Pharmacology, Biochemistry and Behavior 131 (2015) 87–90

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Effects of cannabinoid and glutamate receptor antagonists and their interactions on learning and memory in male rats Somayeh Barzegar, Alireza Komaki ⁎, Siamak Shahidi, Abdolrahman Sarihi, Naser Mirazi, Iraj Salehi Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

a r t i c l e

i n f o

Article history: Received 25 July 2014 Received in revised form 28 January 2015 Accepted 2 February 2015 Available online 13 February 2015 Keywords: Cannabinoid Glutamate Memory Learning Passive avoidance test

a b s t r a c t Introduction: Despite previous findings on the effects of cannabinoid and glutamatergic systems on learning and memory, the effects of the combined stimulation or the simultaneous inactivation of these two systems on learning and memory have not been studied. In addition, it is not clear whether the effects of the cannabinoid system on learning and memory occur through the modulation of glutamatergic synaptic transmission. Hence, in this study, we examined the effects of the simultaneous inactivation of the cannabinoid and glutamatergic systems on learning and memory using a passive avoidance (PA) test in rats. Materials and methods: On the test day, AM251, which is a CB1 cannabinoid receptor antagonist; MK-801, which is a glutamate receptor antagonist; or both substances were injected intraperitoneally into male Wistar rats 30 min before placing the animal in a shuttle box. A learning test (acquisition) was then performed, and a retrieval test was performed the following day. Results: Learning and memory in the PA test were significantly different among the groups. The CB1 receptor antagonist improved the scores on the PA acquisition and retention tests. However, the glutamatergic receptor antagonist decreased the acquisition and retrieval scores on the PA task. The CB1 receptor antagonist partly decreased the glutamatergic receptor antagonist effects on PA learning and memory. Conclusions: These results indicated that the acute administration of a CB1 antagonist improved cognitive performance on a PA task in normal rats and that a glutamate-related mechanism may underlie the antagonism of cannabinoid by AM251 in learning and memory. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Many chemical factors, including neurotransmitters, influence learning and memory through actions in different brain regions (Phale and Korgaonkar, 2009). Decreased or increased levels of neurotransmitters or the activation or blockade of their receptors may alter learning and memory (Levin, 2006). Glutamate (Glu), which is the major excitatory neurotransmitter in the brain, has a prominent role in learning and memory processes (Phale and Korgaonkar, 2009). The endocannabinoid system is one of the main neuromodulators of the mammalian central nervous system (López-Moreno et al., 2008). In addition, cognitive effects have been described after cannabinoid use in humans (Riedel and Davies, 2005; Schoedel et al., 2012) and, more recently, in animals (Swartzwelder et al., 2012; Stumm et al., 2013; Renard et al., 2013).

⁎ Corresponding author at: Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Shahid Fahmideh Street, Hamadan 65178/518, Iran. Tel.: +98 811 8380267; fax: +98 811 8380131. E-mail addresses: [email protected], [email protected] (A. Komaki). URL: http://www.umsha.ac.ir (A. Komaki).

http://dx.doi.org/10.1016/j.pbb.2015.02.005 0091-3057/© 2015 Elsevier Inc. All rights reserved.

Glu neurotransmitter, which is stored in presynaptic vesicles, has been estimated to be released in up to half of the synapses in the brain (Olney, 1990). Glu receptors have been identified as important interfaces in learning and memory paradigms as well as in mechanisms of synaptic plasticity (Phale and Korgaonkar, 2009), such as long-term potentiation (LTP) and long-term depression, which are believed to be the underlying cellular basis of at least some forms of learning (Riedel and Reymann, 1996; Riedel et al., 2003; Phale and Korgaonkar, 2009). The N-methyl-D-aspartate (NMDA) receptor (NMDAR) subtype of Glu receptors plays a substantial role in neural physiology, synaptic plasticity, and behavioral learning and memory (Shapiro, 2001). A large body of evidence from animal models and human studies has indicated that Cannabis sativa preparations, such as marijuana, induce numerous and complex effects on cognitive functions, including attention, learning, emotional reactivity, enhancement of the perceptions of the senses, and impairments in short-term memory (Pattij et al., 2008). These preparations act through two types of receptors—CB1 and CB2 (Wise et al., 2009). Despite numerous studies on the effects of the cannabinoid system in learning and memory, there have been conflicting results (Terranova et al., 1995; Puighermanal et al., 2009). In addition, the effects of the cannabinoid system on synaptic plasticity and LTP remain controversial

