Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 83–90
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The hippocampal NMDA receptors may be involved in acquisition, but not expression of ACPA-induced place preference Mohammad Nasehi a,⁎, Elmira Sharaf-Dolgari b, Mohaddeseh Ebrahimi-Ghiri c, Mohammad-Reza Zarrindast a,d,e,f,g,⁎⁎ a Neuroscience and Cognitive Research Center (NCRC), Medical Genomics Research Center and School of Advanced Sciences in Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran b Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Northern branch, Tehran, Iran c Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran d Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran e Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran f Institute for Cognitive Science Studies (ICSS), Tehran, Iran g School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
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Article history: Received 6 April 2015 Received in revised form 23 May 2015 Accepted 4 June 2015 Available online 11 June 2015 Keywords: ACPA CA1 region Conditioned place preference D-AP7 NMDA
a b s t r a c t Numerous studies have investigated the functional interactions between the endocannabinoid and glutamate systems in the hippocampus. The present study was made to test whether N-methyl-D-aspartate (NMDA) receptors of the CA1 region of the dorsal hippocampus (CA1) are implicated in ACPA (a selective cannabinoid CB1 receptor agonist)-induced place preference. Using a 3-day schedule of conditioning, it was found that intraperitoneal (i.p.) administration of ACPA (0.02 mg/kg) caused a significant conditioned place preference (CPP) in male albino NMRI mice. Intra-CA1 microinjection of the NMDA or D-[1]-2-amino-7-Phosphonoheptanoic acid (D-AP7, NMDA receptor antagonist), failed to induce CPP or CPA (condition place aversion), while NMDA (0.5 μg/mouse) potentiated the ACPA (0.01 mg/kg)-induced CPP; and D-AP7 (a specific NMDA receptor antagonist; 0.5 and 1 μg/mouse) reversed the ACPA (0.02 mg/kg)-induced CPP. Moreover, microinjection of different doses of glutamatergic agents on the testing day did not alter the expression of ACPA-induced place preference. None of the treatments, with the exception of ACPA (0.04 mg/kg), had an effect on locomotor activity. In conclusion, these observations provide evidence that glutamate NMDA receptors of the CA1 may be involved in the potentiation of ACPA rewarding properties in the acquisition, but not expression, of CPP in mice. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Mesolimbic dopamine (DA) neurons originated from the ventral tegmental area (VTA) and projected to the nucleus accumbens (NAc) are main components of the brain reward system (Schultz, Dayan and Montague, 1997; McBride, Murphy and Ikemoto, 1999; Cohen et al., 2012). The natural rewards as well as the reinforcing actions of abused drugs are mediated by the release of DA in the NAc (Robinson and Berridge, 1993; Legault, Rompre and Wise, 2000). There is also report indicating that midbrain neurons contain the machinery for the Abbreviations: ACPA, Arachidonylcyclopropylamide; NMDA, N-Methyl-D-aspartate; CPP, Conditioned Place Preference; CPA, Condition Place Aversion; D-AP7, D-(-)-2amino-7-phosphonoheptanoic acid. ⁎ Corresponding author. Tel./fax: +98 21 66402569. ⁎⁎ Correspondence to: M.-R. Zarrindast, Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, P.O.Box 13145-784. Tel./ fax: +98 21 66402569. E-mail addresses: [email protected] (M. Nasehi), [email protected] (M.-R. Zarrindast).
http://dx.doi.org/10.1016/j.pnpbp.2015.06.004 0278-5846/© 2015 Elsevier Inc. All rights reserved.
synthesis and degradation of the endocannabinoid (Matyas et al., 2008). In addition, cannabinoid CB1 receptors (CB1Rs) are located on axon terminals impinging upon these DA neurons (Melis et al., 2004; Matyas et al., 2008). It seems that endocannabinoids modify reward behavior through actions in the VTA (Wang and Lupica, 2014). The endocannabinoid molecules in CNS, through acting on CB1Rs, inhibit the release of neurotransmitters such as GABA and glutamate (Alger, 2002; Riegel and Lupica, 2004). The dorsal hippocampus, as a limbic brain structure, receives collateral DA innervation from the dopamine projection. Also, CB1Rs in the dorsal hippocampus are prevalent in inhibitory and in some excitatory-type terminals (Freund, Katona and Piomelli, 2003; Bodor et al., 2005; El Khoury et al., 2012). In addition, this structure is involved in mediating reward-related learning (Rezayof et al., 2003), in a way that its experimental inactivation can block conditioned place preference (CPP) induced by psychostimulants (Meyers, Zavala and Neisewander, 2003; Shen, Meredith and Napier, 2006; Sakurai, Yu and Tan, 2007). Moreover, it has been suggested that cannabinoid receptor
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activation indirectly impairs long-term potentiation (LTP) and longterm depression (LTD) in hippocampal CA1 neurons. It has been shown that inhibition of neurotransmitter release from pre-synaptic membrane to a level below can block induction of post-synaptic depolarization via inhibition of Mg2 + removing from NMDA receptor (Misner and Sullivan, 1999). There is suggestion that the enhancement of NMDA-mediated hippocampal outputs activate NAc neurons, which promote behaviors critically involved in the reward system (Botreau, Paolone and Stewart, 2006). Furthermore, our previous study suggested that NMDA receptors of dorsal hippocampus are involved in the acquisition of morphineinduced CPP (Zarrindast et al., 2007). With the view of the insights including (1) expression of cannabinoid CB1 receptors and NMDA receptors in the CA1 region of the dorsal hippocampus, (2) the role of the dorsal hippocampus (CA1 region) in rewarding behaviors, and (3) assessment of the rewarding properties of drugs by CPP test (Tzschentke, 2007), the aim of the current investigation was to examine the role of NMDA receptors of the dorsal hippocampal CA1 region in mediating arachidonylcyclopropylamide (ACPA) reward. Therefore, we studied whether the acquisition and expression of ACPAinduced place preference could be affected by intra-hippocampus microinjections of NMDA-receptor agonist and/or antagonist. 2. Materials and methods 2.1. Animals Male albino NMRI mice, weighting 25–30 g at the time surgery, were used. The animals were housed in groups of eight and had free access to standard mouse diet and water except during behavioral experiments. They were kept under the standard laboratory conditions (22 °C, 12-h light: 12-h dark cycle). All mice were acclimatized for at least 1 week before surgery. The experiments were performed between 9:00 am and 5:00 pm. Each animal was used once only. Eight animals were used in each group of experiments. The study was conducted in compliance with the international laws on animal experimentation and approved by the Committee of Ethics of Tehran University of Medical Sciences, Tehran, Iran. All procedures were carried out in accordance with the guidelines for Animal Care and Use of Laboratory Animals (National Institutes of Health Publication No. 85-23, revised 2010). 2.2. Surgery Animals were anesthetized by i.p. injection of ketamine/xylazine mixture (50 and 5 mg/kg, respectively) and placed in a stereotaxic frame (Stoelting Instruments, USA) with flat-skull position. A midline incision was made to retract the skin and the underlying periosteum. Bilateral stainless steel guide cannulae (22 gauge) were implanted 1 mm above the CA1 regions of the dorsal hippocampi according to the stereotaxic coordinates; AP, − 2 mm posterior to the bregma; L, ± 1.6 mm from midline; V, −1.5 mm relative to dura (Paxinos, 2001). The cannulae were anchored to the skull by means of dental cement, after which stainless steel stylets (27 gauge) were inserted into the guide cannulae to maintain patency prior to microinjections (Nasehi et al., 2015a; Nasehi et al., 2015b).
ACPA was injected intraperitoneally (i.p.) at a volume of 10 ml/kg. NMDA and D-AP7 were bilaterally injected into the CA1 region of dorsal hippocampus (intra-CA1) at a volume 1 μl (0.5 μl per each CA1 region). Intra-CA1 injections of the drug or saline were given by lowering a 27gauge injector cannula to extend 1 mm beyond the tip of the guide cannula to the site of injection. The injector cannula was attached to a 2.5 μl Hamilton syringe via a polyethylene tubing. Injection time was 60 s, followed by an additional 60 s to facilitate diffusion of the drug from the tip of the injection cannula (Nasehi et al., 2013; Nasehi et al., 2014). 2.4. CPP protocol and apparatus CPP method draws on Pavlovian learning in order to identify the hedonic properties of drugs and other stimuli. In this procedure, animals are trained to associate a specific environment with experimenteradministered drugs. Following several such conditioning sessions, animals are presented a choice of returning to the drug-paired or a placebo-paired environment. If the drug under study is rewarding, then animals will favor the drug-associated environment. Accordingly, the increased time spent in the drug-paired environment is termed “conditioned place preference” (Bardo and Bevins, 2000). The CPP apparatus was based on one that was used previously (Zarrindast et al., 2005; Ebrahimi-ghiri et al., 2012). Compartments A and B were identical in size (40 × 30 × 30 cm) but differed in shading and texture. Compartment A was white with black horizontal stripes 2 cm wide on the walls and also had a net-like floor. Compartment B was black with vertical white stripes 2 cm wide with a smooth floor. Compartment C (40 × 15 × 30 cm) was painted red and was attached to the rear of compartments A and B; it had removable wooden partitions that separated it from the other compartments. When the partitions were removed, the animal could freely move between the two compartments (A and B) via compartment C. In this apparatus, mice showed no consistent preference for either large compartments (A and B), which is in support of our unbiased CPP paradigm. This method (unbiased design) was similar to that used by Rodriguez De Fonseca et al. (1995). Preference times and locomotor activity were recorded by a video camera with the monitor and a computer-recording system installed in an adjacent room. Raw data of the behaviors were manually analyzed. 2.4.1. Conditioned place preference procedure Place conditioning consisted of a 5-day schedule with three distinct phases: preconditioning, conditioning, and testing. 2.4.1.1. Preconditioning phase. The animals were placed separately in the compartment C for 15 min (900 s), with free access to all compartments. The amount of time spent in each compartment was recorded for 900 s. The position of the mice was defined by the position of their front paws. Animals that showed strong unconditioned aversion (less than 33% of the session time, i.e., 300 s) or preference (more than 67%, i.e., 600 s) for any compartment were discarded. Animals were then randomly assigned to one of two groups for place conditioning. After assigning the compartments, there were no significant differences between time spent in the drug-paired and the vehicle-paired compartments during the preconditioning phase.
