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Sub-chronic administration of AM251, CB1 receptor antagonist, within the nucleus accumbens induced sensitization to morphine in the rat
Neuroscience Letters 467 (2009) 43–47
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Sub-chronic administration of AM251, CB1 receptor antagonist, within the nucleus accumbens induced sensitization to morphine in the rat Abbas Haghparast a,∗ , Pegah Azizi a,b , Majid Hassanpour-Ezatti b , Hossein Khorrami a , Nima Naderi a a b
Neuroscience Research Center, Shahid Beheshti University, M.C., P.O. Box 19615-1178, Tehran, Iran Department of Biology, Faculty of Science, Shahed University, Tehran, Iran
a r t i c l e
i n f o
Article history: Received 15 February 2009 Received in revised form 18 June 2009 Accepted 30 September 2009 Keywords: Nucleus accumbens CB1 receptor AM251 Morphine Conditioned place preference Rat
a b s t r a c t It seems that there is a cross-talk between the cannabinoid CB1 and opioid receptors in the process of sensitization to opiates. In present study, we tried to examine the effect of solely administration of AM251, a CB1 receptor antagonist, on conditioned place preference (CPP) by ineffective dose of morphine in the rat. 102 adult male albino Wistar rats were used in these experiments. Subcutaneous administration of morphine (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg) induced CPP only at the doses of ≥5 mg/kg. The dose of 0.5 mg/kg of morphine was selected as the appropriate (ineffective) dose for induction of CPP in animals which were previously received AM251 (5, 25 and 125 ng/0.5 l per side) once daily for three days as a sub-chronic administration or those that received a single dose on the test day. Bilateral intra-accumbal sub-chronic but not single administration of AM251 dose-dependently produced sensitization to morphine and induced CPP by ineffective dose of morphine (0.5 mg/kg) in the rat. Bilateral intra-accumbal administration of neither saline nor DMSO (0.5 l/side) had effects on sensitization to morphine. Our findings indicated that CB1 receptors within the nucleus accumbens are involved in the sensitization to morphine in rats. © 2009 Elsevier Ireland Ltd. All rights reserved.
Compounds active at cannabinoid 1 (CB1) receptors have a profound impact on reward in part through the nucleus accumbens (NAc) shell and core [2,23]. Endogenous opioids as well as muopioid receptors are prevalent in the NAc shell and also expressed in the NAc core [17,34]. Several observations show that there are multiple substrates for convergent actions mediated through CB1 and mu-opioid receptors in the NAc [10,13]. Growing evidence suggests that many of the behavioral and physiological effects of opiates are modulated by the brain’s cannabinoid system [15]. Cannabinoid and opioid receptors are co-localized densely in the brain in key areas implicated in reward and addiction [18]. In addition, behavioral data indicate functional links between CB1 cannabinoid receptors and the opioid reward circuitry [28]. Interactions involving cannabinoids and opioids are suggested by their many similar pharmacological properties [18]. Moreover, it is noticeable that the endocannabinoid system might be a component of the brain reward circuitry and thus plays a role not only in cannabinoid addiction [8] but also in dependence to other drugs of abuse [3,11,33]. However, as we showed in our
∗ Corresponding author. Tel.: +98 21 2243 1624; fax: +98 21 2243 1624. E-mail address: [email protected] (A. Haghparast). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.09.062
recent study [1], the bilateral intra-accumbal administration of CB1 receptor antagonist (AM251) during the sensitization period (three days) or single application just before the conditioned place preference (CPP) test dose-dependently reduced the acquisition but lesser the expression of CPP induced by ineffective dose of morphine in morphine-sensitized rats. Therefore, in the present study, we try to determine the effects of intra-accumbal sub-chronic and single administration of AM251 themselves on the sensitization to morphine in rats. Experiments were carried out on adult male three-month old Wistar rats (Pasture Institute, Tehran, Iran) weighing 250 ± 30 g. Animals were housed in groups of three per cage in a 12/12 h light/dark cycle (light on between 7:00 A.M. and 7:00 P.M.) with free access to chow and tap water. All procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication No. 80-23, revised 1996). In the present study the following drugs were used: morphine sulfate (Temad, Tehran, Iran) that was dissolved in sterile saline (0.9%). 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251; Sigma–Aldrich, Germany), as a CB1 receptor antagonist that was dissolved in pure dimethylsulfoxide (DMSO; Sigma–Aldrich, Germany) as a vehicle. The injection volume of drugs was 1 l/rat
