Rimonabant blocks the expression but not the development of locomotor sensitization to nicotine in rats

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1 Psychopharmacology (2008) 198: DOI /s x ORIGINAL INVESTIGATION Rimonabant blocks the expression but not the development of locomotor sensitization to nicotine in rats John E. Kelsey & Siena Calabro Received: 10 August 2006 / Accepted: 6 August 2007 / Published online: 6 September 2007 # Springer-Verlag 2007 Abstract Rationale Cannabinoid, especially CB 1, receptors have been implicated in the development and expression of a variety of behaviors produced by addictive drugs. Objectives The intent was to determine if coadministration of the selective CB 1 receptor antagonist, rimonabant (SR141716A), would block the development or expression of locomotor sensitization to repeated injections of nicotine. Materials and methods Male Long Evans rats were injected with either 2 mg/kg rimonabant or its vehicle 30 min before an injection of 0.4 mg/kg nicotine or saline and immediately placed in activity chambers for 1 h on each of six sessions on alternating days. Before the two subsequent challenge sessions, all rats were injected with the vehicle and 0.4 mg/kg nicotine combination and then with the 2 mg/kg rimonabant and 0.4 mg/kg nicotine combination, respectively. Results Repeated injections of nicotine produced a progressive increase in locomotion that was blocked by coadministration of rimonabant. However, the subsequent nicotine challenge increased locomotion in both nicotinepretreated groups equally more than in the saline-pretreated groups. Coadministration of rimonabant along with nicotine on the second challenge decreased the locomotion of the nicotine-pretreated rats to equal that of the saline-pretreated rats. Rimonabant had no effect on the saline-pretreated rats. Conclusion These data suggest that rimonabant blocks the expression but not the development of locomotor sensitization to nicotine. J. E. Kelsey (*) : S. Calabro Department of Psychology and Program in Neuroscience, Bates College, Lewiston, ME 04240, USA jkelsey@bates.edu Keywords Rimonabant. Locomotor sensitization. Cannabinoids. CB 1 receptors. Nicotine. Rats Introduction In addition to producing rewarding effects of their own (see Gardner 2005; Maldonado et al for reviews), the endogenous cannabinoids have been implicated in the modulation of the effects of many natural and drug rewards (see Arnold 2005; Beardsley and Thomas 2005; Cohen et al. 2005a; Maldonado et al for reviews). In particular, selective antagonists of the cannabinoid-1 (CB 1 ) receptor, such as rimonabant (SR141716A; Rinaldi-Carmona et al. 1994), have been found to reduce the effects of a variety of addictive substances in rodents. For example, doses in the range of mg/kg rimonabant reduce self-administration of nicotine (Cohen et al. 2002), heroin (Navarro et al. 2001; Solinas et al. 2003), and alcohol (Arnone et al. 1997; Cippitelli et al. 2005; Economidou et al. 2006) but not cocaine (De Vries et al. 2001; Fattore et al. 1999; Lesscher et al. 2005). Similar doses of rimonabant also reduce the reinstatement of self-administration produced by nicotinerelated cues (Cohen et al. 2005b; De Vries et al. 2005), heroin (Fattore et al. 2003) and heroin-related cues (De Vries et al. 2003), alcohol (Serra et al. 2002) and alcohol-related cues (Cippitelli et al. 2005; Economidou et al. 2006), and cocaine and cocaine-related cues (De Vries et al. 2001). Finally, similar doses of rimonabant have been found to block the acquisition or expression of conditioned place preferences (CPP) produced by nicotine (Forget et al. 2005, 2006; Le Foll and Goldberg 2004), morphine (Chaperon et al. 1998; Singh et al. 2004), and cocaine (Chaperon et al. 1998). On the other hand, rimonabant apparently fails to block the development of locomotor sensitization produced by the