2.3. Drugs and injections All the drugs were purchased from Tocris (Tocris, Cookson, Bristol, UK) including ACPA (arachidonylcyclopropylamide; a selective potent CB1 agonist), NMDA (N-ethyl-d-aspartate, a selective NMDA receptor agonist), and D-AP7 (DL-2-amino-7-phosphonoheptanoate, a specific NMDA receptor antagonist). The drugs were dissolved in sterile 0.9% saline, just before the experiment. A pilot study was first designed in order to set the doses used. Control groups received saline injections of the same volume and by the same route.
2.4.1.2. Conditioning phase. Place conditioning phase started 1 day after preconditioning phase. This phase consisted of a 3-day schedule of conditioning sessions. The conditioning training was carried out twice a day each for 45 min with an interval of 6 h for vehicle and ACPA pairing in an alternated morning–afternoon design. 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 vehicle while confined to the other compartment by closing the removable gate.
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2.4.1.3. Testing phase. This phase was carried out on day 5, 1 day after the last conditioning session. Each animal was tested only once. For testing, the removable wall was raised and the animals had free choice in the apparatus for 15 min. The time spent in drug-paired compartment was recorded for each animal and the change of preference was calculated as the difference (in seconds) between the time spent in the drug-paired compartment on the testing day and the time spent in this compartment on the preconditioning day. 2.4.2. Locomotor testing Locomotor testing was carried out on the fifth day of the schedule for rats that received place conditioning, using the CPP apparatus. To measure the locomotor activity, the ground area of the CPP compartments was divided into four equal-sized squares. Locomotion was measured as the number of crossings from one square to another during 15 min. 2.5. Experimental design 2.5.1. Experiment 1. Dose-response effects of place conditioning produced by ACPA In this experiment, four groups (n = 8/ group) of animals were used. Three groups of animals received different doses of ACPA (0.01, 0.02, and 0.04 mg/kg, i.p.) on conditioning days. A separate group of animals received saline (10 ml/kg) in order to confirm that the injection and conditioning schedule was not affecting the time allotment in the apparatus, this group was used as control. Locomotor activity was also measured in the testing phase (Fig. 1). 2.5.2. Experiment 2. Effects of intra-CA1 injection of NMDA on the acquisition of CPP with or without ACPA Four groups of animals (n = 8 in each group), different doses of NMDA (0, 0.125, 0.25, and 0.5 μg/ mouse, intra-CA1), were given just before the administration of saline (10 ml/kg, i.p.), during the conditioning phase. In other groups, animals received the same doses of NMDA immediately before i.p. administration of ACPA (0.01 mg/kg) during the conditioning sessions. Animals were tested 24 h after the last
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conditioning session with no preceding injection. Locomotor activity was also measured in the testing phase (Fig. 2). 2.5.3. Experiment 3. Effects of intra-CA1 injection of D-AP7 on the acquisition of CPP with or without ACPA In four groups of animals (n = 8 in each group), different doses of DAP7 (0, 0.25, 0.5, and 1 μg/mouse, intra-CA1) were given just before the administration of saline (10 ml/kg, i. p.), during the conditioning phase. In other groups, animals received the same doses of D-AP7 immediately before i.p. administration of ACPA (0.02 mg /kg) during the conditioning sessions. Animals were tested 24 h after the last conditioning session with no preceding injection. Locomotor activity was also measured in the testing phase (Fig. 3). 2.5.4. Experiment 4. Effects of NMDA on the expression of ACPA-induced place preference In this experiment, eight groups of animals were used. In four groups, the animals underwent the experimental procedure of place conditioning with saline (10 ml/kg, i.p.) and the other four groups underwent the experimental procedure of place conditioning with ACPA (0.01 mg/kg, i.p.). On the 5th day, 5 min before testing, the groups were injected with NMDA (0, 0.125, 0.25, and 0.5 μg/mouse, intra-CA1). Locomotor activity was also evaluated during the testing phase in these groups (Fig. 4). 2.5.5. Experiment 5. Effects of D-AP7 on the expression of ACPA-induced place preference In this experiment, eight groups of animals were used. In four groups, the animals underwent the experimental procedure of place conditioning with saline (10 ml/kg, i.p.) and the other four groups underwent the experimental procedure of place conditioning with ACPA (0.02 mg/kg, i.p.). On the 5th day, 5 min before testing, the groups were injected with D-AP7 (0, 0.25, 0.5, and 1 μg/mouse, intra-CA1). Locomotor activity was also evaluated during the testing phase in these groups (Fig. 5). 2.6. Verification of cannulae placements When behavioral testing sessions were concluded, animals were killed by anesthetic overdose and received microinjection of methylene blue (1%) at the same volume as drug microinjections. This was to mark the site of the drug injection. Mice brains were removed and injection sites were histologically verified according to the atlas of Paxinos and Franklin, 2001. Data from the animals with injection sites located outside the CA1 regions were not used in the analysis. 2.7. Statistical analysis The between-groups comparisons were made using the two-way analysis of variance (two-way ANOVA) in SPSS 17.0 software. Drug was defined as ACPA factor and dose as NMDA or D-AP7 factor in the experiments 2 and 4 or 3 and 5, respectively. Following a significant F value, post hoc analysis (Tukey's test) was performed for specific inter-group comparisons. Post hoc tests were not required in the absence of a significant interaction. A difference with P b 0.05 between the experimental groups was considered statistically significant. We used the Sigma plot 12 software to draw figures. 3. Results
Fig. 1. Place preference produced by ACPA. Different doses of ACPA (0.01, 0.02, and 0.04 mg/kg) and saline (10 ml/kg) were administered intraperitoneally (i.p.) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. *P b 0.05 and **P b 0.01different from the saline control group.
3.1. Dose–response effects of place conditioning produced by ACPA Fig. 1A demonstrates that intraperitoneal administration of ACPA (0.01, 0.02, and 0.04 mg/kg, i.p.) during the conditioning phase induced a CPP for the drug-associated place. One-way ANOVA showed that ACPA caused a significant place preference [F (3, 28) = 9.68, P b 0.001].