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(0.5 l drug solution in each side) over a period of 60 s. Control animals received either saline or DMSO. Rats were anaesthetized with intraperitoneal injection of ketamine (100 mg/kg) plus xylazine (10 mg/kg) and placed in a stereotaxic apparatus, while maintaining the incisor bar at approximately 3.3 mm below horizontal zero. Two stainless-steel, 23-gauge guide cannulae 10 mm in length were aimed at the NAc (between shell and core sub-regions; stereotaxic coordinates [22]: 1.2 mm anterior to the bregma, ±0.8 mm lateral to the sagittal suture and 6.8–7 mm down from top of the skull). Cannulae were secured to anchor jewelers’ screws with dental acrylic. Stainlesssteel stylets were inserted into the guide cannulae to keep them free of debris. All animals were allowed one week to recover from surgery. All microinjections were bilaterally performed. The testing apparatus consisted of three wooden compartments. Two compartments were identical in size (30 cm × 30 cm × 40 cm) but differed in shading and texture. Compartment A was white with black horizontal stripes 2 cm wide on walls and also had a textured floor. Compartment B was black with vertical white stripes 2 cm wide and also had a smooth floor. The third compartment (C) was a red tunnel (30 cm × 15 cm × 40 cm). It protruded from the rear of two large compartments and connected the entrances to them. The CPP paradigm took place on five consecutive days by using an unbiased procedure [20]. The experiment consisted of three distinct phases: pre-conditioning, conditioning and postconditioning. Conditioning score (CPP score) during 10 min (600 s) pre- and post-test was calculated. On day 1 (pre-exposure), each rat was placed separately into the apparatus for 10 min, with free access to all compartments. Animal displacement was recorded and analyzed on this day (pre-test day). In the experimental setup used in this study, animals did not show an unconditioned preference for either of the compartments. Animals were then randomly assigned to one of two groups for place conditioning and 6 animals were used for each subsequent experiment. This phase consisted of a three-day schedule of conditioning sessions. In this phase, animals received three trials in which they experienced the effects of the drugs while confined to one compartment for 45 min and three trials in which they experienced the effects of saline while confined to the other compartment by closing the removable wall. Access to the compartments was blocked on these days. On the 5th day (test day) the partition was removed, and the rats could access the entire apparatus. The mean time spent for each rat in both compartments during a 10-min period was recorded. In order to calculate the conditioning score, the difference in time spent for the drug-paired place and saline-paired place was considered as the preference criteria. Total distance traveled for each animal was also considered as the locomotor activity in control and experimental groups. Conditioning scores represent the time spent in drug-paired compartment minus the time spent in the saline-paired compartment. Animal displacement was recorded by ethovision software (Version 3.1), a video tracking system for automation of behavioral experiments (Noldus Information Technology, the Netherlands). Mean time spent in each compartment of CPP apparatus and total distance traveled during 10 min, both on the pre- and postconditioning phases were measured. It is noticeable that the locomotion was considered, only horizontally, because we tried to show that the obtained results are not due to change in locomotor activity. In these experiments, a dose–response relationship for morphine on conditioned place preference paradigm was established. Subcutaneous (s.c.) administration of different doses of morphine (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg) were tested for induction of CPP
Fig. 1. A typical photomicrograph scan of a coronal section (50 m) showing the guide cannulae tracks and microinjection sites in the nucleus accumbens of rat. aca, anterior commissure, anterior part; AcbC, accumbens nucleus, core; AcbSh, accumbens nucleus, shell; CPu, caudate putamen (striatum); LV, lateral ventricle.
during three days of conditioning. Conditioning score and distance traveled are calculated for each rat during 10 min on the test day. Then the appropriate (ineffective) dose of morphine, that it normally could not be induced CPP, was selected for the next experiments. Control animals received saline (1 ml/kg; s.c.). In order to examine the possible influence of single intraaccumbal injections of AM251 (as a CB1 receptor antagonist) on sensitization to morphine, conditioning with ineffective dose of morphine (0.5 mg/kg; s.c.) was preformed. Then, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally injected into the NAc on the post-conditioning phase, 5 min before the test. In control group, DMSO (0.5 l/side), as a vehicle was bilaterally injected into the NAc instead of AM251. To test the effects of three days sub-chronic administration of CB1 receptor antagonist on the sensitization to morphine, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally microinjected into the NAc once daily for three days, 5 min before saline injection (s.c.) during the sensitization period. After five days free of drug, according to sensitization protocol that has been described in our recent study [1] conditioning with an ineffective dose of morphine (0.5 mg/kg; s.c.) was preformed. In control group, DMSO as a vehicle (0.5 l/side) was bilaterally injected into the NAc instead of AM251 during three days sub-chronic treatment. After the completion of behavioral testing, all animals were deeply anaesthetized with ketamine and xylazine and transcardially perfused with 0.9% saline, followed by 10% buffered formalin. The brains were removed, blocked and cut coronally in 50 m sections stained with Cresyl violet through the cannulae placements. The drug injection sites subsequently examined by an observer unfamiliar with the behavioral data. Injection site was histologically verified (Fig. 1) and plotted on standardized sections derived from the atlas of Paxinos and Watson [22]. Only the animals with correct cannulae placements were included in the data analysis.
