Cannabinoid CB1 Receptor Antagonist Rimonabant Attenuates Reinstatement of Ketamine Conditioned Place Preference in Rats

European Journal of Pharmacology 589 (2008) 122–126

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European Journal of Pharmacology

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Cannabinoid CB1 receptor antagonist rimonabant attenuates reinstatement of ketamine conditioned place preference in rats

Fangqiong Li a, Qin Fang a, Yu Liu b, Mei Zhao b, Dapeng Li a, Jishi Wang a,⁎, Lin Lu b,⁎ a School of Pharmacology and the Afﬁliated Hospital of Guiyang Medical College, Guiyang 550004, China b National Institute on Drug Dependence, Peking University, Beijing 100082, China

ARTICLE INFO ABSTRACT

Article history: Recent evidence suggests that cannabinoid CB1 receptors may represent effective targets for therapeutic Received 5 July 2007 agents used to treat cocaine and heroin relapse. However, the role of cannabinoid CB1 receptors in the Received in revised form 6 April 2008 potential treatment for other drugs of abuse is still largely unknown. The present study was conducted to Accepted 22 April 2008 determine whether cannabinoid CB receptors play a similar role in relapse to ketamine abuse. To establish a Available online 6 May 2008 1 ketamine reinstatement model in the conditioned place preference paradigm, rats were trained to develop place preference conditioned by ketamine, which was subsequently extinguished through daily exposure to Keywords: the test chambers in the absence of ketamine. On the day following the last extinction session, four groups of Cannabinoid CB1 receptor antagonist Conditioned place preference rats were injected with ketamine (1, 5, 10 and 15 mg/kg, i.p.) to reinstate previously extinguished conditioned Ketamine place preference. To investigate the effects of rimonabant, a cannabinoid CB1 receptor antagonist, on Rimonabant reinstatement of ketamine-induced place preference, different doses of rimonabant (0.1, 0.5 and 3 mg/kg, i.p) Relapse were injected 30 min prior to the ketamine (5 and 15 mg/kg, i.p.) priming injection in a separate group of Reinstatement rats. To determine whether rimonabant itself produces conditioned place preference or conditioned place aversion, rats were trained for conditioned place preference or place aversion with rimonabant (0, 0.1, 0.5, 3.0 mg/kg, i.p.). While ketamine priming injections reinstated extinguished place preference, rimonabant administration signiﬁcantly attenuated the reinstatement of ketamine-induced place preference in a dose- dependent manner. Importantly, rimonabant itself did not produce conditioned place preference or place aversion. Since the reinstatement effects of ketamine administration were inhibited by rimonabant, these

1. Introduction aspartate (NMDA) receptor antagonist, can also inﬂuence various behavioral effects of other addictive drugs. For instance, ketamine has Ketamine, also known as “special K,” has been used recreationally been shown to prevent morphine-induced place preference (Suzuki in many countries over the past decade (Curran and Morgan, 2000; et al., 2000) and analgesic tolerance (Shimoyama et al., 1996; Trujillo Fang et al., 2006). Ketamine is an anesthetic derivative of phencycli- and Akil, 1994). Ketamine can also suppress rapid tolerance of ethanol dine that has dissociative, analgesic, and psychedelic properties (Wolff or barbiturates (Khanna et al., 1998; Khanna et al., 2002; Khanna et al., and Winstock, 2006). Ample evidence from animal research has 1997). When given in combination with ethanol, ketamine poten- shown strong similarities between ketamine and other addictive tiated ethanol-induced locomotion (Meyer and Phillips, 2003) and drugs in a wide range of behavioral paradigms, including self- neutralized ethanol's anxiolytic-like effect (Silvestre et al., 2002). administration (Marquis et al., 1989; Winger et al., 1989), locomotor The conditioned place preference model has been used widely to sensitization (Meyer and Phillips, 2003; Trujillo et al., 2007; Uchihashi assess the rewarding effect of addictive drugs (Tzschentke, 1998, et al., 1993; Wiley et al., 2007), drug discrimination (Grant et al., 1991; 2007). Although the vast majority of research using this model has Shelton and Balster, 1994), and conditioned place preference (CPP) concentrated on the development and expression of drug-induced (Suzuki et al., 2000). Ketamine, which functions as an N-methyl-D- place preference, a growing number of place preference studies incorporate extinction and reinstatement phases. Extinction of previously established drug-induced place preference can be accom- ⁎ Corresponding authors. Wang is to be contacted School of Pharmacology, and the plished with either repeated place preference testing without any Afﬁliated Hospital of Guiyang Medical College, Guiyang 550004, China. Lu, National Institute on Drug Dependence, Peking University, 38 Xueyuan Road, Beijing, China. drug exposure or by pairing the two environments of the test E-mail addresses: [email protected] (J. Wang), [email protected] (L. Lu). apparatus with saline injections. Drug priming injections (Mueller