2 462 Psychopharmacology (2008) 198: repeated administration of these same drugs. Norwood et al. (2003) and Singh et al. (2004) found that the development of locomotor sensitization caused by repeated injections of morphine in rats was not reduced by coadministration of rimonabant (0.1, 0.5, and 3 mg/kg) as measured during the induction of sensitization and during a subsequent morphine challenge in the absence of rimonabant. Similarly, Vigano et al. (2004) found that coadministration of 3 mg/kg rimonabant, which had no effect by itself, did not affect the development of sensitization to repeated injections of morphine in rats as measured during a subsequent morphine challenge in the absence of rimonabant. However, when administered before the subsequent morphine challenge, rimonabant reduced the expression of sensitized nonstereotyped activity. Finally, Lesscher et al. (2005) found that coadministration of 1 mg/kg rimonabant did not affect the development of locomotor sensitization to repeated injections of cocaine in mice as measured during a subsequent cocaine challenge in the absence of rimonabant. Thus, in contrast to the studies on self-administration, reinstatement, and CPP, research has failed to reveal a major role for CB 1 receptors at least on the development of locomotor sensitization. Given that the neural systems mediating locomotor sensitization overlap those mediating reward (Berridge and Robinson 1998; Vanderschuren and Kalivas 2000) and that prior locomotor sensitization enhances the apparent reward value of subsequent drug administration as measured in self-administration, reinstatement, and CPP tasks (Deroche et al. 1999; Lett 1989; Woolverton et al. 1984), the finding that rimonabant appears not to affect the development of locomotor sensitization is surprising. Consequently, we examined the effects of coadministration of 2 mg/kg rimonabant on both the development and subsequent expression of locomotor sensitization to repeated injections of 0.4 mg/kg nicotine. Nicotine is of particular interest as the effects of nicotine are very sensitive to the influence of environmental drug-related cues (see Cohen et al. 2005a; Le Foll and Goldberg 2005 for reviews), and Arnold (2005) and De Vries and Schoffelmeer (2005) have argued that rimonabant is particularly effective in reducing the control of behavior by drug-related cues. Materials and methods Animals Male Long Evans rats (n=34), weighing g at the beginning of the experiment were housed individually in stainless-steel mesh cages with free access to food and water in a colony that was lighted from 07:00 to 19:00. Drugs Rimonabant (SR141716) was generously donated by the National Institute of Mental Health and suspended in a vehicle of alcohol, Tween 80 (Fisher Scientific, Pittsburgh, PA), and water in a 1:1:18 ratio, respectively, at a concentration of 2 mg/ml. Nicotine bitartrate (Sigma Chemical, St. Louis, MO) was dissolved in water at a concentration of 0.4 mg/ml measured as the base, and the ph was adjusted to 7 with sodium hydroxide. Isotonic saline and the vehicle in which rimonabant was suspended were used as controls for nicotine and rimonabant, respectively. Apparatus Locomotor activity was recorded in a box made of black Cidex that was divided into four cm compartments. Locomotion was tracked by a video camera centered 135 cm above the box and linked to a Polytrack video tracking system (San Diego Instruments, San Diego, CA), which recorded the rats locations every s. Three red 25-W light bulbs indirectly lit the room, and 75 db of white noise was supplied during testing to mask auditory stimuli. Procedure The rats were randomly divided into four experimental groups: Vehicle saline (n=8), vehicle nicotine (n= 9), rimonabant saline (n=8), and rimonabant nicotine (n=9). Induction sessions Each rat was injected intraperitoneally (IP) with either 2 mg/kg rimonabant or its vehicle in the colony 30 min before each session and then was injected subcutaneously (SC) with either 0.4 mg/kg nicotine or isotonic saline outside the testing room just before being placed into an activity compartment for 1 h. All injections were given at 1 ml/kg. Groups were counterbalanced across the four compartments and time, and each rat was always placed in the same compartment. Injections and testing occurred every other day for six sessions. Challenge sessions Beginning 3 9 days after the last induction session, two challenge sessions were given on alternate days. Before the first challenge session, all rats received an IP injection of the vehicle in the colony 30 min before a SC injection of 0.4 mg/kg nicotine just before being placed in the activity compartments for 1 h. Before the second challenge session, all rats were injected IP with 2 mg/kg rimonabant in the