A. Haghparast et al. / Neuroscience Letters 467 (2009) 43–47
Conditioning score is expressed as mean ± SEM (standard error of mean). Data were processed by commercially available software Graph Pad Prism® 5.0. In order to compare the conditioning scores and distance traveled obtained in all groups (vehicle and experimental groups) one-way analysis of variance (ANOVA) and randomized blocks model followed by post hoc analysis (Dunnett’s or Tukey’s test) were used, as appropriated. P-values less than 0.05 (P < 0.05) were considered to be statistically significant. In this experiment, naive animals were injected with different doses of morphine sulfate (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg; s.c.). The doses of more than 5 mg/kg caused a significant increase in time spent in the drug-paired compartment compared to the saline-paired. [F(6,41) = 11.65, P < 0.0001]. Injection of saline to the animals (saline control group) in the conditioning compartments did not produce any preference or aversion for either place. Therefore, the dose of 0.5 mg/kg of morphine was selected as the appropriate (ineffective) dose for the rest of the experiments in CPP paradigm in rats. In this set of experiment, to determine the effects of intraaccumbal single injection of CB1 receptor antagonist on the CPP of morphine (0.5 mg/kg) in rats, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally injected into the NAc on the test day (post-conditioning phase), 5 min before the test. The control groups received saline (0.5 l/side) or vehicle (DMSO; 0.5 l/side) instead of AM251 into the NAc, bilaterally. One-way ANOVA indicated that microinjection of AM251 (5, 25 and 125 ng/0.5 l DMSO) on the test day, was unable to induce sensitization to morphine (0.5 mg/kg; s.c.) compared to saline and/or DMSO groups [F(4,29) = 1.697, P = 0.1822; Fig. 2A]. To test the effects of three days sub-chronic administration of CB1 receptor antagonist on the CPP by ineffective dose of morphine, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally microinjected into the NAc once daily for three days. One-way ANOVA indicated that microinjection of AM251 (5, 25 and 125 ng/0.5 l DMSO) for three consecutive days as sub-chronic treatment significantly induced sensitization to morphine compared to saline and/or DMSO groups [F(4,29) = 8.639, P = 0.0002] as shown in Fig. 2B. The control groups received saline (0.5 l/side) or vehicle (DMSO; 0.5 l/side) instead of AM251 into the NAc, bilaterally. Data obtained in this set of experiment indicated that bilateral intra-accumbal sub-chronic administration of AM251 dose-dependently produced sensitization to morphine and induced CPP by ineffective dose of morphine (0.5 mg/kg) in the rat. Data obtained in this study revealed that the single or subchronic intra-accumbal administration of different doses of AM251 (5, 25 and 125 ng/0.5 l DMSO per side) and DMSO did not alter locomotor activity in rats. One-way ANOVA followed by Tukey’s multiple comparison test indicated that single [F(4,29) = 0.3169, P = 0.8639; Fig. 3A] or sub-chronic [F(4,29) = 0.2163, P = 0.9268; Fig. 3B] administration of AM251 did not affect on the locomotor activity during 10-min test period (post-conditioning phase) in comparison with that of the saline and/or DMSO (vehicle) control groups. Therefore, in this study, single and sub-chronic intraaccumbal administrations CB1 receptor antagonist (AM251) into the NAc did not impress the conditioning scores because of alteration to the locomotor activity. The major finding of this study was intra-accumbal sub-chronic but not single administration of AM251 as a CB1 receptor antagonist dose-dependently induced the rewarding behavior of morphine at its ineffective dose in rats. On the other hand, our result also showed that neither administration of different doses of morphine nor bilateral intra-accumbal administration of CB1 receptor antagonist can affect the locomotor activity in this study. This is in agreement with other evidence indicating that the conditioned stimulus is a critical determinant of the form of conditioned locomotor response in a morphine conditioning setup [30]. It is well known that the
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Fig. 2. Effects of (A) single and (B) three days sub-chronic intra-accumbal injection of CB1 receptor antagonist (AM251) on the conditioned place preference of ineffective dose of morphine. Animals received AM251 (5, 25 and 125 ng/0.5 l saline per side) or DMSO (0.5 l/side) as a vehicle on (A) the post-conditioning phase, 5 min before the test and (B) once daily for three days, 5 min before saline injection during sensitization period, respectively. Each point shows the mean ± SEM for 6 rats. *P < 0.05, **P < 0.01 different from the saline control group. † P < 0.05; †† P < 0.01 different from the vehicle (DMSO) group.