0014-2999/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2008.04.051 F. Li et al. / European Journal of Pharmacology 589 (2008) 122–126 123 et al., 2002; Mueller and Stewart, 2000), presentation of stress (Lu et (1 ml/kg, i.p.) (De Vries et al., 2001). After 8 consecutive sessions, rats al., 2001, 2002; Zhao et al., 2007), and conditioned fear stimuli were re-tested for place preference or place aversion induced by the (Sanchez and Sorg, 2001) can then reinstate the extinguished place rimonabant. The control rats received saline injections throughout the preference. Although ketamine has been shown to produce signiﬁcant conditioning and post-conditioning phases. conditioned place preference in mice (Suzuki et al., 2000), extinction and reinstatement of ketamine-induced place preference has not been 2.3. Extinction and reinstatement of ketamine conditioned place tested experimentally. The primary goal of the current study was to preference characterize the extinction and reinstatement of ketamine conditioned place preference. A cannabinoid CB1 receptor antagonist, During the ketamine conditioned place preference extinction rimonabant, was also used to determine the effect of cannabinoid phase, rats were injected with saline and conﬁned to the previous

CB1 receptor blockade on the reinstatement of ketamine conditioned ketamine- or saline-paired compartment for 45 min a day for 28 days place preference following extinction. (Lu et al., 2000; Wang et al., 2006). Immediately following the last extinction session, rats were injected with ketamine (1, 5, 10 and 2. Materials and methods 15 mg/kg) to reinstate extinguished place preference conditioned by ketamine. To investigate the effect of rimonabant on the reinstatement 2.1. Animals and drugs

A total of 100 male Sprague–Dawley rats (200–220 g) obtained from the animal laboratory at Guiyang Medical College were used in the experiments. The animals were housed at a room temperature of 22±2 °C with a 12 h light–dark cycle and allowed to habituate for seven days prior to the experiment. Food and water were available ad libitum. The animals weighed 250–300 g at the start of the experiment. All experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The procedures were approved by the local Committee for Animal Use and Protection. The drugs used in the present study were ketamine hydrochloride (Shanghai First Biochem. & Pharma. Co., Ltd, Shanghai, China) and rimonabant (Xinxiang Crude Medicinal Drugs Co., Jiangsu, China). Ketamine hydrochloride was diluted to 10 mg/ml with saline. Rimonabant was dissolved with saline containing 1% Tween 80.