3 Psychopharmacology (2008) 198: colony 30 min before a SC injection of 0.4 mg/kg nicotine just before the 1-h session. Statistical analyses The induction data were analyzed by a Rimonabant (vehicle, rimonabant) Nicotine (saline, nicotine) Session (six) analysis of variance (ANOVA) with repeated measures on session, and the challenge data were analyzed by a Prior Nicotine (two) Prior Rimonabant (two) Challenge (vehicle/ nicotine, rimonabant/nicotine) ANOVA with repeated measures on challenge. Significant interactions were further analyzed by simple effects tests comparing the effects of each significant factor at all levels of the other factor. Results Induction sessions Figure 1 shows that repeated injections of 0.4 mg/kg nicotine progressively increased activity across sessions, and this increase was blocked by coadministration of 2 mg/kg rimonabant, which had no effect by itself. These conclusions were confirmed by the three-way ANOVA, which revealed main effects of nicotine (F[1, 32]=12.69, P < 0.01), rimonabant (F[1, 32] = 12.50, P < 0.01), and session (F[5, 160]=3.25, P<0.01). A Nicotine Session interaction (F[5, 160] =3.18, P<0.01) indicated that nicotine increased activity across sessions more than did saline, and a Nicotine Rimonabant interaction (F[1, 32] =6.67, P<0.02) indicated that rimonabant blocked the ability of nicotine to increase locomotion. Supporting this latter conclusion, subsequent pairwise comparisons (simple effects tests) indicated that the vehicle nicotine rats locomoted more than the vehicle saline rats (F[1, 32] = 18.88, P<0.001) and the rimonabant-nicotine rats (F[1, 32]= 18.71, P<0.001). No other group differences were close to being significant. Challenge sessions Mean Distance Traveled (cm) Veh-Sal (n=8) Veh-Nic (n=9) Rim-Sal (n=8) Rim-Nic (n=9) Sessions Fig. 1 Effects of 2 mg/kg rimonabant (Rim) or vehicle (Veh) on the development of locomotor sensitization to repeated injections of 0.4 mg/kg nicotine (Nic) or saline (Sal) during the six induction sessions. Pairwise simple effects tests after a significant Nicotine Rimonabant interaction indicated that the vehicle nicotine group was more active as measured by mean (±SEM) distance traveled (cm) than the other groups (P<0.001), which did not differ from each other Figure 2 shows that both groups of rats previously injected with nicotine were equally more active in response to the initial 0.4 mg/kg nicotine challenge than were the two groups previously injected with saline. However, coadministration of 2 mg/kg rimonabant along with nicotine in the second challenge eliminated the expression of sensitization in the groups previously exposed to nicotine. These conclusions were confirmed by the three-way ANOVA, which revealed an almost significant main effect of prior nicotine (F[1, 32] = 3.81, P < 0.06), a main effect of challenge (F[1, 32] =10.26, P<0.01), and a Prior Nicotine Challenge interaction (F[1,32] =5.19, P<0.03). Subsequent pairwise comparisons (simple effects tests) indicated that in response to the initial nicotine challenge, the rats previously exposed to nicotine locomoted more than the rats previously exposed to saline (F[1, 64] =7.16, P<0.01). Mean Distance Traveled (cm) ** Vehicle/Nicotine ** Veh-Sal (n=8) Veh-Nic (n=9) Rim-Sal (n=8) Rim-Nic (n=9) Rimonabant/Nicotine Drug Challenges Fig. 2 A Prior Nicotine Challenge interaction and subsequent pairwise simple effects tests indicated that the initial challenge injection of 0.4 mg/kg nicotine (and vehicle) produced more locomotion in the groups previously exposed to nicotine (Veh Nic and Rim Nic) than in the groups previously exposed to saline (Veh Sal and Rim Sal). These simple effects tests also indicated that the addition of rimonabant to the second nicotine challenge selectively decreased locomotion in the rats previously exposed to nicotine, such that there were no longer any differences among the four groups. The legend reflects the drug conditions during the development of sensitization. Double asterisk, P<0.01 in comparison to the previously saline-injected rats in the initial challenge and in comparison to the previously nicotine-injected rats in the second challenge

4 464 Psychopharmacology (2008) 198: Simple effects tests also indicated that coadministration of rimonabant along with nicotine on the second challenge session decreased the locomotion of the previously nicotine-sensitized rats (F[1, 32] =15.01, P<0.01) but had no effect on the previously saline-injected rats, such that there were no differences in activity among the four groups. Although none of the other interactions approached significance, this reduction in locomotion caused by adding rimonabant to the nicotine challenge was more apparent in the rimonabant nicotine rats than in the vehicle nicotine rats. Body weight Although the rats injected with rimonabant tended to gain less weight than the rats injected with vehicle, there were no significant differences among the groups in body