking (reinstatement) behaviors. Indeed, as mentioned above, rimonabant effectively attenuated reinstatement of cocaine seeking behavior while it did not alter cocaine selfadministration, suggesting that two dissociable neuronal mechanisms underlie these behaviors. Cocaine is known to exert its reinforcing and rewarding effects elevating dopamine levels via inhibition of dopamine reuptake in the presynaptic terminals of the mesolimbic dopamine neurons (see Spanagel and Weiss, 1999; Carnı´ and Farre´, 2003); this effect is apparently not under any control of cannabinoid CB1 receptor (De Vries et al., 2001). In contrast, an increased dopamine transmission in the VTA likely contributes to reinstatement of cocaine seeking behavior; as an example, morphine infusion into the VTA (a condition which results in a stimulation of the function of the mesolimbic dopamine neuron) reinstated cocaine seeking behavior (see Stewart, 2000). The above-mentioned rimonabant-induced disinhibition of GABA interneurons in the VTA may be the mechanism of action by which rimonabant suppresses cocaine seeking behavior. Taken together, these results consistently suggest that functioning of the CB1 receptor is essential for the expression of the reinforcing and rewarding properties of morphine, heroin, nicotine, cannabinoids, alcohol and, to some extent, cocaine. These lines of evidence also suggest that rimonabant may be considered a novel and promising therapeutic approach for the treatment of drug addiction.

Rimonabant and food Different lines of experimental evidence have repeatedly and unanimously indicated that the acute and chronic administration of rimonabant specifically reduced food intake and body weight in laboratory animals tested under multiple experimental procedures. Specifically, administration of doses of rimonabant in the 1–10 mg/kg-range (i.p. or i.g.) for 14–35 consecutive days resulted in a marked reduction in food intake in lean and genetically or diet-induced obese rats and mice given unlimited access to regular rodent chow and water (Colombo et al., 1998a; Bensaid et al., 2003; Ravinet Trillou et al., 2003; Vickers et al., 2003). The reducing effect of rimonabant on food intake was associated to a

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

2345

rapid reduction in body weight. As an example, rimonabant administration (2.5 and 10 mg/kg, once a day for 14 consecutive days) produced a dose-dependent reduction in food intake (Fig. 2, top panel) and body weight (Fig. 2, bottom panel) in obese Zucker rats offered regular food and water for 24 h/day. Upon treatment discontinuation, an initial overeating was recorded in the rats previously treated with rimonabant, leading to a body weight gaining (Colombo et al., 1998a; Vickers et al., 2003; Fig. 2). However, when re-administered after an off-treatment period at the end of which daily food intake was similar among rat groups, the magnitude of the reducing effect of rimonabant on food intake and body weight in Zucker rats was greater than those recorded in the first treatment (Fig. 2). When rimonabant was administered repeatedly, tolerance to its anorectic effect was reported to develop rather rapidly in both rats and mice (Colombo et al., 1998a; Bensaid et al., 2003; Ravinet Trillou et al., 2003; Vickers et al., 2003) (Fig. 2, top panel). For instance, the reduction in food intake produced by the daily administration of 10 mg/kg rimonabant (i.p.) in rats maintained statistical significance only for the first 4 days of treatment (Colombo et al., 1998a). Development of tolerance was more rapid in

DAILY FOOD INTAKE (g/kg)

TREATMENT 1

100

TREATMENT 2 OFF-TREATMENT 1

OFF-TREATMENT 2

80 60 40 20

RIMONABANT 0 mg/kg RIMONABANT 2.5 mg/kg

0

RIMONABANT 10 mg/kg

DAYS TREATMENT 1

BODY WEIGHT (% OF BASELINE)