plasmalemmal CB1 receptor labeling is usually seen near asymmetric excitatory-type synapses on dendritic spines in both the NAc shell and core [26]. The accumbens has dense projections carrying GABA to several brain regions. The glutamatergic afferents to the NAc control the firing of the NAc GABAergic neurons, which in turn inhibit the dopaminergic neurons of the VTA [25]. Many GABAergic neurons in the NAc also contain -opioid receptors [31]. The CB1-labeled terminals also formed symmetric, inhibitorytype synapses on dendritic shafts expressing -opioid receptors. Since cannabinoids potently inhibit GABA release in the NAc [12], this latter distribution would facilitate cannabinoid disinhibition of the opiate-sensitive output neurons [24]. However, the intensity and quality of behavioral output are strongly influenced by both dopaminergic and glutamatergic input to the accumbens, and activity at these synapses produces morphological changes in the dendrites of accumbens GABAergic spiny cells [14].
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preformed, and they show an enhanced response to morphine. However our previous paper [1] indicated that AM251 in combination with morphine significantly and dose-dependently decreased the sensitization to morphine in the rat. In agreement with us, De Vries and Schoffelmeer [7] and Maldonado et al. [16] showed that the endocannabinoid system is clearly involved in the behavioral effects of drugs of abuse. So, regarding these studies, we suggest that this induction of sensitization may be influenced by the alteration in the endogenous cannabinoids such as anandamide and 2-arachydonyl glycerol. Robbe et al. [25] indicated that AM251 alone significantly increased extracellular NAc glutamate but not dopamine or GABA, suggesting that CB1 receptors exert tonic inhibition on glutamate release. Navarro et al. [21] also indicated that the CB1 cannabinoid receptor antagonist, SR141716A, induces withdrawal in morphine-dependent rats. It is interesting to note that SR141716A is ineffective in blocking the dopamine-releasing effect of opiates in the NAc [32]. In contrast, some previous studies have been described that cannabinoid CB1 receptor knockout mice did not self-administer morphine [5] or develop morphine-induced CPP, but they reported that other important effects of morphine were not affected by the absence of the CB1 receptor [19]. Surprisingly De Vries et al. [6] and Solinas et al. [29] indicated that SR141716A markedly reduced responding for intravenous heroin injections in rats. Taken together our result indicated that AM251, when administered by itself, could induce place preference in saline treated rats. Some previous studies showed that there is a down-regulation in all three types of opioid receptor protein in morphine treated animals [4]. Several groups have indicated that there is a down-regulation of the CB1 receptor in tolerant rats [9]. So, we suggest that the upregulation of opioid receptor in the absence of the CB1 receptor is involved in our obtained result. It seems that and CB1 receptors may display interactions between antagonists. However, the mechanisms involved in this phenomenon need more investigations. Acknowledgement This work was supported by the grant (No. 86-436-A) from Neuroscience Research Center, Shahid Beheshti University, M.C., Tehran, Iran. References
Fig. 3. Effects of intra-accumbal injections of CB1 receptor antagonist on locomotor activity when animals received AM251 (5, 25 and 125 ng/0.5 l saline per side) or DMSO (0.5 l/side) as a vehicle for (A) three days sub-chronic administration or (B) on the post-conditioning phase, 5 min before the test. Each point shows the mean ± SEM for 6 rats.