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Further analysis showed that the maximum response was obtained with 0.02 mg/kg of ACPA. Furthermore, Fig. 1B indicates that ACPA induced an increased significant locomotion [F (3, 28) = 9.68, P b 0.001]. Post hoc analysis showed that the higher dose of ACPA increased locomotor activity. 3.2. Effects of intra-CA1 injection of NMDA on the acquisition of CPP with or without ACPA Fig. 2A shows the effects of bilateral intra-CA1 microinjection of NMDA (0.125, 0.25, and 0.5 μg/mouse) with or without ACPA (0.01 mg/kg) on the acquisition of CPP. Two-way ANOVA revealed a significant interaction between NMDA and ACPA in the acquisition of CPP [within group comparison: for Drug, F (1, 56) = 20.43, P b 0.001; Dose, F (3, 56) = 10.36, P b 0.001; and Drug × Dose interaction, F (3, 56) = 2.82, P b 0.05]. Further analysis exhibited that a higher dose of NMDA (0.5 μg/ mouse) in combination with ACPA increased CPP [one-way ANOVA: F (3, 28) = 9.36, P b 0.001]. Fig. 2B shows the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received NMDA alone and those which received NMDA plus ACPA on locomotor activity [within group comparison: for Drug, F (1, 56) = 0.24, P N 0.05; Dose, F (3, 56) = 0.93, P N 0.05; and Drug × Dose interaction, F (3, 56) = 1.03, P N 0.05]. 3.3. Effects of intra-CA1 injection of D-AP7 on the acquisition of CPP with or without ACPA Fig. 3A indicates the effects of bilateral intra-CA1 microinjection of D-AP7 (0.25, 0.5, and 1 μg/mouse) with or without ACPA (0.02 mg/kg) on the acquisition of CPP. Two-way ANOVA revealed a significant interaction between D-AP7 and ACPA in the acquisition of CPP [within group
comparison: for Drug, F (1, 56) = 0.39, P N 0.05; Dose, F (3, 56) = 3.64, P b 0.05; and Drug × Dose interaction, F (3, 56) = 3.12, P b 0.05]. Further analysis revealed that a higher dose of D-AP7 (1 μg/mouse) in combination with ACPA decreased CPP [one-way ANOVA: F (3, 28) = 4.57, P b 0.05]. Fig. 3B illustrates the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received D-AP7 alone and those which received D-AP7 plus ACPA on locomotor activity [within group comparison: for Drug, F (1, 56) = 0.00, P N 0.05; Dose, F (3, 56) = 1.80, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.06, P N 0.05]. 3.4. Effects of NMDA on the expression of ACPA-induced place preference Fig. 4A shows the effects of bilateral intra-CA1 microinjection of NMDA (0.125, 0.25, and 0.5 μg/mouse) with or without ACPA (0.01 mg/kg) on the expression of CPP. Two-way ANOVA revealed no significant interaction between NMDA and ACPA in the expression of CPP [within group comparison: for Drug, F (1, 56) = 5.98, P b 0.05; Dose, F (3, 56) = 2.00, P N 0.05; and Drug × Dose interaction, F (3, 56) = 1.66, P N 0.05]. Fig. 4B shows the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received NMDA alone and those which received NMDA plus ACPA on locomotor activity [within group comparison: for Drug, F (1, 56) = 13.64, P b 0.01; Dose, F (3, 56) = 2.10, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.15, P N 0.05]. 3.5. Effects of D-AP7 on the expression of ACPA-induced place preference Fig. 5A indicates the effects of bilateral intra-CA1 microinjection of DAP7 (0.25, 0.5, and 1 μg/mouse) with or without ACPA (0.02 mg/kg) on
Fig. 2. The effects of bilateral intra-CA1 injection of NMDA, either alone or in combination with ACPA, on the acquisition of a conditioned place preference. The animals received NMDA (0.125, 0.25, and 0.5 μg/Mouse) or saline (1 μl/Mouse) with or without ACPA (0.01 mg/kg, i.p.), in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15 min period. The change of preference was assessed as the difference between the times spent in the drug-paired compartment on the day of testing and the time spent in the drugpaired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. +++P b 0.001 different from the saline/ACPA group.
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Fig. 3. The effects of bilateral intra-CA1 injection of D-AP7, either alone or in combination with ACPA, on the acquisition of a conditioned place preference. The animals received D-AP7 (0.25, 0.5, and 1 μg/mouse) or saline (1 μl/rat) in combination with ACPA (0.02 mg/kg, i.p.) or without ACPA, in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drugpaired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. *P b 0.05 different from the saline/saline group and +P b 0.05 different from the saline/ACPA group.
the expression of CPP. Two-way ANOVA revealed no significant interaction between D-AP7 and ACPA in the expression of CPP [within group comparison: for Drug, F (1, 56) = 49.30, P b 0.001; Dose, F (3, 56) = 0.12, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.42, P N 0.05].
Fig. 5B illustrates the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received D-AP7 alone and those which received D-AP7 plus ACPA on locomotor activity
Fig. 4. The effects of bilateral microinjection of NMDA into the CA1on the expression of ACPA-induced place preference. All animals received ACPA (0.01 mg/kg, i.p.) or saline (10 ml/kg, i.p.) in a 3-day schedule of conditioning. On the test day, the different doses of NMDA (0.125, 0.25, and 0.05 μg/mouse) were administered into the CA1 immediately before testing and each animal was observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group.
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Fig. 5. The effects of bilateral microinjection of D-AP7 into the CA1on the expression of ACPA-induced place preference. All animals received ACPA (0.02 mg/kg, i.p.) or saline (10 ml/kg, i.p.) in a 3-day schedule of conditioning. On the test day, the different doses of D-AP7 (0.25, 0.5, and 1 μg/mouse) were administered into the CA1 immediately before testing, and each animal was observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. *P b 0.05 different from saline/saline group.
[within group comparison: for Drug, F (1, 56) = 3.05, P N 0.05; Dose, F (3, 56) = 0.07, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.90, P N 0.05]. 4. Discussion In the present study, ACPA as a cannabinoid CB1 receptor agonist, in a moderate dose, caused a significant conditioned place preference (CPP), when it was administered intraperitoneally. The higher dose of the drug did not induce place preference, but increased locomotion. It has been reported that cannabinoid receptor agonists induce biphasic effects on movement that are time and dose dependent. There is a report showing that very low doses of the cannabinoid receptor agonist Δ9-tetrahydrocannabinol decrease locomotor activity while higher doses dose-dependently stimulate movement until catalepsy emerges accompanied by decreases in activity (Sanudo-Pena et al., 2000). Indeed, ACPA at dose that increased locomotion did not induce place preference in the present study. Moreover, it is important to note here that our mice were tested in a drug-free state. More specifically, these observations indicate that locomotor activity was not a confounding factor in the interpretation of the present results. It has been suggested that cannabinoids can induce both rewarding and aversive responses in a variety of animal models, such as drug self-administration, intracranial self-stimulation, CPP, and reinstatement procedures. However, aversion is the predominant effect of cannabinoids (Vlachou, Nomikos and Panagis, 2005). Conversely, other investigators have demonstrated unambiguously positive reinforcing effects of Δ9-THC in squirrel monkeys using the intravenous self-administration paradigm (Justinova et al., 2003). Furthermore, in some particular experimental conditions (e.g., pre-exposure to the drug or the homeostatic state of the animal), rewarding effects of cannabinoids can be achieved (Tanda, Munzar and Goldberg, 2000; Valjent and Maldonado, 2000). Furthermore, CB1
receptors have been reported to be involved in the primary reinforcing effects of cannabinoids, alcohol, nicotine, and opioids (Maldonado, Valverde and Berrendero, 2006). In addition, the CB1 receptors are densely expressed in brain regions related to motivation and reward (Chambers, Taylor and Potenza, 2003) and play a modulatory role in the dopamine system (Robbe et al., 2002). There is a general agreement that cannabinoids regulate DA firing via inhibitory CB1 receptors located on GABA and glutamatergic terminals. The net effect being the result of the functional balance between excitatory and inhibitory inputs, generally favoring a CB1-GABAergic-mediated disinhibition of DA neuronal activation (El Khoury et al., 2012). In addition to the excitatory effect of this CB1-GABA disinhibitory component, cannabinoids with affinity for TRPV1 receptors can also increase DA firing rate through excitatory TRPV1 receptors, most probably present in glutamatergic terminals (Marinelli et al., 2003; Marinelli et al., 2007). Our present data indicate that the bilateral injections of NMDA into the dorsal hippocampus failed to induce CPP or CPA. Moreover, pretreatment administration of a higher dose of NMDA with a subthreshold dose of ACPA could potentiate ACPA-induced place preference. It has been widely accepted that drugs of abuse produce their reinforcing effects through increase in dopamine release in the NAc (Wise, 2004; Pierce and Kumaresan, 2006). In addition, there are glutamatergic projections from the hippocampus to the NAc (Floresco, Todd and Grace, 2001), which regulate DA transmission in this structure (Everitt and Robbins, 2005). It is still not clear if CB1 in forebrain GABAergic or in cortical glutamatergic neurons modulate the rewarding properties of CB1 agonist in the CPP. The endocannabinoid system, mainly through CB1 receptors located on glutamatergic or GABAergic neurons, controls both excitatory and inhibitory neurotransmissions, thereby modulated dopaminergic functions. Thus, full genetic deletion or pharmacological blockade of CB1 has revealed that the endocannabinoid system modulates reward-related behaviors. There is a general agreement that CB1
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receptors mediate the influence of conditioned factors on drug seeking mainly through modulation of glutamatergic neurotransmission. For example, the alteration of glutamate-mediated transmission, especially the increase of glutamatergic transmission in the NAc, may promote the seeking and relapse of abused drugs (Zhu, Rockhold and Ho, 1998; Xi et al., 2006). Considering these findings, one may conclude that intraCA1 injection of NMDA activates glutamatergic projections to the NAc and, in turn, potentiate ACPA effect on dopamine release in this structure. Previously, we reported that injection of NMDA into the dorsal hippocampus potentiates morphine-CPP (Zarrindast et al., 2007). These results confirm that cannabinoids act on brain reward processes and reward-related behaviors in strikingly similar fashion to other addictive drugs (Gardner, 2002). The present results also showed that the bilateral microinjection of D-AP7, a specific NMDA receptor antagonist, into the CA1 region of dorsal hippocampus alone, did not induce a significant place preference or aversion by itself, while co-administration of the antagonist with ACPA, during the conditioning phase, inhibited the ACPA (0.02 mg/kg)-induced place preference. Several behavioral studies have examined the role of NMDARs in the development of addiction-related memory, primarily by co-administering dizocilpine (MK801), a noncompetitive NMDAR antagonist, with psychostimulants (Wolf, 1998). Coadministration of MK801 prevents the development of sensitization to cocaine (Parada and Soares-da-Silva, 2000), amphetamine (Ranaldi et al., 2000), and methamphetamine (Ohno and Watanabe, 1995). Moreover, MK801 similarly prevents the development of cocaine, amphetamine, and methamphetamine-induced CPP, a prominent associative memory model of drug-seeking behavior (Kim and Jang, 1997). As previously mentioned, increase in dopamine release in the NAc represents a common feature for the reinforcing properties of drugs of abuse (Pierce and Kumaresan, 2006). Moreover, glutamatergic projections from the hippocampus to the NAc have a modulatory control on the NAc neurons (Bardgett and Henry, 1999). It has been reported that endocannabinoid function through CB1 receptors was necessary for long-term depression (LTD-a type of synaptic plasticity) to be seen in glutamatergic inputs to the GABAergic medium spiny neurons of the NAc (Gerdeman et al., 2003), and synaptic plasticity may be involved in the learning processes (Izquierdo et al., 2006). Therefore, one may propose that D-AP7 may alter modulatory role of ACPA on dopamine release in the NAc so that induces a CPA response. Another explanation for the results of the present study would be that the blockade of the hippocampal NMDA receptors may decrease reward-related learning induced by ACPA and block the establishment of the association between drug-reward and conditioning compartmental cues. Intra-CA1 administration of NMDA or D-AP7 immediately before the test did not induce any change on the expression of ACPA-induced place preference. Collectively, the present data suggest that NMDA receptors of dorsal hippocampus may be important for the development but not the expression of ACPA-induced place preference. On the other hand, intra-CA1 injection of the different doses of NMDA or D-AP7 during the conditioning phase alone had no effect on the locomotor activity in the testing phase. Therefore, the interactions of locomotor activity with the results obtained seem unlikely. From the results of this study, it is concluded that the acquisition of ACPAinduced place preference, but not the expression, may be associated with the glutamatergic activation modulated by NMDA receptors of the CA1 region of hippocampus, because the ACPA reward was potentiated by NMDA and blocked by D-AP7. Moreover, the present data suggest that the dorsal hippocampal NMDA receptors may play an important role in mediating reward-related learning induced by activation of cannabinoid CB1 receptors. Acknowledgement Authors wish to thank the Iran National Science Foundation (INSF) for providing financial support to this project.