180

TREATMENT 2 OFF-TREATMENT 1

OFF-TREATMENT 2

160 140 120 100

RIMONABANT 0 mg/kg RIMONABANT 2.5 mg/kg RIMONABANT 10 mg/kg

DAYS

Fig. 2. Reducing effect of rimonabant on daily food intake (top panel) and body weight (bottom panel) in obese Zucker fa/fa rats. Rats were individually housed and offered standard rat chow (Mucedola, Settimo Milanese, MI, Italy) and water ad libitum throughout the study. Rimonabant was administered in two different periods: 14-day Treatment 1 and 7-day Treatment 2, separated by a 28-day Off-treatment period. Rimonabant was injected i.p. once daily, at the doses of 0 (n = 6), 2.5 (n = 7) and 10 (n = 6) mg/kg, 30 min before the start of the dark phase of the light–dark cycle. Rimonabant (Sanofi-Synthelabo, Montpellier, France) was suspended in 2 ml/kg saline with 0.1% Tween 80. Food intake and body weight were recorded once daily immediately before lights-off. Food intake was expressed as g/kg; body weight was expressed as percentage of the body weight monitored on the last day prior to the start of Treatment 1. Data on food intake and body weight in each experimental phase were analyzed by separate 2-way (treatment; time) ANOVAs with repeated measurements on the factor btimeQ. Results of ANOVA on food intake data (factor btreatmentQ): Treatment 1: F(2273) = 34.33, P b 0.0001; Off-treatment 1: F(2567) = 21.17, P b 0.0001; Treatment 2: F(2126) = 54.48, P b 0.0001; Off-treatment 2: F(2420) = 4.25, P b 0.05. Results of ANOVA on body weight data (factor btreatmentQ): Treatment 1: F(2273) = 72.30, P b 0.0001; Off-treatment 1: F(2567) = 3.25, P N 0.05; Treatment 2: F(2126) = 6.55, P b 0.01; Off-treatment 2: F(2420) = 3.17, P N 0.05.

2346

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

lean than in obese rats (Vickers et al., 2003). Interestingly, development of tolerance to the reducing effect of rimonabant on body weight appeared to be much slower than development of tolerance to its anorectic effect. Indeed, the reduction in body weight was significantly and steadily maintained even when food intake had returned to control values (Colombo et al., 1998a; Bensaid et al., 2003; Vickers et al., 2003). Rimonabant was effective in reducing food intake even in rats given a 1 h/day access to food (Rowland et al., 2001; Gomez et al., 2002), suggesting the drug’s capability to overcome the rat hunger. Consistently, acutely administered rimonabant (1–3 mg/kg, i.p.) has been found to suppress leverpressing for food in food-restricted rats (Freedland et al., 2000; McLaughlin et al., 2003; De Vry et al., 2004), without altering locomotor activity. Further, the combination of rimonabant plus the opioid receptor antagonist, naloxone, resulted in a synergistic potentiation of the anorectic effect of each drug in rats (Kirkham and Williams, 2001; Rowland et al., 2001). The results of further experimental studies suggested a selectivity of the reducing effect of rimonabant on