weight or weight gain (data not shown). Discussion Repeated injections of 0.4 mg/kg nicotine increased locomotion in the vehicle-injected rats more than did saline across the six induction sessions, indicating the development of locomotor sensitization. Confirming this, the rats repeatedly injected with nicotine were more active than the saline-pretreated rats in response to a subsequent challenge injection of nicotine. Locomotor sensitization to repeated injections of this dose of nicotine is a reliable finding in our laboratory (Kelsey et al. 2002; Kelsey and Willmore 2006), as well as in that of others (Clarke and Kumar 1983; Ksir et al. 1985), although we seldom find such a large increase in activity on the first session. Coadministration of 2 mg/kg rimonabant during the six induction sessions blocked both the initial increase in locomotion and the subsequent induction of sensitization produced by nicotine. The ability of rimonabant to block these effects of nicotine did not reflect a general suppression of activity because rimonabant had no effect on rats that did not receive nicotine. These results suggest that the CB 1 antagonist selectively decreased the development of nicotine-induced sensitization. However, the challenge data suggest an alternative hypothesis. When all rats were challenged with just 0.4 mg/kg nicotine (and the vehicle) on session 7, nicotine also increased activity in the rimonabant nicotine rats such that both groups of rats previously treated with nicotine were now equally more active than the previously salineinjected controls. This indicates that both nicotine groups had been equally sensitized to nicotine and that coadministration of rimonabant did not block the development of sensitization. Rather, these data suggest that rimonabant may have reduced the appearance of sensitization during the first six sessions by blocking or masking the expression of sensitization that was, in fact, developing normally. The hypothesis that rimonabant blocked the expression of locomotor sensitization was supported by the second challenge in which all rats were given rimonabant in conjunction with nicotine. Rimonabant selectively blocked the nicotine-induced increase in locomotion in both groups previously sensitized to nicotine such that they were no more active than the rats previously given saline. Although the differences are not statistically significant, we do note that the suppressant effect of rimonabant is somewhat smaller in the animals previously sensitized to just nicotine. Indicating that the ability of rimonabant to block the expression of nicotine-induced sensitization did not reflect a blockade of the expression of conditioned sensitization, we have never observed conditioned sensitization after sensitization to nicotine; that is, challenge injections of saline into rats previously sensitized to 0.4 mg/kg nicotine for five to seven sessions produced no more locomotion than in rats previously injected with saline (Kelsey et al. 2002; Kelsey and Willmore 2006). Again, illustrating that rimonabant was not merely acting as a sedative, rimonabant had no effect on locomotion of the rats previously injected with saline. Although our interpretation is different, our data are largely consistent with those of others. As do ours, data from all four of the other sensitization studies indicate that coadministration of rimonabant during the induction phase had no effect on activity measured on a subsequent challenge test in the absence of rimonabant (Lesscher et al. 2005; Norwood et al. 2003; Singh et al. 2004; Vigano et al. 2004). Moreover, Vigano et al. (2004) found that rimonabant interfered with the expression of prior sensitization to morphine, and Filip et al. (2006) found that 5 and 10 but not 1.25 or 2.5 mg/kg rimonabant reduced the expression of cocaine-induced locomotor sensitization. The only apparent difference between our and prior studies is that Norwood et al. (2003) and Singh et al. (2004) reported that rimonabant had no effect on locomotion during the induction phase, whereas we found suppression (Lesscher et al. [2005] and Vigano et al. [2004] did not measure activity during the induction phase). However, in examining their data, it appears as though rimonabant did suppress the development of sensitization to morphine for the first three to five sessions, at least during the second hour of each 3-h session in the study by Norwood et al. (2003), and appeared to suppress locomotion in the second session in the study by Singh et al. (2004). Thus, there is evidence that rimonabant at least temporarily suppressed the development of sensitization in those studies as well. Why their initial suppression was not longer lasting is not clear. What is clear is that in our study and those of Vigano et al. (2004)