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References Alger BE. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 2002;68:247–86. Bardgett ME, Henry JD. Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D1 and D2 receptors. Neuroscience 1999; 94:59–70. Bardo MT, Bevins RA. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 2000;153:31–43. Bodor AL, Katona I, Nyiri G, Mackie K, Ledent C, Hajos N, et al. Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types. J Neurosci 2005;25:6845–56. Botreau F, Paolone G, Stewart J. d-Cycloserine facilitates extinction of a cocaine-induced conditioned place preference. Behav Brain Res 2006;172:173–8. Chambers RA, Taylor JR, Potenza MN. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 2003;160: 1041–52. Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 2012;482:85–8. Ebrahimi-ghiri M, Nasehi M, Rostami P, Mohseni-Kouchesfehani H, Zarrindast MR. The effect of cholestasis on rewarding and exploratory behaviors induced by opioidergic and dopaminergic agents in mice. Arch Iran Med 2012;15:617–24. El Khoury MA, Gorgievski V, Moutsimilli L, Giros B, Tzavara ET. Interactions between the cannabinoid and dopaminergic systems: evidence from animal studies. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:36–50. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 2005;8:1481–9. Floresco SB, Todd CL, Grace AA. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 2001;21:4915–22. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 2003;83:1017–66. Gardner EL. Addictive potential of cannabinoids: the underlying neurobiology. Chem Phys Lipids 2002;121:267–90. Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM. It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci 2003;26:184–92. Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M. Different molecular cascades in different sites of the brain control memory consolidation. Trends Neurosci 2006;29:496–505. Justinova Z, Tanda G, Redhi GH, Goldberg SR. Self-administration of delta9tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl) 2003;169:135–40. Kim HS, Jang CG. MK-801 inhibits methamphetamine-induced conditioned place preference and behavioral sensitization to apomorphine in mice. Brain Res Bull 1997;44:221–7. Legault M, Rompre PP, Wise RA. Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area. J Neurosci 2000;20:1635–42. Maldonado R, Valverde O, Berrendero F. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 2006;29:225–32. Marinelli S, Di Marzo V, Berretta N, Matias I, Maccarrone M, Bernardi G, et al. Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J Neurosci 2003;23:3136–44. Marinelli S, Di Marzo V, Florenzano F, Fezza F, Viscomi MT, van der Stelt M, et al. Narachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors. Neuropsychopharmacology 2007;32:298–308. Matyas F, Urban GM, Watanabe M, Mackie K, Zimmer A, Freund TF, et al. Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology 2008;54:95–107. McBride WJ, Murphy JM, Ikemoto S. Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies. Behav Brain Res 1999;101:129–52. Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL. Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 2004;24:53–62. Meyers RA, Zavala AR, Neisewander JL. Dorsal, but not ventral, hippocampal lesions disrupt cocaine place conditioning. Neuroreport 2003;14:2127–31. Misner DL, Sullivan JM. Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons. J Neurosci 1999;19:6795–805. Nasehi M, Amin-Yavari S, Ebrahimi-Ghiri M, Torabi-Nami M, Zarrindast MR. The dual effect of CA1 NMDA receptor modulation on ACPA-induced amnesia in step-down passive avoidance learning task. Eur Neuropsychopharmacol 2015a;25:557–65. Nasehi M, Jamshidi-Mehr M, Khakpai F, Zarrindast MR. Possible involvement of CA1 5HT1B/1D and 5-HT2A/2B/2C receptors in harmaline-induced amnesia. Pharmacol Biochem Behav 2014;125:70–7. Nasehi M, Ketabchi M, Khakpai F, Zarrindast MR. The effect of CA1 dopaminergic system in harmaline-induced amnesia. Neuroscience 2015b;285:47–59. Nasehi M, Mashaghi E, Khakpai F, Zarrindast MR. Suggesting a possible role of CA1 histaminergic system in harmane-induced amnesia. Neurosci Lett 2013;556:5–9. Ohno M, Watanabe S. Nitric oxide synthase inhibitors block behavioral sensitization to methamphetamine in mice. Eur J Pharmacol 1995;275:39–44. Parada A, Soares-da-Silva P. The dopamine antagonist sch 23390 reverses dizocilpineinduced blockade of cocaine sensitization. Neuropharmacology 2000;39:1645–52. Paxinos G, Franklin KBJ. The Mouse Brain in Stereotaxic Coordinates. 2nd Ed. Academic Press; 2001.
90
M. Nasehi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 83–90
Pierce RC, Kumaresan V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 2006;30:215–38. Ranaldi R, Munn E, Neklesa T, Wise RA. Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK801 (dizocilpine). Psychopharmacology (Berl) 2000;151:192–201. Rezayof A, Zarrindast MR, Sahraei H, Haeri-Rohani A. Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats. J Psychopharmacol 2003;17:415–23. Riegel AC, Lupica CR. Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area. J Neurosci 2004;24:11070–8. Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci U S A 2002;99:8384–8. Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 1993;18:247–91. Rodriguez De Fonseca F, Rubio P, Martin-Calderon JL, Caine SB, Koob GF, Navarro M. The dopamine receptor agonist 7-OH-DPAT modulates the acquisition and expression of morphine-induced place preference. Eur J Pharmacol 1995;274:47–55. Sakurai S, Yu L, Tan SE. Roles of hippocampal N-methyl-D-aspartate receptors and calcium/calmodulin-dependent protein kinase II in amphetamine-produced conditioned place preference in rats. Behav Pharmacol 2007;18:497–506. Sanudo-Pena MC, Romero J, Seale GE, Fernandez-Ruiz JJ, Walker JM. Activational role of cannabinoids on movement. Eur J Pharmacol 2000;391:269–74. Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science 1997;275:1593–9. Shen F, Meredith GE, Napier TC. Amphetamine-induced place preference and conditioned motor sensitization requires activation of tyrosine kinase receptors in the hippocampus. J Neurosci 2006;26:11041–51.
Tanda G, Munzar P, Goldberg SR. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 2000;3:1073–4. Tzschentke TM. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 2007;12:227–462. Valjent E, Maldonado R. A behavioural model to reveal place preference to delta 9tetrahydrocannabinol in mice. Psychopharmacology (Berl) 2000;147:436–8. Vlachou S, Nomikos GG, Panagis G. CB1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat. Psychopharmacology (Berl) 2005;179: 498–508. Wang H, Lupica CR. Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes. Prog Neuropsychopharmacol Biol Psychiatry 2014;52:24–7. Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci 2004;5:483–94. Wolf ME. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 1998;54:679–720. Xi ZX, Gilbert JG, Peng XQ, Pak AC, Li X, Gardner EL. Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J Neurosci 2006;26:8531–6. Zarrindast MR, Lashgari R, Rezayof A, Motamedi F, Nazari-Serenjeh F. NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference. Eur J Pharmacol 2007;568:192–8. Zarrindast MR, Nasehi M, Rostami P, Rezayof A, Fazli-Tabaei S. Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference. Behav Pharmacol 2005;16:85–92. Zhu H, Rockhold RW, Ho IK. The role of glutamate in physical dependence on opioids. Jpn J Pharmacol 1998;76:1–14.