intake of palatable, sweet foods when compared to that of regular food. Specifically, rimonabant (0.1– 3 mg/kg, i.g.) markedly reduced the intake of sucrose pellets and a sucrose solution while being much less effective in controlling regular chow in rats (Arnone et al., 1997). Consistently, administration of rimonabant (1–3 mg/kg, i.g.) to marmosets reduced the consumption of a palatable mixture made of sucrose, milk and cereals, but not of a standard primate food (Simiand et al., 1998). Rimonabant (1–3 mg/kg, i.p.) decreased the number of licks and duration of the drinking bout in rats exposed to a 10% sucrose solution (Higgs et al., 2003). However, other studies found that rimonabant suppressed to the same extent the intake of three diets differing in composition (high carbohydrate content; high fat content; normal rat chow) and palatability in food-non-deprived rats (McLaughlin et al., 2003; Verty et al., 2004). Taken together, the above results are in line with the number of experimental and clinical data (e.g.: Tart, 1970; Foltin et al., 1986; see Harrold and Williams, 2003, for review) clearly indicating the involvement of the cannabinoid CB1 receptor in the neuronal pathway controlling appetite, food intake and body weight. If the initial reduction of body weight was the likely result of the severe anorexia induced by rimonabant over the first days of treatment, the longer lasting effect of the drug on body weight might be due to different mechanisms. This separation in the length of the anorectic and body weight-reducing effect of rimonabant has been suggested to be secondary to a rimonabant-induced increase in energy expenditure, which would have resulted in a sustained reduction in body weight even when the anorectic effect had vanished (Colombo et al., 1998a; Bensaid et al., 2003; Vickers et al., 2003). Accordingly, a recent study found that both acute and chronic treatment with rimonabant (10 mg/kg, i.p.) activated thermogenesis in obese mice, as revealed by an increase in oxygen consumption (Liu et al., 2005); this effect was accompanied by a rimonabant-induced increase in glucose uptake in isolated skeletal muscle, suggesting an effect of rimonabant on glucose homeostasis. In addition, it has recently been reported that the repeated administration of rimonabant (10 mg/kg, i.p.) to obese Zucker rats stimulated the mRNA expression of a plasma protein, named Acrp30, secreted by adipose tissue and known to stimulate free fatty acid oxidation, decrease hyperglycemia and hyperinsulinemia, and reduce body weight (Bensaid et al., 2003). These results suggest the involvement of adipose tissue CB1 receptors and a possible peripheral mechanism for the reducing effect of rimonabant on body weight. Recent randomized double-blind placebo-controlled surveys investigated the effect of rimonabant on different parameters in overweight/obese patients. Rimonabant was administered once daily at the doses