2.2. Conditioned place preference procedure

The conditioned place preference system (Shanghai Jiliang Soft Co. Shanghai, China) was computer controlled and consisted of three PVC compartments. Two of the compartments were identical in size (L×W×H: 30 cm×30 cm×50 cm) with different colors and floor textures. The black compartment had a textured floor and the white compartment had a smooth floor. The middle compartment was a 12 cm×30 cm×50 cm (L×W×H) grey tunnel. The conditioning procedure for ketamine-induced place preference was modified from previous studies (Calcagnetti and Schechter, 1993; Lu et al., 2005; Suzuki et al., 1999). In order to determine compartment bias, rats were initially placed in the middle chamber and permitted to move freely through the apparatus for a period of 15 min during the pre-conditioning period. Animals that spent more than 150 s in one compartment compared to the other were considered to have compartment bias and excluded from the study. During the conditioning trial, each rat was treated for 8 consecutive sessions with alternate injections of either ketamine (10 mg/kg, i.p.) or saline (1 ml/kg, i.p.). Rats were confined to the white compartment for 45 min immediately after ketamine administration and to the black compartment after saline injection. After 8 consecutive sessions, rats were re-tested for ketamine (post-conditioning) conditioned place preference by being allowed free access to both the white and black chambers for 15 min. Rats in the control group Fig. 1. Acquisition, extinction and reinstatement of ketamine conditioned place preference: received saline injections throughout the conditioning and post- (A) Acquisition of ketamine conditioned place preference. Data are depicted as the time spent (mean±SEM) in the drug-paired chamber during the pre-conditioning and post- conditioning phases. conditioning phases of conditioned place preference. ⁎Different from pre-conditioning, In order to exclude the possibility that rimonabant produced place P b0.05; #different from the saline group, P b0.05. (B) Extinction of ketamine preference or place aversion, five groups of rats received place conditioned place preference. Data are depicted as the conditioned place preference preference training with different doses of rimonabant (saline group, scores (mean ± SEM) during the pre- and post-extinction of conditioned place preference. ⁎Different from pre-extinction, Pb0.05. (C) Reinstatement of ketamine 0, 0.1, 0.5, and 3.0 mg/kg) administered in a similar fashion to the conditioned place preference. Data are depicted as the place preference scores (mean± fl ketamine. Brie y, animals underwent 8 consecutive sessions in which SEM). ⁎Different from 1 mg/kg ketamine group within post-priming, Pb0.05; #Different they received alternating injections of either rimonabant or saline from the pre-priming, Pb0.05. 124 F. Li et al. / European Journal of Pharmacology 589 (2008) 122–126 of ketamine conditioned place preference, rimonabant (0, 0.1, 0.5, extinguished place preference was reinstated by ketamine at a dose of 3.0 mg/kg) was administered 30 min prior to the priming injection of 15 mg/kg (Fig. 2C). As shown in Fig. 2C, the ANOVA analysis revealed ketamine. that there were significant effects of rimonabant treatment on place

preference score across groups (F(1, 30) =129.06, P b0.001). The 2.4. Data analysis and statistics reinstatement of extinguished ketamine place preference primed by 15 mg/kg ketamine was attenuated by pretreatment with rimonabant The place preference score was deﬁned as the time spent in the in a dose-dependent manner (r=0.91, Pb0.05). The reinstatement of drug-paired chamber during the post-conditioning (pre-extinction), extinguished ketamine place preference was attenuated by rimona- post-extinction (pre-priming) or post-priming session minus the time bant at doses of 0.5 and 3 mg/kg (Pb0.001), but not at a dose of spent in the drug-paired chamber during the pre-conditioning 0.1 mg/kg. session. The data were expressed as means±SEM. The statistical analysis was performed using two-way analysis of variance (ANOVA) with the place preference scores as the dependent factor. When appropriate, post-hoc comparison of means was carried out with the Tukey test for multiple comparisons. A linear regression was used to assess the correlation between the reinstatement of ketamine place preference by different doses of the drug, and the effects of different doses of rimonabant on the reinstatement of ketamine place preference. The level of statistical signiﬁcance was set at Pb0.05.

3. Results

3.1. Acquisition, extinction and reinstatement of ketamine conditioned place preference

After the 8 conditioning sessions with ketamine, rats demonstrated significantplacepreferencefortheketamine-pairedcham- ber. As shown in Fig. 1A, ANOVA analysis revealed that there was a significant effect of treatment and phase (Treatment: F(1,156) =54.2, P b0.001; Phase: F(1,156) =57.6, P b0.001; Treatment×Phase: F(1,156) = 61.3, P b0.001). Post hoc analysis showed that there were significant differences in the time spent in the drug-paired chamber between the pre- and post-conditioning periods in ketamine group (P b0.001). Ketamine place preference was significantly extinguished after 28 extinction sessions. Ketamine-induced place preference was reinstated by a single injection of ketamine. As shown in Fig. 1B, there were significant differences in the place preference scores before (pre- extinction) and after (post-extinction) the extinction phase (Pb0.01). As shown in Fig. 1C, ANOVA analysis revealed that there were significant differences for place preference scores between pre- priming and post-priming treatment (F(1, 24) =60.6, Pb0.001). Also, ketamine significantly reinstated extinguished conditioned place preference in a dose-dependent manner (r=0.97 Pb0.05). There were significant differences for place preference score between pre- and post-priming in the groups at the doses of 5, 10 and 15 mg/kg, but not at 1 mg/kg, ketamine.