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The hippocampal NMDA receptors may be involved in acquisition, but not expression of ACPA-induced place preference Mohammad Nasehi a,⁎, Elmira Sharaf-Dolgari b, Mohaddeseh Ebrahimi-Ghiri c, Mohammad-Reza Zarrindast a,d,e,f,g,⁎⁎ a Neuroscience and Cognitive Research Center (NCRC), Medical Genomics Research Center and School of Advanced Sciences in Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran b Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Northern branch, Tehran, Iran c Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran d Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran e Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran f Institute for Cognitive Science Studies (ICSS), Tehran, Iran g School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
a r t i c l e
i n f o
Article history: Received 6 April 2015 Received in revised form 23 May 2015 Accepted 4 June 2015 Available online 11 June 2015 Keywords: ACPA CA1 region Conditioned place preference D-AP7 NMDA
a b s t r a c t Numerous studies have investigated the functional interactions between the endocannabinoid and glutamate systems in the hippocampus. The present study was made to test whether N-methyl-D-aspartate (NMDA) receptors of the CA1 region of the dorsal hippocampus (CA1) are implicated in ACPA (a selective cannabinoid CB1 receptor agonist)-induced place preference. Using a 3-day schedule of conditioning, it was found that intraperitoneal (i.p.) administration of ACPA (0.02 mg/kg) caused a significant conditioned place preference (CPP) in male albino NMRI mice. Intra-CA1 microinjection of the NMDA or D-[1]-2-amino-7-Phosphonoheptanoic acid (D-AP7, NMDA receptor antagonist), failed to induce CPP or CPA (condition place aversion), while NMDA (0.5 μg/mouse) potentiated the ACPA (0.01 mg/kg)-induced CPP; and D-AP7 (a specific NMDA receptor antagonist; 0.5 and 1 μg/mouse) reversed the ACPA (0.02 mg/kg)-induced CPP. Moreover, microinjection of different doses of glutamatergic agents on the testing day did not alter the expression of ACPA-induced place preference. None of the treatments, with the exception of ACPA (0.04 mg/kg), had an effect on locomotor activity. In conclusion, these observations provide evidence that glutamate NMDA receptors of the CA1 may be involved in the potentiation of ACPA rewarding properties in the acquisition, but not expression, of CPP in mice. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Mesolimbic dopamine (DA) neurons originated from the ventral tegmental area (VTA) and projected to the nucleus accumbens (NAc) are main components of the brain reward system (Schultz, Dayan and Montague, 1997; McBride, Murphy and Ikemoto, 1999; Cohen et al., 2012). The natural rewards as well as the reinforcing actions of abused drugs are mediated by the release of DA in the NAc (Robinson and Berridge, 1993; Legault, Rompre and Wise, 2000). There is also report indicating that midbrain neurons contain the machinery for the Abbreviations: ACPA, Arachidonylcyclopropylamide; NMDA, N-Methyl-D-aspartate; CPP, Conditioned Place Preference; CPA, Condition Place Aversion; D-AP7, D-(-)-2amino-7-phosphonoheptanoic acid. ⁎ Corresponding author. Tel./fax: +98 21 66402569. ⁎⁎ Correspondence to: M.-R. Zarrindast, Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, P.O.Box 13145-784. Tel./ fax: +98 21 66402569. E-mail addresses: [email protected] (M. Nasehi), [email protected] (M.-R. Zarrindast).
http://dx.doi.org/10.1016/j.pnpbp.2015.06.004 0278-5846/© 2015 Elsevier Inc. All rights reserved.
synthesis and degradation of the endocannabinoid (Matyas et al., 2008). In addition, cannabinoid CB1 receptors (CB1Rs) are located on axon terminals impinging upon these DA neurons (Melis et al., 2004; Matyas et al., 2008). It seems that endocannabinoids modify reward behavior through actions in the VTA (Wang and Lupica, 2014). The endocannabinoid molecules in CNS, through acting on CB1Rs, inhibit the release of neurotransmitters such as GABA and glutamate (Alger, 2002; Riegel and Lupica, 2004). The dorsal hippocampus, as a limbic brain structure, receives collateral DA innervation from the dopamine projection. Also, CB1Rs in the dorsal hippocampus are prevalent in inhibitory and in some excitatory-type terminals (Freund, Katona and Piomelli, 2003; Bodor et al., 2005; El Khoury et al., 2012). In addition, this structure is involved in mediating reward-related learning (Rezayof et al., 2003), in a way that its experimental inactivation can block conditioned place preference (CPP) induced by psychostimulants (Meyers, Zavala and Neisewander, 2003; Shen, Meredith and Napier, 2006; Sakurai, Yu and Tan, 2007). Moreover, it has been suggested that cannabinoid receptor
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activation indirectly impairs long-term potentiation (LTP) and longterm depression (LTD) in hippocampal CA1 neurons. It has been shown that inhibition of neurotransmitter release from pre-synaptic membrane to a level below can block induction of post-synaptic depolarization via inhibition of Mg2 + removing from NMDA receptor (Misner and Sullivan, 1999). There is suggestion that the enhancement of NMDA-mediated hippocampal outputs activate NAc neurons, which promote behaviors critically involved in the reward system (Botreau, Paolone and Stewart, 2006). Furthermore, our previous study suggested that NMDA receptors of dorsal hippocampus are involved in the acquisition of morphineinduced CPP (Zarrindast et al., 2007). With the view of the insights including (1) expression of cannabinoid CB1 receptors and NMDA receptors in the CA1 region of the dorsal hippocampus, (2) the role of the dorsal hippocampus (CA1 region) in rewarding behaviors, and (3) assessment of the rewarding properties of drugs by CPP test (Tzschentke, 2007), the aim of the current investigation was to examine the role of NMDA receptors of the dorsal hippocampal CA1 region in mediating arachidonylcyclopropylamide (ACPA) reward. Therefore, we studied whether the acquisition and expression of ACPAinduced place preference could be affected by intra-hippocampus microinjections of NMDA-receptor agonist and/or antagonist. 2. Materials and methods 2.1. Animals Male albino NMRI mice, weighting 25–30 g at the time surgery, were used. The animals were housed in groups of eight and had free access to standard mouse diet and water except during behavioral experiments. They were kept under the standard laboratory conditions (22 °C, 12-h light: 12-h dark cycle). All mice were acclimatized for at least 1 week before surgery. The experiments were performed between 9:00 am and 5:00 pm. Each animal was used once only. Eight animals were used in each group of experiments. The study was conducted in compliance with the international laws on animal experimentation and approved by the Committee of Ethics of Tehran University of Medical Sciences, Tehran, Iran. All procedures were carried out in accordance with the guidelines for Animal Care and Use of Laboratory Animals (National Institutes of Health Publication No. 85-23, revised 2010). 2.2. Surgery Animals were anesthetized by i.p. injection of ketamine/xylazine mixture (50 and 5 mg/kg, respectively) and placed in a stereotaxic frame (Stoelting Instruments, USA) with flat-skull position. A midline incision was made to retract the skin and the underlying periosteum. Bilateral stainless steel guide cannulae (22 gauge) were implanted 1 mm above the CA1 regions of the dorsal hippocampi according to the stereotaxic coordinates; AP, − 2 mm posterior to the bregma; L, ± 1.6 mm from midline; V, −1.5 mm relative to dura (Paxinos, 2001). The cannulae were anchored to the skull by means of dental cement, after which stainless steel stylets (27 gauge) were inserted into the guide cannulae to maintain patency prior to microinjections (Nasehi et al., 2015a; Nasehi et al., 2015b).
ACPA was injected intraperitoneally (i.p.) at a volume of 10 ml/kg. NMDA and D-AP7 were bilaterally injected into the CA1 region of dorsal hippocampus (intra-CA1) at a volume 1 μl (0.5 μl per each CA1 region). Intra-CA1 injections of the drug or saline were given by lowering a 27gauge injector cannula to extend 1 mm beyond the tip of the guide cannula to the site of injection. The injector cannula was attached to a 2.5 μl Hamilton syringe via a polyethylene tubing. Injection time was 60 s, followed by an additional 60 s to facilitate diffusion of the drug from the tip of the injection cannula (Nasehi et al., 2013; Nasehi et al., 2014). 2.4. CPP protocol and apparatus CPP method draws on Pavlovian learning in order to identify the hedonic properties of drugs and other stimuli. In this procedure, animals are trained to associate a specific environment with experimenteradministered drugs. Following several such conditioning sessions, animals are presented a choice of returning to the drug-paired or a placebo-paired environment. If the drug under study is rewarding, then animals will favor the drug-associated environment. Accordingly, the increased time spent in the drug-paired environment is termed “conditioned place preference” (Bardo and Bevins, 2000). The CPP apparatus was based on one that was used previously (Zarrindast et al., 2005; Ebrahimi-ghiri et al., 2012). Compartments A and B were identical in size (40 × 30 × 30 cm) but differed in shading and texture. Compartment A was white with black horizontal stripes 2 cm wide on the walls and also had a net-like floor. Compartment B was black with vertical white stripes 2 cm wide with a smooth floor. Compartment C (40 × 15 × 30 cm) was painted red and was attached to the rear of compartments A and B; it had removable wooden partitions that separated it from the other compartments. When the partitions were removed, the animal could freely move between the two compartments (A and B) via compartment C. In this apparatus, mice showed no consistent preference for either large compartments (A and B), which is in support of our unbiased CPP paradigm. This method (unbiased design) was similar to that used by Rodriguez De Fonseca et al. (1995). Preference times and locomotor activity were recorded by a video camera with the monitor and a computer-recording system installed in an adjacent room. Raw data of the behaviors were manually analyzed. 2.4.1. Conditioned place preference procedure Place conditioning consisted of a 5-day schedule with three distinct phases: preconditioning, conditioning, and testing. 2.4.1.1. Preconditioning phase. The animals were placed separately in the compartment C for 15 min (900 s), with free access to all compartments. The amount of time spent in each compartment was recorded for 900 s. The position of the mice was defined by the position of their front paws. Animals that showed strong unconditioned aversion (less than 33% of the session time, i.e., 300 s) or preference (more than 67%, i.e., 600 s) for any compartment were discarded. Animals were then randomly assigned to one of two groups for place conditioning. After assigning the compartments, there were no significant differences between time spent in the drug-paired and the vehicle-paired compartments during the preconditioning phase.