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

2347

of 5 and 20 mg for 1–2 years. The results, anticipated in the website of the drug company developing rimonabant (www.sanofi-synthelabo.us), indicate that the loss of body weight was significantly greater in patients treated with 20 mg rimonabant than in those receiving placebo. Further, treatment with 20 mg rimonabant was associated with a significantly greater increase in HDL (high density lipoprotein)cholesterol levels as well as a significant decrease in triglyceridemia than in placebo-treated patients. Confirmation of these clinical results would open a new strategy for treating some of those overweight-related disorders which afflict an increasing number of patients in the developed countries.

References Arnone, M., Maruani, J., Chaperon, F., Thie´bot, M.E., Poncelet, M., Soubrie´, P., Le Fur, G., 1997. Selective inhibition of sucrose and alcohol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 132, 104 – 106. Bell, R.L., Rodd, Z.A., Sable, H.J.K., McQueen, V.K., Davids, M.R., Murphy, J.M., Lumeng, L., McBride, W.J., 2004. Cannabinoid CB1 antagonist reduces alcohol intake during acquisition, maintenance, and relapse in inbred alcohol preferring (IP) rats. Society for Neuroscience, Washington DC. Program No. 489.6. 2004 Abstract Viewer/It Planner. Bensaid, M., Gary-Bobo, M., Esclangon, A., Maffrand, J.P., Le Fur, G., Oury-Donat, F., Soubrie, P., 2003. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Molecular Pharmacology 63, 908 – 914. Bouaboula, M., Perrachon, S., Milligan, L., Canat, X., Rinaldi-Carmona, M., Portier, M., Barth, F., Calandra, B., Pecceu, F., Lupker, J., Maffrand, J.P., Le Fur, G., Casellas, P., 1997. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. Journal of Biological Chemistry 272, 22330 – 22339. Braida, D., Pozzi, M., Parolaio, D., Sala, M., 2001. Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat: interaction with the opioid system. European Journal of Pharmacology 413, 227 – 234. Caine, S.B., Lintz, R., Koob, G.F., 1993. Intravenous drug self-administration techniques in animals. In: Sahgal, A. (Ed.), Behavioural Neuroscience, A Practical Approach, vol. 2. IRL Press, Oxford, pp. 117 – 144. Carnı´, J., Farre´, M., 2003. Drug addiction. New England Journal of Medicine 239, 975 – 986. Carr, G.D., Fibiger, H.C., Phillips, A.G., 1989. Conditioned place preference as a measure of drug reward. In: Liebman, J.M., Cooper, S.J. (Eds.), The Neuropharmacological Basis of Reward. Oxford Science Publications, Oxford, pp. 264 – 319. Chaperon, F., Soubrie´, P., Puech, A.J., Thie´bot, M.-H., 1998. Involvement of the central cannabonoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology 135, 324 – 332. Cheer, J.F., Wassum, K.M., Heien, M.L., Phillips, P.E., Wightman, R.M., 2004. Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. Journal of Neuroscience 24, 4393 – 4400. Cohen, C., Perrault, G., Voltz, C., Steinberg, R., Soubrie´, P., 2002. SR 141716, a central cannabinoid (CB1) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behavioural Pharmacology 13, 451 – 463. Cohen, C., Perrault, G., Griebel, G., Soubrie, P., 2005. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 30, 145 – 155. Colombo, G., Agabio, R., Diaz, G., Lobina, C., Reali, R., Gessa, G.L., 1998a. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sciences 63, PL113 – PL117. Colombo, G., Agabio, R., Fa, M., Guano, L., Lobina, C., Loche, A., Reali, R., Gessa, G.L., 1998b. Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR 141716. Alcohol and Alcoholism 33, 126 – 130. Colombo, G., Vacca, G., Serra, S., Carai, M.A.M., Gessa, G.L., 2004. Suppressing effect of the cannabinoid CB1 receptor antagonist, SR 141716, on alcohol’s motivational properties in alcohol-preferring rats. European Journal of Pharmacology 498, 119 – 123. Colombo, G., Serra, S., Vacca, G., Carai, M.A.M., Gessa, G.L., 2005. Effect of the combination of naltrexone and baclofen on acquisition of alcohol drinking behavior in alcohol-preferring rats. Drug and Alcohol Dependence 77, 87 – 91.