Hence, it is most likely that blockade of either or CB1 receptor induces a conformational change in the other receptor that no longer supports the interaction of an antagonist, without however affecting that of an agonist. This apparent allosteric interaction between antagonists strongly suggests the involvement of physically associated and CB1 receptors [27]. The results obtained in the present study showed that the bilateral administration of CB1 receptor antagonist (AM251) into the NAc when given by itself produces sensitization to ineffective dose of morphine and mimics the morphine sensitization as we described in our previous study [1] that sensitized animals received the effective dose of morphine once daily for three constitutive days, 5 min before saline injection during the sensitization period. After five days free of drug, according to sensitization protocol [1] conditioning with an ineffective dose of morphine was
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Sub-chronic administration of AM251, CB1 receptor antagonist, within the nucleus accumbens induced sensitization to morphine in the rat Abbas Haghparast a,∗ , Pegah Azizi a,b , Majid Hassanpour-Ezatti b , Hossein Khorrami a , Nima Naderi a a b
Neuroscience Research Center, Shahid Beheshti University, M.C., P.O. Box 19615-1178, Tehran, Iran Department of Biology, Faculty of Science, Shahed University, Tehran, Iran
a r t i c l e
i n f o
Article history: Received 15 February 2009 Received in revised form 18 June 2009 Accepted 30 September 2009 Keywords: Nucleus accumbens CB1 receptor AM251 Morphine Conditioned place preference Rat
a b s t r a c t It seems that there is a cross-talk between the cannabinoid CB1 and opioid receptors in the process of sensitization to opiates. In present study, we tried to examine the effect of solely administration of AM251, a CB1 receptor antagonist, on conditioned place preference (CPP) by ineffective dose of morphine in the rat. 102 adult male albino Wistar rats were used in these experiments. Subcutaneous administration of morphine (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg) induced CPP only at the doses of ≥5 mg/kg. The dose of 0.5 mg/kg of morphine was selected as the appropriate (ineffective) dose for induction of CPP in animals which were previously received AM251 (5, 25 and 125 ng/0.5 l per side) once daily for three days as a sub-chronic administration or those that received a single dose on the test day. Bilateral intra-accumbal sub-chronic but not single administration of AM251 dose-dependently produced sensitization to morphine and induced CPP by ineffective dose of morphine (0.5 mg/kg) in the rat. Bilateral intra-accumbal administration of neither saline nor DMSO (0.5 l/side) had effects on sensitization to morphine. Our findings indicated that CB1 receptors within the nucleus accumbens are involved in the sensitization to morphine in rats. © 2009 Elsevier Ireland Ltd. All rights reserved.
Compounds active at cannabinoid 1 (CB1) receptors have a profound impact on reward in part through the nucleus accumbens (NAc) shell and core [2,23]. Endogenous opioids as well as muopioid receptors are prevalent in the NAc shell and also expressed in the NAc core [17,34]. Several observations show that there are multiple substrates for convergent actions mediated through CB1 and mu-opioid receptors in the NAc [10,13]. Growing evidence suggests that many of the behavioral and physiological effects of opiates are modulated by the brain’s cannabinoid system [15]. Cannabinoid and opioid receptors are co-localized densely in the brain in key areas implicated in reward and addiction [18]. In addition, behavioral data indicate functional links between CB1 cannabinoid receptors and the opioid reward circuitry [28]. Interactions involving cannabinoids and opioids are suggested by their many similar pharmacological properties [18]. Moreover, it is noticeable that the endocannabinoid system might be a component of the brain reward circuitry and thus plays a role not only in cannabinoid addiction [8] but also in dependence to other drugs of abuse [3,11,33]. However, as we showed in our
∗ Corresponding author. Tel.: +98 21 2243 1624; fax: +98 21 2243 1624. E-mail address: [email protected] (A. Haghparast). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.09.062
recent study [1], the bilateral intra-accumbal administration of CB1 receptor antagonist (AM251) during the sensitization period (three days) or single application just before the conditioned place preference (CPP) test dose-dependently reduced the acquisition but lesser the expression of CPP induced by ineffective dose of morphine in morphine-sensitized rats. Therefore, in the present study, we try to determine the effects of intra-accumbal sub-chronic and single administration of AM251 themselves on the sensitization to morphine in rats. Experiments were carried out on adult male three-month old Wistar rats (Pasture Institute, Tehran, Iran) weighing 250 ± 30 g. Animals were housed in groups of three per cage in a 12/12 h light/dark cycle (light on between 7:00 A.M. and 7:00 P.M.) with free access to chow and tap water. All procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication No. 80-23, revised 1996). In the present study the following drugs were used: morphine sulfate (Temad, Tehran, Iran) that was dissolved in sterile saline (0.9%). 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251; Sigma–Aldrich, Germany), as a CB1 receptor antagonist that was dissolved in pure dimethylsulfoxide (DMSO; Sigma–Aldrich, Germany) as a vehicle. The injection volume of drugs was 1 l/rat