2.3. Drugs and injections All the drugs were purchased from Tocris (Tocris, Cookson, Bristol, UK) including ACPA (arachidonylcyclopropylamide; a selective potent CB1 agonist), NMDA (N-ethyl-d-aspartate, a selective NMDA receptor agonist), and D-AP7 (DL-2-amino-7-phosphonoheptanoate, a specific NMDA receptor antagonist). The drugs were dissolved in sterile 0.9% saline, just before the experiment. A pilot study was first designed in order to set the doses used. Control groups received saline injections of the same volume and by the same route.
2.4.1.2. Conditioning phase. Place conditioning phase started 1 day after preconditioning phase. This phase consisted of a 3-day schedule of conditioning sessions. The conditioning training was carried out twice a day each for 45 min with an interval of 6 h for vehicle and ACPA pairing in an alternated morning–afternoon design. 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 vehicle while confined to the other compartment by closing the removable gate.
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2.4.1.3. Testing phase. This phase was carried out on day 5, 1 day after the last conditioning session. Each animal was tested only once. For testing, the removable wall was raised and the animals had free choice in the apparatus for 15 min. The time spent in drug-paired compartment was recorded for each animal and the change of preference was calculated as the difference (in seconds) between the time spent in the drug-paired compartment on the testing day and the time spent in this compartment on the preconditioning day. 2.4.2. Locomotor testing Locomotor testing was carried out on the fifth day of the schedule for rats that received place conditioning, using the CPP apparatus. To measure the locomotor activity, the ground area of the CPP compartments was divided into four equal-sized squares. Locomotion was measured as the number of crossings from one square to another during 15 min. 2.5. Experimental design 2.5.1. Experiment 1. Dose-response effects of place conditioning produced by ACPA In this experiment, four groups (n = 8/ group) of animals were used. Three groups of animals received different doses of ACPA (0.01, 0.02, and 0.04 mg/kg, i.p.) on conditioning days. A separate group of animals received saline (10 ml/kg) in order to confirm that the injection and conditioning schedule was not affecting the time allotment in the apparatus, this group was used as control. Locomotor activity was also measured in the testing phase (Fig. 1). 2.5.2. Experiment 2. Effects of intra-CA1 injection of NMDA on the acquisition of CPP with or without ACPA Four groups of animals (n = 8 in each group), different doses of NMDA (0, 0.125, 0.25, and 0.5 μg/ mouse, intra-CA1), were given just before the administration of saline (10 ml/kg, i.p.), during the conditioning phase. In other groups, animals received the same doses of NMDA immediately before i.p. administration of ACPA (0.01 mg/kg) during the conditioning sessions. Animals were tested 24 h after the last
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conditioning session with no preceding injection. Locomotor activity was also measured in the testing phase (Fig. 2). 2.5.3. Experiment 3. Effects of intra-CA1 injection of D-AP7 on the acquisition of CPP with or without ACPA In four groups of animals (n = 8 in each group), different doses of DAP7 (0, 0.25, 0.5, and 1 μg/mouse, intra-CA1) were given just before the administration of saline (10 ml/kg, i. p.), during the conditioning phase. In other groups, animals received the same doses of D-AP7 immediately before i.p. administration of ACPA (0.02 mg /kg) during the conditioning sessions. Animals were tested 24 h after the last conditioning session with no preceding injection. Locomotor activity was also measured in the testing phase (Fig. 3). 2.5.4. Experiment 4. Effects of NMDA on the expression of ACPA-induced place preference In this experiment, eight groups of animals were used. In four groups, the animals underwent the experimental procedure of place conditioning with saline (10 ml/kg, i.p.) and the other four groups underwent the experimental procedure of place conditioning with ACPA (0.01 mg/kg, i.p.). On the 5th day, 5 min before testing, the groups were injected with NMDA (0, 0.125, 0.25, and 0.5 μg/mouse, intra-CA1). Locomotor activity was also evaluated during the testing phase in these groups (Fig. 4). 2.5.5. Experiment 5. Effects of D-AP7 on the expression of ACPA-induced place preference In this experiment, eight groups of animals were used. In four groups, the animals underwent the experimental procedure of place conditioning with saline (10 ml/kg, i.p.) and the other four groups underwent the experimental procedure of place conditioning with ACPA (0.02 mg/kg, i.p.). On the 5th day, 5 min before testing, the groups were injected with D-AP7 (0, 0.25, 0.5, and 1 μg/mouse, intra-CA1). Locomotor activity was also evaluated during the testing phase in these groups (Fig. 5). 2.6. Verification of cannulae placements When behavioral testing sessions were concluded, animals were killed by anesthetic overdose and received microinjection of methylene blue (1%) at the same volume as drug microinjections. This was to mark the site of the drug injection. Mice brains were removed and injection sites were histologically verified according to the atlas of Paxinos and Franklin, 2001. Data from the animals with injection sites located outside the CA1 regions were not used in the analysis. 2.7. Statistical analysis The between-groups comparisons were made using the two-way analysis of variance (two-way ANOVA) in SPSS 17.0 software. Drug was defined as ACPA factor and dose as NMDA or D-AP7 factor in the experiments 2 and 4 or 3 and 5, respectively. Following a significant F value, post hoc analysis (Tukey's test) was performed for specific inter-group comparisons. Post hoc tests were not required in the absence of a significant interaction. A difference with P b 0.05 between the experimental groups was considered statistically significant. We used the Sigma plot 12 software to draw figures. 3. Results
Fig. 1. Place preference produced by ACPA. Different doses of ACPA (0.01, 0.02, and 0.04 mg/kg) and saline (10 ml/kg) were administered intraperitoneally (i.p.) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. *P b 0.05 and **P b 0.01different from the saline control group.
3.1. Dose–response effects of place conditioning produced by ACPA Fig. 1A demonstrates that intraperitoneal administration of ACPA (0.01, 0.02, and 0.04 mg/kg, i.p.) during the conditioning phase induced a CPP for the drug-associated place. One-way ANOVA showed that ACPA caused a significant place preference [F (3, 28) = 9.68, P b 0.001].
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Further analysis showed that the maximum response was obtained with 0.02 mg/kg of ACPA. Furthermore, Fig. 1B indicates that ACPA induced an increased significant locomotion [F (3, 28) = 9.68, P b 0.001]. Post hoc analysis showed that the higher dose of ACPA increased locomotor activity. 3.2. Effects of intra-CA1 injection of NMDA on the acquisition of CPP with or without ACPA Fig. 2A shows the effects of bilateral intra-CA1 microinjection of NMDA (0.125, 0.25, and 0.5 μg/mouse) with or without ACPA (0.01 mg/kg) on the acquisition of CPP. Two-way ANOVA revealed a significant interaction between NMDA and ACPA in the acquisition of CPP [within group comparison: for Drug, F (1, 56) = 20.43, P b 0.001; Dose, F (3, 56) = 10.36, P b 0.001; and Drug × Dose interaction, F (3, 56) = 2.82, P b 0.05]. Further analysis exhibited that a higher dose of NMDA (0.5 μg/ mouse) in combination with ACPA increased CPP [one-way ANOVA: F (3, 28) = 9.36, P b 0.001]. Fig. 2B shows the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received NMDA alone and those which received NMDA plus ACPA on locomotor activity [within group comparison: for Drug, F (1, 56) = 0.24, P N 0.05; Dose, F (3, 56) = 0.93, P N 0.05; and Drug × Dose interaction, F (3, 56) = 1.03, P N 0.05]. 3.3. Effects of intra-CA1 injection of D-AP7 on the acquisition of CPP with or without ACPA Fig. 3A indicates the effects of bilateral intra-CA1 microinjection of D-AP7 (0.25, 0.5, and 1 μg/mouse) with or without ACPA (0.02 mg/kg) on the acquisition of CPP. Two-way ANOVA revealed a significant interaction between D-AP7 and ACPA in the acquisition of CPP [within group
comparison: for Drug, F (1, 56) = 0.39, P N 0.05; Dose, F (3, 56) = 3.64, P b 0.05; and Drug × Dose interaction, F (3, 56) = 3.12, P b 0.05]. Further analysis revealed that a higher dose of D-AP7 (1 μg/mouse) in combination with ACPA decreased CPP [one-way ANOVA: F (3, 28) = 4.57, P b 0.05]. Fig. 3B illustrates the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received D-AP7 alone and those which received D-AP7 plus ACPA on locomotor activity [within group comparison: for Drug, F (1, 56) = 0.00, P N 0.05; Dose, F (3, 56) = 1.80, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.06, P N 0.05]. 3.4. Effects of NMDA on the expression of ACPA-induced place preference Fig. 4A shows the effects of bilateral intra-CA1 microinjection of NMDA (0.125, 0.25, and 0.5 μg/mouse) with or without ACPA (0.01 mg/kg) on the expression of CPP. Two-way ANOVA revealed no significant interaction between NMDA and ACPA in the expression of CPP [within group comparison: for Drug, F (1, 56) = 5.98, P b 0.05; Dose, F (3, 56) = 2.00, P N 0.05; and Drug × Dose interaction, F (3, 56) = 1.66, P N 0.05]. Fig. 4B shows the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received NMDA alone and those which received NMDA plus ACPA on locomotor activity [within group comparison: for Drug, F (1, 56) = 13.64, P b 0.01; Dose, F (3, 56) = 2.10, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.15, P N 0.05]. 3.5. Effects of D-AP7 on the expression of ACPA-induced place preference Fig. 5A indicates the effects of bilateral intra-CA1 microinjection of DAP7 (0.25, 0.5, and 1 μg/mouse) with or without ACPA (0.02 mg/kg) on
Fig. 2. The effects of bilateral intra-CA1 injection of NMDA, either alone or in combination with ACPA, on the acquisition of a conditioned place preference. The animals received NMDA (0.125, 0.25, and 0.5 μg/Mouse) or saline (1 μl/Mouse) with or without ACPA (0.01 mg/kg, i.p.), in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15 min period. The change of preference was assessed as the difference between the times spent in the drug-paired compartment on the day of testing and the time spent in the drugpaired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. +++P b 0.001 different from the saline/ACPA group.