3.2. Effects of rimonabant on drug-primed reinstatement of ketamine conditioned place preference

The reinstatement of conditioned place preference induced by priming injections of ketamine was signiﬁcantly attenuated by pretreatment with rimonabant. As shown in Fig. 2B, the ANOVA analysis revealed that there were signiﬁcant effects of rimonabant Fig. 2. Effects of rimonabant on ketamine-primed reinstatement of extinguished ketamine treatment (pre-priming and post-priming) on place preference scores conditioned place preference: (A) Acquisition and extinction of ketamine conditioned place preference (data was combined from the 5 mg/kg and 15 mg/kg ketamine-primed across groups (F(1, 30) =18.0, Pb0.001). The reinstatement of extinguished ketamine conditioned place preference primed by 5 mg/kg groups). Data are depicted as place preference scores (mean ±SEM) during the acquisition (pre-extinction) and extinction (post-extinction) of conditioned place ketamine was dose-dependently attenuated by pretreatment with preference. ⁎Different from pre-extinction, Pb0.001. (B) Rimonabant (0, 01, 0.5 and rimonabant (r =0.934, P b0.05) (Fig. 2B). The reinstatement of 3.0 mg/kg) attenuated 5 mg/kg ketamine-primed reinstatement of extinguished extinguished ketamine conditioned place preference was attenuated ketamine conditioned place preference. Data are depicted as the place preference by rimonabant at doses of 0.5 and 3 mg/kg (Pb0.01), but not at a dose scores during pre- and post-priming. #Different from pre-priming, Pb0.05 and ⁎different from saline group within post-priming, Pb0.05. (C) Rimonabant (0, 01, 0.5 of 0.1 mg/kg. and 3.0 mg/kg) attenuated 15 mg/kg drug-primed extinguished ketamine conditioned To explore whether rimonabant attenuated the reinstatement of place preference. Data are depicted as place preference scores. #Different from pre- ketamine place preference induced by a higher dose of ketamine, priming, Pb0.05 and ⁎different from saline group within post-priming, Pb0.05. F. Li et al. / European Journal of Pharmacology 589 (2008) 122–126 125

likely associated with the distribution of these receptors in the brain and the interaction between the endogenous cannabinoid system and other neurotransmitters, such as dopamine and glutamate. High

levels of cannabinoid CB1 receptors are present in brain regions that are thought to play a key role in relapse-like behavior and conditioning processes, including prefrontal cortex, amygdala, nucleus accumbens, striatum, ventral tegmental area, and hippocampus (Everitt et al., 1999; Kalivas and McFarland, 2003; Tanda et

al., 1997). Cannabinoid CB1 receptor activation has been shown consistently to inﬂuence dopaminergic transmission (Di Chiara and Imperato, 1988). For example, extracellular dopamine levels were increased in the shell of the nucleus accumbens in rats trained to self-