2348

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

De Vries, T.J., Shaham, Y., Homberg, J.R., Crombag, H., Schuurman, K., Dieben, J., Vanderschuren, L.J., Schoffelmeer, A.N., 2001. A cannabinoid mechanism in relapse to cocaine seeking. Nature Medicine 7, 1151 – 1154. De Vries, T.J., Homberg, J.R., Binnekade, R., Raaso, H., Schoffelmeer, A.N., 2003. Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology 168, 164 – 169. De Vry, J., Schreiber, R., Eckel, G., Jentzsch, K.R., 2004. Behavioral mechanisms underlying inhibition of food-maintained responding by the cannabinoid receptor antagonist/inverse agonist SR141716A. European Journal of Pharmacology 483, 55 – 63. Di Marzo, V., Bifulco, M., De Petrocellis, L., 2004. The endocannabinoid system and its therapeutic exploitation. Nature Reviews Drug Discovery 3, 771 – 784. Drysdale, A.J., Platt, B., 2003. Cannabinoids: mechanisms and therapeutic applications in the CNS. Current Medicinal Chemistry 10, 2719 – 2732. Fattore, L., Martellotta, M.C., Cossu, G., Mascia, M.S., Fratta, W., 1999. CB1 cannabinoid receptor agonist WIN 55,212-2 decreases intravenous cocaine self-administration in rats. Behavioural Brain Research 104, 141 – 146. Fattore, L., Cossu, G., Martellotta, M.C., Fratta, W., 2001. Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats. Psychopharmacology 156, 410 – 416. Fattore, L., Spano, M.S., Cossu, G., Deiana, S., Fratta, W., 2003. Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats. European Journal of Neuroscience 17, 1723 – 1726. Fattore, L., Spano, M.S., Cossu, G., Deiana, S., Fadda, P., Fratta, W., in press. Cannabinoid CB1 antagonist SR 141716A attenuates reinstatement of heroin self-administration in heroin abstinent rats. Neuropharmacology. Foltin, R.W., Brady, J.V., Fischman, M.W., 1986. Behavioral analysis of marijuana effects of food intake in humans. Pharmacology, Biochemistry and Behavior 25, 577 – 582. Freedland, C.S., Poston, J.S., Porrino, L.J., 2000. Effects of SR141716A, a central cannabinoid receptor antagonist, on foodmaintained responding. Pharmacology, Biochemistry and Behavior 67, 265 – 270. Freedland, C.S., Sharpe, A.L., Samson, H.H., Porrino, L.J., 2001. Effects of SR 1417161A on alcohol and sucrose selfadministration. Alcoholism, Clinical and Experimental Research 25, 277 – 282. Gallate, J.E., McGregor, I.S., 1999. The motivation for beer in rats: effects of ritanserin, naloxone and SR 141716. Psychopharmacology 142, 302 – 308. Gessa, G.L., Serra, S., Vacca, G., Carai, M.A.M., Colombo, G., 2005. Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational properties of alcohol in alcohol-preferring sP rats. Alcohol and Alcoholism 40, 46 – 53. Gomez, R., Navarro, M., Ferrer, B., Trigo, J.M., Bilbao, A., Del Arco, I., Cippitelli, A., Nava, F., Pomelli, D., Rodriguez de Fonseca, F., 2002. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. Journal of Neuroscience 22, 9612 – 9617. Harrold, J.A., Williams, G., 2003. The cannabinoid system: a role in both the homeostatic and hedonic control of eating? British Journal of Nutrition 90, 729 – 734. Higgs, S., Williams, C.M., Kirkham, T.C., 2003. Cannabinoid influences on palatability: microstructural analysis of sucrose drinking after delta(9)-tetrahydrocannabinol, anandamide, 2-arachidonoyl glycerol and SR141716. Psychopharmacology 165, 370 – 377. Iversen, L., 2003. Cannabis and the brain. Brain 126, 1252 – 1270. Katz, J.L., 1989. Drugs as reinforcers: pharmacological and behavioural factors. In: Liebman, J.M., Cooper, S.J. (Eds.), The Neuropharmacological Basis of Reward. Oxford Science Publications, Oxford, pp. 164 – 213. Katz, J.L., Higgins, S.T., 2003. The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology 168, 21 – 30. Kirkham, T.C., Williams, C.M., 2001. Synergistic effects of opioid and cannabinoid antagonists on food intake. Psychopharmacology 153, 267 – 270. Lallemand, F., Soubrie´, P.H., De Witte, P.H., 2001. Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic ethanol administration. Alcoholism, Clinical and Experimental Research 25, 1317 – 1323. Lange, J.H., Kruse, C.G., 2004. Recent advances in CB1 cannabinoid receptor antagonists. Current Opinion in Drug Discovery and Development 7, 498 – 506. Liu, Y.L., Connoley, I.P., Wilson, C.A., Stock, M.J., 2005. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. International Journal of Obesity 29, 183 – 187.