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Fig. 3. The effects of bilateral intra-CA1 injection of D-AP7, either alone or in combination with ACPA, on the acquisition of a conditioned place preference. The animals received D-AP7 (0.25, 0.5, and 1 μg/mouse) or saline (1 μl/rat) in combination with ACPA (0.02 mg/kg, i.p.) or without ACPA, in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drugpaired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. *P b 0.05 different from the saline/saline group and +P b 0.05 different from the saline/ACPA group.
the expression of CPP. Two-way ANOVA revealed no significant interaction between D-AP7 and ACPA in the expression of CPP [within group comparison: for Drug, F (1, 56) = 49.30, P b 0.001; Dose, F (3, 56) = 0.12, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.42, P N 0.05].
Fig. 5B illustrates the effects of the drugs on the locomotor activity in the testing phase. Two-way ANOVA also indicated no significant interaction between the groups of animals which received D-AP7 alone and those which received D-AP7 plus ACPA on locomotor activity
Fig. 4. The effects of bilateral microinjection of NMDA into the CA1on the expression of ACPA-induced place preference. All animals received ACPA (0.01 mg/kg, i.p.) or saline (10 ml/kg, i.p.) in a 3-day schedule of conditioning. On the test day, the different doses of NMDA (0.125, 0.25, and 0.05 μg/mouse) were administered into the CA1 immediately before testing and each animal was observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group.
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Fig. 5. The effects of bilateral microinjection of D-AP7 into the CA1on the expression of ACPA-induced place preference. All animals received ACPA (0.02 mg/kg, i.p.) or saline (10 ml/kg, i.p.) in a 3-day schedule of conditioning. On the test day, the different doses of D-AP7 (0.25, 0.5, and 1 μg/mouse) were administered into the CA1 immediately before testing, and each animal was observed for a 15 min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the preconditioning session. Data are expressed as mean ± S.E.M. of 8 animals per group. *P b 0.05 different from saline/saline group.
[within group comparison: for Drug, F (1, 56) = 3.05, P N 0.05; Dose, F (3, 56) = 0.07, P N 0.05; and Drug × Dose interaction, F (3, 56) = 0.90, P N 0.05]. 4. Discussion In the present study, ACPA as a cannabinoid CB1 receptor agonist, in a moderate dose, caused a significant conditioned place preference (CPP), when it was administered intraperitoneally. The higher dose of the drug did not induce place preference, but increased locomotion. It has been reported that cannabinoid receptor agonists induce biphasic effects on movement that are time and dose dependent. There is a report showing that very low doses of the cannabinoid receptor agonist Δ9-tetrahydrocannabinol decrease locomotor activity while higher doses dose-dependently stimulate movement until catalepsy emerges accompanied by decreases in activity (Sanudo-Pena et al., 2000). Indeed, ACPA at dose that increased locomotion did not induce place preference in the present study. Moreover, it is important to note here that our mice were tested in a drug-free state. More specifically, these observations indicate that locomotor activity was not a confounding factor in the interpretation of the present results. It has been suggested that cannabinoids can induce both rewarding and aversive responses in a variety of animal models, such as drug self-administration, intracranial self-stimulation, CPP, and reinstatement procedures. However, aversion is the predominant effect of cannabinoids (Vlachou, Nomikos and Panagis, 2005). Conversely, other investigators have demonstrated unambiguously positive reinforcing effects of Δ9-THC in squirrel monkeys using the intravenous self-administration paradigm (Justinova et al., 2003). Furthermore, in some particular experimental conditions (e.g., pre-exposure to the drug or the homeostatic state of the animal), rewarding effects of cannabinoids can be achieved (Tanda, Munzar and Goldberg, 2000; Valjent and Maldonado, 2000). Furthermore, CB1
receptors have been reported to be involved in the primary reinforcing effects of cannabinoids, alcohol, nicotine, and opioids (Maldonado, Valverde and Berrendero, 2006). In addition, the CB1 receptors are densely expressed in brain regions related to motivation and reward (Chambers, Taylor and Potenza, 2003) and play a modulatory role in the dopamine system (Robbe et al., 2002). There is a general agreement that cannabinoids regulate DA firing via inhibitory CB1 receptors located on GABA and glutamatergic terminals. The net effect being the result of the functional balance between excitatory and inhibitory inputs, generally favoring a CB1-GABAergic-mediated disinhibition of DA neuronal activation (El Khoury et al., 2012). In addition to the excitatory effect of this CB1-GABA disinhibitory component, cannabinoids with affinity for TRPV1 receptors can also increase DA firing rate through excitatory TRPV1 receptors, most probably present in glutamatergic terminals (Marinelli et al., 2003; Marinelli et al., 2007). Our present data indicate that the bilateral injections of NMDA into the dorsal hippocampus failed to induce CPP or CPA. Moreover, pretreatment administration of a higher dose of NMDA with a subthreshold dose of ACPA could potentiate ACPA-induced place preference. It has been widely accepted that drugs of abuse produce their reinforcing effects through increase in dopamine release in the NAc (Wise, 2004; Pierce and Kumaresan, 2006). In addition, there are glutamatergic projections from the hippocampus to the NAc (Floresco, Todd and Grace, 2001), which regulate DA transmission in this structure (Everitt and Robbins, 2005). It is still not clear if CB1 in forebrain GABAergic or in cortical glutamatergic neurons modulate the rewarding properties of CB1 agonist in the CPP. The endocannabinoid system, mainly through CB1 receptors located on glutamatergic or GABAergic neurons, controls both excitatory and inhibitory neurotransmissions, thereby modulated dopaminergic functions. Thus, full genetic deletion or pharmacological blockade of CB1 has revealed that the endocannabinoid system modulates reward-related behaviors. There is a general agreement that CB1
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receptors mediate the influence of conditioned factors on drug seeking mainly through modulation of glutamatergic neurotransmission. For example, the alteration of glutamate-mediated transmission, especially the increase of glutamatergic transmission in the NAc, may promote the seeking and relapse of abused drugs (Zhu, Rockhold and Ho, 1998; Xi et al., 2006). Considering these findings, one may conclude that intraCA1 injection of NMDA activates glutamatergic projections to the NAc and, in turn, potentiate ACPA effect on dopamine release in this structure. Previously, we reported that injection of NMDA into the dorsal hippocampus potentiates morphine-CPP (Zarrindast et al., 2007). These results confirm that cannabinoids act on brain reward processes and reward-related behaviors in strikingly similar fashion to other addictive drugs (Gardner, 2002). The present results also showed that the bilateral microinjection of D-AP7, a specific NMDA receptor antagonist, into the CA1 region of dorsal hippocampus alone, did not induce a significant place preference or aversion by itself, while co-administration of the antagonist with ACPA, during the conditioning phase, inhibited the ACPA (0.02 mg/kg)-induced place preference. Several behavioral studies have examined the role of NMDARs in the development of addiction-related memory, primarily by co-administering dizocilpine (MK801), a noncompetitive NMDAR antagonist, with psychostimulants (Wolf, 1998). Coadministration of MK801 prevents the development of sensitization to cocaine (Parada and Soares-da-Silva, 2000), amphetamine (Ranaldi et al., 2000), and methamphetamine (Ohno and Watanabe, 1995). Moreover, MK801 similarly prevents the development of cocaine, amphetamine, and methamphetamine-induced CPP, a prominent associative memory model of drug-seeking behavior (Kim and Jang, 1997). As previously mentioned, increase in dopamine release in the NAc represents a common feature for the reinforcing properties of drugs of abuse (Pierce and Kumaresan, 2006). Moreover, glutamatergic projections from the hippocampus to the NAc have a modulatory control on the NAc neurons (Bardgett and Henry, 1999). It has been reported that endocannabinoid function through CB1 receptors was necessary for long-term depression (LTD-a type of synaptic plasticity) to be seen in glutamatergic inputs to the GABAergic medium spiny neurons of the NAc (Gerdeman et al., 2003), and synaptic plasticity may be involved in the learning processes (Izquierdo et al., 2006). Therefore, one may propose that D-AP7 may alter modulatory role of ACPA on dopamine release in the NAc so that induces a CPA response. Another explanation for the results of the present study would be that the blockade of the hippocampal NMDA receptors may decrease reward-related learning induced by ACPA and block the establishment of the association between drug-reward and conditioning compartmental cues. Intra-CA1 administration of NMDA or D-AP7 immediately before the test did not induce any change on the expression of ACPA-induced place preference. Collectively, the present data suggest that NMDA receptors of dorsal hippocampus may be important for the development but not the expression of ACPA-induced place preference. On the other hand, intra-CA1 injection of the different doses of NMDA or D-AP7 during the conditioning phase alone had no effect on the locomotor activity in the testing phase. Therefore, the interactions of locomotor activity with the results obtained seem unlikely. From the results of this study, it is concluded that the acquisition of ACPAinduced place preference, but not the expression, may be associated with the glutamatergic activation modulated by NMDA receptors of the CA1 region of hippocampus, because the ACPA reward was potentiated by NMDA and blocked by D-AP7. Moreover, the present data suggest that the dorsal hippocampal NMDA receptors may play an important role in mediating reward-related learning induced by activation of cannabinoid CB1 receptors. Acknowledgement Authors wish to thank the Iran National Science Foundation (INSF) for providing financial support to this project.