administer the cannabinoid CB1 receptor agonist, WIN, 55 212-2 Fig. 3. Acquisition of rimonabant conditioned place preference or conditioned place (Fadda et al., 2006). In contrast, rimonabant, given systemically, can aversion: Data are depicted as the time spent (mean±SEM) in the drug-paired chamber reduce increased dopamine levels from the same region induced by during the pre-conditioning and post-conditioning phases of conditioned place preference. There were no significant differences between pre- and post-conditioning novel and highly palatable food (Melis et al., 2007). In addition, after training with any dose of rimonabant (PN0.05). cannabinoids have been shown to mediate presynaptic inhibition of glutamatergic transmission in various brain regions, including hippocampus (Ohno-Shosaku et al., 2002; Shen et al., 1996), 3.3. Rimonabant conditioned place preference or conditioned place substantia nigra pars reticulata (Szabo et al., 2000), striatum aversion (Gerdeman and Lovinger, 2001; Huang et al., 2002), VTA (Melis et al., 2004), and amygdala (Azad et al., 2003). A recent report has To determine whether rimonabant itself could produce place pre- demonstrated that transient release of endogenous cannabinoids can ference or place aversion, naïve rats were trained with different doses be induced by postsynaptic dopamine neurons within the VTA in a 2+ of rimonabant during the conditioning phase. As shown in Fig. 3, Ca and CB1 receptor-dependent fashion and that they act retro- there were no significant differences between the time spent in the gradely and inhibit glutamatergic release from the presynaptic drug- and saline-paired chambers across all tested doses of rimona- terminals (Melis et al., 2004). Thus, blockade of the reinstatement bant (saline and 0, 0.1, 0.5 3.0 mg/kg rimonabant) (PN0.05). These of ketamine conditioned place preference by rimonabant is possibly findings indicate that rimonabant itself does not have any rewarding via the alteration of glutamatergic transmission in the brain. or aversive properties. Certainly, further studies are necessary to explore the critical role of the dopaminergic system in the reinstatement of ketamine 4. Discussion conditioned place preference. The possibility of any potential behavioral effect of rimonabant The current study was conducted to experimentally verify the interfering with the place preference effect of ketamine was also extinction and reinstatement of ketamine-induced place preference in addressed in the present study. Our present findings demonstrate that rats and to determine the effect of rimonabant, a cannabinoid CB1 neither place preference nor place aversion was evident in the animals receptor antagonist, on the reinstatement of ketamine-induced place repeatedly treated with rimonabant. Since ketamine can function as a preference. The major findings are (1) rats expressed significant place discriminative stimulus (De Vry and Jentzsch, 2003; Narita et al., preference conditioned by ketamine; (2) their place preference to 2001), it is rather possible that the inhibitory effect of rimonabant on ketamine was extinguished following 28 days of extinction and this the conditioning effect of ketamine is indeed caused by its suppres- extinguished place preference response was reinstated by priming sion on the discriminative effect, instead of place preference of injections of ketamine across a wide range of doses; (3) the ketamine. However, previous studies have demonstrated that rimo- reinstatement of ketamine conditioned place preference was dose- nabant did not affect the discriminative stimulus effects of cocaine dependently attenuated by rimonabant, which itself failed to induce (Filip et al., 2006) or nicotine (Le Foll and Goldberg, 2004).Thus, while either conditioned place preference or place aversion in the animals. the question of whether rimonabant affects the discriminative Taken together, these findings demonstrate that the establishment, stimulus effect of ketamine remains unknown, it seems unlikely to extinction and reinstatement of ketamine conditioned place pre- be the case in present study. ference response can be induced in rats, and that cannabinoid CB1 In conclusion, re-exposure to ketamine reinstated extinguished receptors play an important role in the reinstatement of ketamine ketamine conditioned place preference, which was, however, conditioned place preference. blocked by the cannabinoid CB1 receptor antagonist rimonabant. The extinction and reinstatement of ketamine conditioned place Recent findings suggest that cannabinoid CB1 receptors may be a preference has not been previously demonstrated, despite the fact novel target for a new class of therapeutic agents used to treat that a growing number of studies have shown a similar pattern of cocaine and heroin addiction (De Vries et al., 2003; De Vries et al., extinction and reinstatement of conditioned place preference induced 2001; De Vries and Schoffelmeer, 2005). Like these studies, our by a wide range of other drugs, including cocaine (Mueller and findings also suggest that the cannabinoid CB1 receptor plays a role Stewart, 2000; Parker et al., 2004), morphine (Lu et al., 2002; Mueller in relapse to ketamine abuse, and thus that cannabinoid CB1 et al., 2002), ethanol (Cunningham et al.,1998), and nicotine (Biala and receptor antagonists may be useful in the treatment of ketamine Budzynska, 2006). Only one report has demonstrated that adminis- addiction. tration of ketamine was sufficient to induce conditioned place preference (Suzuki et al., 2000) in mice. Our findings confirmed that Acknowledgments ketamine produces conditioned place preference in rats, and further we provide the first demonstration that ketamine conditioned place This work was supported in part by the Program for New Century preference can be extinguished in rats, and then dose-dependently Excellent Talents in University, the National Basic Research Program of reinstated by priming injections of the drug. China (973 Program, 2007CB512302 and 2003CB515400), and the

The mechanisms underlying the role of cannabinoid CB1 receptors National High Technology Research and Development Program of in the reinstatement of ketamine conditioned place preference are China (863 Program, 2006AA02Z4D1). 126 F. Li et al. / European Journal of Pharmacology 589 (2008) 122–126

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