5 Psychopharmacology (2008) 198: and Filip et al. (2006), rimonabant was quite capable of suppressing previously acquired sensitization. Our hypothesis that rimonabant blocks only the expression of behavioral sensitization is also consistent with research showing that rimonabant can inhibit the expression of previously developed self-administration (Arnone et al. 1997; Cohen et al. 2002; Navarro et al. 2001), reinstatement (De Vries et al. 2001, 2003, 2005), and CPP (Forget et al. 2005, 2006; Le Foll and Goldberg 2004; Vigano et al. 2004; although see Chaperon et al. 1998) produced by a variety of drugs, including nicotine. However, this conclusion appears to be inconsistent with studies indicating that the acquisition of CPP produced by a variety of drugs, including nicotine, can be blocked by rimonabant (Chaperon et al. 1998; Forget et al. 2005; Singh et al. 2004). Singh et al. (2004) plausibly suggested that this difference may reflect differences in the behaviors measured by the two tasks. However, it is also possible that these latter data reflect not the blockade of acquisition as implied but a state-dependent effect (Overton 1964). In the CPP studies, rimonabant was given during acquisition only in the drug-paired chamber. Thus, any learning about the drug was occurring in the rimonabant condition. However, the testing that determined if a CPP had been acquired occurred in a rimonabant- (and drug-)free state. Thus, it is possible that the rimonabanttreated rats showed no preference for the drug-associated chamber, not because rimonabant blocked the formation of such a preference but because that preference was stored in a rimonabant state that was not accessible when they were tested without rimonabant. Unfortunately, none of the studies that examined the effects of rimonabant on the expression of a previously acquired CPP gave rimonabant to animals that had also received rimonabant during the acquisition phase. Although the literature is, thus, somewhat ambiguous in indicating whether rimonabant can block the development of a variety of behaviors produced by repeated injections of rewarding/addictive drugs, the data are consistent in indicating that rimonabant can at least temporarily block the expression of these behaviors. Thus, these data are consistent with the hypothesis that rimonabant may be useful in treating, if not preventing, a variety of addictionrelated behaviors (De Vries and Schoffelmeer 2005; Maldonado et al. 2006), although the data also suggest some limitations. Our data that the suppressive effects of rimonabant observed during induction were no longer apparent during the rimonabant-free nicotine challenge suggest that the suppressant effects are transient and may require relatively frequent administration of the drug. Moreover, the findings of Forget et al. (2005, 2006) that the ability of rimonabant to block the expression of a nicotine-induced CPP disappeared if rimonabant was first given 2 12 weeks, rather than 1 day, after the establishment of the CPP, suggests that there may be a limited window of opportunity for rimonabant to be effective, even in blocking the expression of addictive behavior (although see Cohen et al. 2005b). Acknowledgments This study was based on research submitted by S. Calabro as partial fulfillment for the Bachelor of Arts degree. We gratefully acknowledge and thank the National Institute of Mental Health for providing the rimonabant. The National Science Foundation Instrumentation and Laboratory Improvement Program through Grant CSI provided partial support for this research. All experiments were approved by the Bates College IACUC and were conducted in accordance with the Guide for Care and Use of Laboratory Animals from the National Institutes of Health (1996). References Arnold JC (2005) The role of endocannabinoid transmission in cocaine addiction. Pharmacol Biochem Behav 81: Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelet M, Soubrie P, Le Fur G (1997) Selective inhibition of sucrose and ethanol intake by SR , an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 132: Beardsley PM, Thomas BF (2005) Current evidence supporting a role of cannabinoid CB 1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders. 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