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(0.5 l drug solution in each side) over a period of 60 s. Control animals received either saline or DMSO. Rats were anaesthetized with intraperitoneal injection of ketamine (100 mg/kg) plus xylazine (10 mg/kg) and placed in a stereotaxic apparatus, while maintaining the incisor bar at approximately 3.3 mm below horizontal zero. Two stainless-steel, 23-gauge guide cannulae 10 mm in length were aimed at the NAc (between shell and core sub-regions; stereotaxic coordinates [22]: 1.2 mm anterior to the bregma, ±0.8 mm lateral to the sagittal suture and 6.8–7 mm down from top of the skull). Cannulae were secured to anchor jewelers’ screws with dental acrylic. Stainlesssteel stylets were inserted into the guide cannulae to keep them free of debris. All animals were allowed one week to recover from surgery. All microinjections were bilaterally performed. The testing apparatus consisted of three wooden compartments. Two compartments were identical in size (30 cm × 30 cm × 40 cm) but differed in shading and texture. Compartment A was white with black horizontal stripes 2 cm wide on walls and also had a textured floor. Compartment B was black with vertical white stripes 2 cm wide and also had a smooth floor. The third compartment (C) was a red tunnel (30 cm × 15 cm × 40 cm). It protruded from the rear of two large compartments and connected the entrances to them. The CPP paradigm took place on five consecutive days by using an unbiased procedure [20]. The experiment consisted of three distinct phases: pre-conditioning, conditioning and postconditioning. Conditioning score (CPP score) during 10 min (600 s) pre- and post-test was calculated. On day 1 (pre-exposure), each rat was placed separately into the apparatus for 10 min, with free access to all compartments. Animal displacement was recorded and analyzed on this day (pre-test day). In the experimental setup used in this study, animals did not show an unconditioned preference for either of the compartments. Animals were then randomly assigned to one of two groups for place conditioning and 6 animals were used for each subsequent experiment. This phase consisted of a three-day schedule of conditioning sessions. In this phase, animals received three trials in which they experienced the effects of the drugs while confined to one compartment for 45 min and three trials in which they experienced the effects of saline while confined to the other compartment by closing the removable wall. Access to the compartments was blocked on these days. On the 5th day (test day) the partition was removed, and the rats could access the entire apparatus. The mean time spent for each rat in both compartments during a 10-min period was recorded. In order to calculate the conditioning score, the difference in time spent for the drug-paired place and saline-paired place was considered as the preference criteria. Total distance traveled for each animal was also considered as the locomotor activity in control and experimental groups. Conditioning scores represent the time spent in drug-paired compartment minus the time spent in the saline-paired compartment. Animal displacement was recorded by ethovision software (Version 3.1), a video tracking system for automation of behavioral experiments (Noldus Information Technology, the Netherlands). Mean time spent in each compartment of CPP apparatus and total distance traveled during 10 min, both on the pre- and postconditioning phases were measured. It is noticeable that the locomotion was considered, only horizontally, because we tried to show that the obtained results are not due to change in locomotor activity. In these experiments, a dose–response relationship for morphine on conditioned place preference paradigm was established. Subcutaneous (s.c.) administration of different doses of morphine (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg) were tested for induction of CPP
Fig. 1. A typical photomicrograph scan of a coronal section (50 m) showing the guide cannulae tracks and microinjection sites in the nucleus accumbens of rat. aca, anterior commissure, anterior part; AcbC, accumbens nucleus, core; AcbSh, accumbens nucleus, shell; CPu, caudate putamen (striatum); LV, lateral ventricle.
during three days of conditioning. Conditioning score and distance traveled are calculated for each rat during 10 min on the test day. Then the appropriate (ineffective) dose of morphine, that it normally could not be induced CPP, was selected for the next experiments. Control animals received saline (1 ml/kg; s.c.). In order to examine the possible influence of single intraaccumbal injections of AM251 (as a CB1 receptor antagonist) on sensitization to morphine, conditioning with ineffective dose of morphine (0.5 mg/kg; s.c.) was preformed. Then, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally injected into the NAc on the post-conditioning phase, 5 min before the test. In control group, DMSO (0.5 l/side), as a vehicle was bilaterally injected into the NAc instead of AM251. To test the effects of three days sub-chronic administration of CB1 receptor antagonist on the sensitization to morphine, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally microinjected into the NAc once daily for three days, 5 min before saline injection (s.c.) during the sensitization period. After five days free of drug, according to sensitization protocol that has been described in our recent study [1] conditioning with an ineffective dose of morphine (0.5 mg/kg; s.c.) was preformed. In control group, DMSO as a vehicle (0.5 l/side) was bilaterally injected into the NAc instead of AM251 during three days sub-chronic treatment. After the completion of behavioral testing, all animals were deeply anaesthetized with ketamine and xylazine and transcardially perfused with 0.9% saline, followed by 10% buffered formalin. The brains were removed, blocked and cut coronally in 50 m sections stained with Cresyl violet through the cannulae placements. The drug injection sites subsequently examined by an observer unfamiliar with the behavioral data. Injection site was histologically verified (Fig. 1) and plotted on standardized sections derived from the atlas of Paxinos and Watson [22]. Only the animals with correct cannulae placements were included in the data analysis.