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(Collins et al., 1994; Terranova et al., 1995; Misner and Sullivan, 1999; Carlson et al., 2002; de Oliveira Alvares et al., 2006; Lin et al., 2011). According to one of these studies, cannabinoid receptor agonists impair memory formation, while antagonists reverse these deficits or act as memory enhancers, and they have revealed reductions in neural plasticity following cannabinoid treatment and increased plasticity following antagonist exposure (Riedel and Davies, 2005). A series of biochemical, molecular, and pharmacological studies have demonstrated functional interactions between the CB1 receptor and the Glu NMDAR (Rodríguez-Muñoz et al., 2012; Sánchez-Blázquez et al., 2013, 2014). However, an understanding of the exact mechanism underlying the neurochemical interactions and/or signaling pathways between CB1 and NMDA receptors requires further studies (Ferraro et al., 2009). Unlike the available data on the effects of the cannabinoid system on learning and memory and the role of the glutamatergic system in learning and memory, the simultaneous stimulation or inactivation effects of these two systems on learning and memory have not been studied. Therefore, in this study, we test the hypothesis that the effects of the cannabinoid system on learning and memory are the result of its effects on glutamatergic synaptic transmission. The interactions of these two systems in the modulation of learning and memory could have important therapeutic implications in clinical settings.

The test lasted 2 days. On the first day, all of the rats in the experimental groups became habituated to the apparatus. The rat was placed in the illuminated compartment, and, 5 s later, the guillotine door was raised. Upon entering the dark compartment, the door was closed, and the rat was taken from the dark compartment into the home cage. The habituation trial was repeated after 30 min. It was followed after the same interval by the acquisition trial, during which the guillotine door was closed, and a 50-Hz 1-mA constant current shock was applied for 1.5 s immediately after the animal had entered the dark compartment (Shahidi et al., 2008; Lashgari et al., 2009; Rasuli et al., 2011; Sarihi et al., 2011). In the experiment, the rat was retained in the apparatus, and it received a foot shock each time it reentered the dark compartment. Training was terminated when the rat remained in the light compartment for 120 consecutive seconds. The number of trials to acquisition (entries into the dark chamber) was recorded (Sarihi et al., 2011).

2. Material and methods

2.5. Retention test

2.1. Animals

Twenty-four hours after the passive avoidance training, the rat was placed in the illuminated chamber, and, 15 s later, the guillotine door was raised. The latency time for entering the dark compartment (stepthrough latency) and the time spent there over 10 min was recorded (Sarihi et al., 2011).

We used male Wistar rats of a laboratory strain weighing 200–240 g, obtained from the Pasteur Institute, Tehran, Iran. The animals were fed a standard diet and housed in plastic cages, five animals per cage, in an air-conditioned and temperature-controlled (22 ± 2 °C) room under a 12-h light/dark cycle (lights on at 8:00). Food and water were freely available. All of the experiments were conducted in a quiet, diffusely lit room between 9:00 and 13:00. Each experimental group consisted of 10 naïve animals. All research and animal care procedures were approved by the Veterinary Ethics Committee of this University and were performed in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication No. 85-23, revised 1985). 2.2. Treatments Saline was administered intraperitoneally (i.p.) in the first (control) group 30 min before the tests. AM251 (1-(2,4-dichlorophenyl)-5(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide), which is a selective cannabinoid CB1 receptor antagonist (AM251; Sigma-Aldrich Co. LLC, St. Louis, MO, USA) and MK-801 (Tocris Bioscience, Bristol, UK) were administered i.p. 30 min before the tests at doses of 1 and 0.1 mg/kg, respectively. In the final group, AM251 + MK-801 were administered i.p. 30 min before the tests. 2.3. Apparatus and procedures Passive avoidance behavior was studied in a one-trial-learning, stepthrough-type passive avoidance task that utilized the natural preference of rats for a dark environment (Gold, 1986). The apparatus consisted of two compartments that had a steel-rod grid floor (3 mm in diameter, 10 mm apart). One of the compartments (30 × 20 × 20 cm) was equipped with a 20 W lamp that was located centrally at a height of 50 cm, and the other was a dark compartment of the same size. The compartments were connected with a guillotine door (20 × 15 cm). A dark room was used during the experimental session. In the training trial, the guillotine door between the light and dark compartment was closed. When each rat was placed in the light compartment with its back to the guillotine door, the door was opened, and, at the same

time, the time (the step-through latency) was measured with a stopwatch until the rat entered the dark compartment. After the rat entered the dark compartment, the door was closed (Shahidi et al., 2008; Lashgari et al., 2009; Rasuli et al., 2011; Sarihi et al., 2011). 2.4. Training procedure