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References Alger BE. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 2002;68:247–86. Bardgett ME, Henry JD. Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D1 and D2 receptors. Neuroscience 1999; 94:59–70. Bardo MT, Bevins RA. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 2000;153:31–43. Bodor AL, Katona I, Nyiri G, Mackie K, Ledent C, Hajos N, et al. Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types. J Neurosci 2005;25:6845–56. Botreau F, Paolone G, Stewart J. d-Cycloserine facilitates extinction of a cocaine-induced conditioned place preference. Behav Brain Res 2006;172:173–8. Chambers RA, Taylor JR, Potenza MN. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 2003;160: 1041–52. Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 2012;482:85–8. Ebrahimi-ghiri M, Nasehi M, Rostami P, Mohseni-Kouchesfehani H, Zarrindast MR. The effect of cholestasis on rewarding and exploratory behaviors induced by opioidergic and dopaminergic agents in mice. Arch Iran Med 2012;15:617–24. El Khoury MA, Gorgievski V, Moutsimilli L, Giros B, Tzavara ET. Interactions between the cannabinoid and dopaminergic systems: evidence from animal studies. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:36–50. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 2005;8:1481–9. Floresco SB, Todd CL, Grace AA. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 2001;21:4915–22. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 2003;83:1017–66. Gardner EL. Addictive potential of cannabinoids: the underlying neurobiology. Chem Phys Lipids 2002;121:267–90. Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM. It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci 2003;26:184–92. Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M. Different molecular cascades in different sites of the brain control memory consolidation. Trends Neurosci 2006;29:496–505. Justinova Z, Tanda G, Redhi GH, Goldberg SR. Self-administration of delta9tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl) 2003;169:135–40. Kim HS, Jang CG. MK-801 inhibits methamphetamine-induced conditioned place preference and behavioral sensitization to apomorphine in mice. Brain Res Bull 1997;44:221–7. Legault M, Rompre PP, Wise RA. Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area. J Neurosci 2000;20:1635–42. Maldonado R, Valverde O, Berrendero F. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 2006;29:225–32. Marinelli S, Di Marzo V, Berretta N, Matias I, Maccarrone M, Bernardi G, et al. Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J Neurosci 2003;23:3136–44. Marinelli S, Di Marzo V, Florenzano F, Fezza F, Viscomi MT, van der Stelt M, et al. Narachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors. Neuropsychopharmacology 2007;32:298–308. Matyas F, Urban GM, Watanabe M, Mackie K, Zimmer A, Freund TF, et al. Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology 2008;54:95–107. McBride WJ, Murphy JM, Ikemoto S. Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies. Behav Brain Res 1999;101:129–52. Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL. Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 2004;24:53–62. Meyers RA, Zavala AR, Neisewander JL. Dorsal, but not ventral, hippocampal lesions disrupt cocaine place conditioning. Neuroreport 2003;14:2127–31. Misner DL, Sullivan JM. Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons. J Neurosci 1999;19:6795–805. Nasehi M, Amin-Yavari S, Ebrahimi-Ghiri M, Torabi-Nami M, Zarrindast MR. The dual effect of CA1 NMDA receptor modulation on ACPA-induced amnesia in step-down passive avoidance learning task. Eur Neuropsychopharmacol 2015a;25:557–65. Nasehi M, Jamshidi-Mehr M, Khakpai F, Zarrindast MR. Possible involvement of CA1 5HT1B/1D and 5-HT2A/2B/2C receptors in harmaline-induced amnesia. Pharmacol Biochem Behav 2014;125:70–7. Nasehi M, Ketabchi M, Khakpai F, Zarrindast MR. The effect of CA1 dopaminergic system in harmaline-induced amnesia. Neuroscience 2015b;285:47–59. Nasehi M, Mashaghi E, Khakpai F, Zarrindast MR. Suggesting a possible role of CA1 histaminergic system in harmane-induced amnesia. Neurosci Lett 2013;556:5–9. Ohno M, Watanabe S. Nitric oxide synthase inhibitors block behavioral sensitization to methamphetamine in mice. Eur J Pharmacol 1995;275:39–44. Parada A, Soares-da-Silva P. The dopamine antagonist sch 23390 reverses dizocilpineinduced blockade of cocaine sensitization. Neuropharmacology 2000;39:1645–52. Paxinos G, Franklin KBJ. The Mouse Brain in Stereotaxic Coordinates. 2nd Ed. Academic Press; 2001.
90
M. Nasehi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 83–90
Pierce RC, Kumaresan V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 2006;30:215–38. Ranaldi R, Munn E, Neklesa T, Wise RA. Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK801 (dizocilpine). Psychopharmacology (Berl) 2000;151:192–201. Rezayof A, Zarrindast MR, Sahraei H, Haeri-Rohani A. Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats. J Psychopharmacol 2003;17:415–23. Riegel AC, Lupica CR. Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area. J Neurosci 2004;24:11070–8. Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci U S A 2002;99:8384–8. Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 1993;18:247–91. Rodriguez De Fonseca F, Rubio P, Martin-Calderon JL, Caine SB, Koob GF, Navarro M. The dopamine receptor agonist 7-OH-DPAT modulates the acquisition and expression of morphine-induced place preference. Eur J Pharmacol 1995;274:47–55. Sakurai S, Yu L, Tan SE. Roles of hippocampal N-methyl-D-aspartate receptors and calcium/calmodulin-dependent protein kinase II in amphetamine-produced conditioned place preference in rats. Behav Pharmacol 2007;18:497–506. Sanudo-Pena MC, Romero J, Seale GE, Fernandez-Ruiz JJ, Walker JM. Activational role of cannabinoids on movement. Eur J Pharmacol 2000;391:269–74. Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science 1997;275:1593–9. Shen F, Meredith GE, Napier TC. Amphetamine-induced place preference and conditioned motor sensitization requires activation of tyrosine kinase receptors in the hippocampus. J Neurosci 2006;26:11041–51.
Tanda G, Munzar P, Goldberg SR. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 2000;3:1073–4. Tzschentke TM. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 2007;12:227–462. Valjent E, Maldonado R. A behavioural model to reveal place preference to delta 9tetrahydrocannabinol in mice. Psychopharmacology (Berl) 2000;147:436–8. Vlachou S, Nomikos GG, Panagis G. CB1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat. Psychopharmacology (Berl) 2005;179: 498–508. Wang H, Lupica CR. Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes. Prog Neuropsychopharmacol Biol Psychiatry 2014;52:24–7. Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci 2004;5:483–94. Wolf ME. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 1998;54:679–720. Xi ZX, Gilbert JG, Peng XQ, Pak AC, Li X, Gardner EL. Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J Neurosci 2006;26:8531–6. Zarrindast MR, Lashgari R, Rezayof A, Motamedi F, Nazari-Serenjeh F. NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference. Eur J Pharmacol 2007;568:192–8. Zarrindast MR, Nasehi M, Rostami P, Rezayof A, Fazli-Tabaei S. Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference. Behav Pharmacol 2005;16:85–92. Zhu H, Rockhold RW, Ho IK. The role of glutamate in physical dependence on opioids. Jpn J Pharmacol 1998;76:1–14.