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Conditioning score is expressed as mean ± SEM (standard error of mean). Data were processed by commercially available software Graph Pad Prism® 5.0. In order to compare the conditioning scores and distance traveled obtained in all groups (vehicle and experimental groups) one-way analysis of variance (ANOVA) and randomized blocks model followed by post hoc analysis (Dunnett’s or Tukey’s test) were used, as appropriated. P-values less than 0.05 (P < 0.05) were considered to be statistically significant. In this experiment, naive animals were injected with different doses of morphine sulfate (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg; s.c.). The doses of more than 5 mg/kg caused a significant increase in time spent in the drug-paired compartment compared to the saline-paired. [F(6,41) = 11.65, P < 0.0001]. Injection of saline to the animals (saline control group) in the conditioning compartments did not produce any preference or aversion for either place. Therefore, the dose of 0.5 mg/kg of morphine was selected as the appropriate (ineffective) dose for the rest of the experiments in CPP paradigm in rats. In this set of experiment, to determine the effects of intraaccumbal single injection of CB1 receptor antagonist on the CPP of morphine (0.5 mg/kg) in rats, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally injected into the NAc on the test day (post-conditioning phase), 5 min before the test. The control groups received saline (0.5 l/side) or vehicle (DMSO; 0.5 l/side) instead of AM251 into the NAc, bilaterally. One-way ANOVA indicated that microinjection of AM251 (5, 25 and 125 ng/0.5 l DMSO) on the test day, was unable to induce sensitization to morphine (0.5 mg/kg; s.c.) compared to saline and/or DMSO groups [F(4,29) = 1.697, P = 0.1822; Fig. 2A]. To test the effects of three days sub-chronic administration of CB1 receptor antagonist on the CPP by ineffective dose of morphine, AM251 (5, 25 and 125 ng/0.5 l DMSO per side) was bilaterally microinjected into the NAc once daily for three days. One-way ANOVA indicated that microinjection of AM251 (5, 25 and 125 ng/0.5 l DMSO) for three consecutive days as sub-chronic treatment significantly induced sensitization to morphine compared to saline and/or DMSO groups [F(4,29) = 8.639, P = 0.0002] as shown in Fig. 2B. The control groups received saline (0.5 l/side) or vehicle (DMSO; 0.5 l/side) instead of AM251 into the NAc, bilaterally. Data obtained in this set of experiment indicated that bilateral intra-accumbal sub-chronic administration of AM251 dose-dependently produced sensitization to morphine and induced CPP by ineffective dose of morphine (0.5 mg/kg) in the rat. Data obtained in this study revealed that the single or subchronic intra-accumbal administration of different doses of AM251 (5, 25 and 125 ng/0.5 l DMSO per side) and DMSO did not alter locomotor activity in rats. One-way ANOVA followed by Tukey’s multiple comparison test indicated that single [F(4,29) = 0.3169, P = 0.8639; Fig. 3A] or sub-chronic [F(4,29) = 0.2163, P = 0.9268; Fig. 3B] administration of AM251 did not affect on the locomotor activity during 10-min test period (post-conditioning phase) in comparison with that of the saline and/or DMSO (vehicle) control groups. Therefore, in this study, single and sub-chronic intraaccumbal administrations CB1 receptor antagonist (AM251) into the NAc did not impress the conditioning scores because of alteration to the locomotor activity. The major finding of this study was intra-accumbal sub-chronic but not single administration of AM251 as a CB1 receptor antagonist dose-dependently induced the rewarding behavior of morphine at its ineffective dose in rats. On the other hand, our result also showed that neither administration of different doses of morphine nor bilateral intra-accumbal administration of CB1 receptor antagonist can affect the locomotor activity in this study. This is in agreement with other evidence indicating that the conditioned stimulus is a critical determinant of the form of conditioned locomotor response in a morphine conditioning setup [30]. It is well known that the
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Fig. 2. Effects of (A) single and (B) three days sub-chronic intra-accumbal injection of CB1 receptor antagonist (AM251) on the conditioned place preference of ineffective dose of morphine. Animals received AM251 (5, 25 and 125 ng/0.5 l saline per side) or DMSO (0.5 l/side) as a vehicle on (A) the post-conditioning phase, 5 min before the test and (B) once daily for three days, 5 min before saline injection during sensitization period, respectively. Each point shows the mean ± SEM for 6 rats. *P < 0.05, **P < 0.01 different from the saline control group. † P < 0.05; †† P < 0.01 different from the vehicle (DMSO) group.