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

2349

Mas-Nieto, M., Pommier, B., Tzavara, E.T., Caneparo, A., Da Nascimento, S., Le Fur, G., Roques, B.P., Noble, F., 2001. Reduction of opioid dependence by the CB(1) antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction. British Journal of Pharmacology 132, 1809 – 1816. McLaughlin, P.J., Winston, K., Swezey, L., Wisniecki, A., Aberman, J., Tardif, D.J., Betz, A.J., Ishiwari, K., Makriyannis, A., Salamone, J.D., 2003. The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and foodreinforced behavior in a variety of tasks in rats. Behavioural Pharmacology 14, 583 – 588. Navarro, M., Carrera, M.R., Fratta, W., Valverde, O., Cossu, G., Fattore, L., Chowen, J.A., Gomez, R., del Arco, I., Villanua, M.A., Maldonado, R., Koob, G.F., Rodriguez de Fonseca, F., 2001. Functional interaction between opioid and cannabinoid receptors in drug self-administration. Journal of Neuroscience 21, 5344 – 5350. Navarro, M., Carrera, M.R., Del Arco, I., Trigo, J.M., Koob, G.F., Rodriguez de Fonseca, F., 2004. Cannabinoid receptor antagonist reduces heroin self-administration only in dependent rats. European Journal of Pharmacology 501, 235 – 237. Ravinet Trillou, C., Arnone, M., Delgorge, C., Gonalons, N., Keane, P., Maffrand, J.P., Soubrie, P., 2003. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 284, R345 – R353. Rinaldi-Carmona, M., Barth, F., He´auime, M., Shire, D., Calandra, B., Congy, C., Martinez, S., Maruani, J., Ne´liat, G., Caput, D., Ferrara, P., Soubrie´, P., Brelie´re, J.C., Le Fur, G., 1994. SR 141716A, a potent and selective antagonist of the cannabinoid receptor. FEBS Letters 350, 240 – 244. Rowland, N.E., Mukherjee, M., Robertson, K., 2001. Effects of the cannabinoid receptor antagonist SR 141716, alone and in combination with dexfenfluramine or naloxone, on food intake in rats. Psychopharmacology 159, 111 – 116. Schlicker, E., Kathmann, M., 2001. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends in Pharmacological Sciences 22, 565 – 572. Serra, S., Carai, M.A.M., Brunetti, G., Gomez, R., Melis, S., Vacca, G., Colombo, G., Gessa, G.L., 2001. The cannabinoid receptor antagonist SR 141716 prevents acquisition of drinking behaviour in alcohol-preferring rats. European Journal of Pharmacology 430, 369 – 371. Serra, S., Brunetti, G., Pani, M., Vacca, G., Carai, M.A.M., Gessa, G.L., Colombo, G., 2002. Blockade by the cannabinoid CB1 receptor antagonist, SR 141716, of alcohol deprivation effect in alcohol-preferring rats. European Journal of Pharmacology 443, 95 – 97. Shaham, Y., Shalev, U., Lu, L., De Wit, H., Stewart, J., 2003. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168, 3 – 20. Simiand, J., Keane, M., Keane, P.E., Soubrie, P., 1998. SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset. Behavioural Pharmacology 9, 179 – 181. Singh, M.E., Verty, A.N.A., McGregor, I.S., Mallet, P.E., 2004. A cannabinoid receptor antagonist attenuates conditioned place preference but not behavioural sensitization to morphine. Brain Research 1026, 244 – 252. Soria, G., Mendizabal, V., Tourino, C., Robledo, P., Ledent, C., Parmentier, M., Maldonado, R., Valverde, O., in press. Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology. Spanagel, R., Weiss, F., 1999. The dopamine hypothesis of reward: past and current status. Trends in Neurosciences 22, 521 – 527. Spano, M.S., Fattore, L., Cossu, G., Deiana, S., Fadda, P., Fratta, W., 2004. CB1 receptor agonist and heroin, but not cocaine, reinstate cannabinoid-seeking behaviour in the rat. British Journal of Pharmacology 143, 343 – 350. Stewart, J., 2000. Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. Journal of Psychiatry and Neuroscience 25, 125 – 136. Stromberg, M.F., 2004. The effect of baclofen alone and in combination with naltrexone on ethanol consumption in the rat. Pharmacology, Biochemestry and Behavior 78, 743 – 750. Tanda, G., Pontieri, F.E., Di Chiara, G., 1997. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common A1 opioid receptor mechanism. Science 276, 2048 – 2050. Tanda, G., Munzar, P., Goldberg, S.R., 2000. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nature NeuroScience 3, 1073 – 1074. Tart, C.T., 1970. Marijuana intoxication: common experiences. Nature 226, 701 – 704. Tzcshentke, T.M., 1998. Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Progress in Neurobiology 56, 613 – 672. Verty, A.N., McGregor, I.S., Mallet, P.E., 2004. Consumption of high carbohydrate, high fat, and normal chow is equally suppressed by a cannabinoid receptor antagonist in non-deprived rats. Neurosci Letters 354, 217 – 220.

2350

M.A.M. Carai et al. / Life Sciences 77 (2005) 2339–2350

Vickers, S.P., Webster, L.J., Wyatt, A., Dourish, C.T., Kennett, G.A., 2003. Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology 167, 103 – 111. Wilson, R.I., Nicoll, R.A., 2002. Endocannabinoid signaling in the brain. Science 296, 678 – 682. Wise, R.A., Bozarth, M.A., 1987. A psychomotor stimulant theory of addiction. Psychological Review 94, 469 – 492.