plasmalemmal CB1 receptor labeling is usually seen near asymmetric excitatory-type synapses on dendritic spines in both the NAc shell and core [26]. The accumbens has dense projections carrying GABA to several brain regions. The glutamatergic afferents to the NAc control the firing of the NAc GABAergic neurons, which in turn inhibit the dopaminergic neurons of the VTA [25]. Many GABAergic neurons in the NAc also contain -opioid receptors [31]. The CB1-labeled terminals also formed symmetric, inhibitorytype synapses on dendritic shafts expressing -opioid receptors. Since cannabinoids potently inhibit GABA release in the NAc [12], this latter distribution would facilitate cannabinoid disinhibition of the opiate-sensitive output neurons [24]. However, the intensity and quality of behavioral output are strongly influenced by both dopaminergic and glutamatergic input to the accumbens, and activity at these synapses produces morphological changes in the dendrites of accumbens GABAergic spiny cells [14].
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preformed, and they show an enhanced response to morphine. However our previous paper [1] indicated that AM251 in combination with morphine significantly and dose-dependently decreased the sensitization to morphine in the rat. In agreement with us, De Vries and Schoffelmeer [7] and Maldonado et al. [16] showed that the endocannabinoid system is clearly involved in the behavioral effects of drugs of abuse. So, regarding these studies, we suggest that this induction of sensitization may be influenced by the alteration in the endogenous cannabinoids such as anandamide and 2-arachydonyl glycerol. Robbe et al. [25] indicated that AM251 alone significantly increased extracellular NAc glutamate but not dopamine or GABA, suggesting that CB1 receptors exert tonic inhibition on glutamate release. Navarro et al. [21] also indicated that the CB1 cannabinoid receptor antagonist, SR141716A, induces withdrawal in morphine-dependent rats. It is interesting to note that SR141716A is ineffective in blocking the dopamine-releasing effect of opiates in the NAc [32]. In contrast, some previous studies have been described that cannabinoid CB1 receptor knockout mice did not self-administer morphine [5] or develop morphine-induced CPP, but they reported that other important effects of morphine were not affected by the absence of the CB1 receptor [19]. Surprisingly De Vries et al. [6] and Solinas et al. [29] indicated that SR141716A markedly reduced responding for intravenous heroin injections in rats. Taken together our result indicated that AM251, when administered by itself, could induce place preference in saline treated rats. Some previous studies showed that there is a down-regulation in all three types of opioid receptor protein in morphine treated animals [4]. Several groups have indicated that there is a down-regulation of the CB1 receptor in tolerant rats [9]. So, we suggest that the upregulation of opioid receptor in the absence of the CB1 receptor is involved in our obtained result. It seems that and CB1 receptors may display interactions between antagonists. However, the mechanisms involved in this phenomenon need more investigations. Acknowledgement This work was supported by the grant (No. 86-436-A) from Neuroscience Research Center, Shahid Beheshti University, M.C., Tehran, Iran. References
Fig. 3. Effects of intra-accumbal injections of CB1 receptor antagonist on locomotor activity when animals received AM251 (5, 25 and 125 ng/0.5 l saline per side) or DMSO (0.5 l/side) as a vehicle for (A) three days sub-chronic administration or (B) on the post-conditioning phase, 5 min before the test. Each point shows the mean ± SEM for 6 rats.
Hence, it is most likely that blockade of either or CB1 receptor induces a conformational change in the other receptor that no longer supports the interaction of an antagonist, without however affecting that of an agonist. This apparent allosteric interaction between antagonists strongly suggests the involvement of physically associated and CB1 receptors [27]. The results obtained in the present study showed that the bilateral administration of CB1 receptor antagonist (AM251) into the NAc when given by itself produces sensitization to ineffective dose of morphine and mimics the morphine sensitization as we described in our previous study [1] that sensitized animals received the effective dose of morphine once daily for three constitutive days, 5 min before saline injection during the sensitization period. After five days free of drug, according to sensitization protocol [1] conditioning with an ineffective dose of morphine was
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