2.6. Statistical analysis The statistical significance of the results was computed by analysis of variance (ANOVA), which was followed by a post hoc Tukey test. In all of the comparisons between particular groups, a probability of 0.05 or less was considered significant. 3. Results 3.1. Effects of AM251, MK-801, and AM251 + MK-801 on acquisition in the passive avoidance test The animals in all of the experimental groups and the control group learned the passive avoidance task (number of trials to acquisition). For the number of trials to acquisition, no significant differences were found between the MK-801, AM251, and MK-801 + AM251 groups compared to the control group (P N 0.05 for all). The difference between the MK801 and AM251 groups was significant (P b 0.05). The effects of these substances on acquisition are summarized in Fig. 1. 3.2. Effects of AM251, MK-801, and AM251 + MK-801 on passive avoidance retrieval 3.2.1. Step-through latency One-way ANOVA indicated that there were significant differences in the step-through latency (STL) among the groups in the retrieval test. A Tukey's multiple comparison test revealed that the STL of the AM251 group (P b 0.05) was significantly higher and the MK-801 (P b 0.01) and AM251 + MK-801 (P b 0.05) groups were significantly lower than that of the control group. The STL of the AM251 + MK-801 group was significantly higher (P b 0.05) than that of the MK-801 group and less (P b 0.05) than that of the AM251 group. The difference between the MK-801 and AM251 groups was significant (P b 0.01). The effects of these substances on step-through latency are shown in Fig. 2.

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Fig. 1. The effects of MK-801, AM251, and MK-801 + AM251 on the number of trials to acquisition. Data are expressed as means ± standard error of the mean (SEM). There were 10 animals in each of the treated groups. Comparisons were made with a one-way analysis of variance (ANOVA), which was followed by a post hoc Tukey test. $: P b 0.05 compared to the MK-801 group.

3.2.2. Time in the dark compartment As shown in Fig. 3, there was a significant difference in the time spent in the dark compartment (TDC) among the groups. A Tukey's test for multiple comparisons showed that the TDCs in the MK-801 (P b 0.001) and AM251 + MK-801 (P b 0.05) groups were significantly higher than that of the control group, whereas the TDC in the MK-801 group (P b 0.05) was significantly less than that of the control. The TDC in the AM251 + MK-801 group was significantly less (P b 0.01) than that of the MK-801 group and higher (P b 0.01) than that of the AM251 groups. The difference between the MK-801 and AM251 groups was significant (P b 0.001).

4. Discussion The results showed that AM251 significantly increased the latency for entering a dark room, while the duration of the TDC was reduced significantly compared to the control group. In addition, the study results showed that MK-801, which is a NMDAR antagonist, had a reverse effect on learning and memory and that an antagonist of the CB1 receptor prevented the somewhat inhibitory effects of the Glu system antagonists on acquisition and retrieval in the passive avoidance test, thus eventually improving memory and learning. The memory-improving effects of AM251 that were observed in our study were in agreement with the results that have been obtained in

Fig. 2. Effects of MK-801, AM251, and MK-801 + AM251 on the step-through latency (STL). Data are expressed as means ± SEM. There were 10 animals in each of the treated groups. Comparisons were made with a one-way ANOVA, which was followed by a post hoc Tukey test. *: P b 0.05. **: P b 0.01 compared to the control group. #: P b 0.05 compared to the MK-801 and AM251 groups. $$: P b 0.01 compared to the MK-801 group.

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Fig. 3. Effects of MK-801, AM251, and MK-801 + AM251 on the time spent in the dark compartment (TDC). Data are expressed as means ± SEM. There were 10 animals in each of the treated groups. Comparisons were made with a one-way ANOVA, which was followed by a post hoc Tukey test. *: P b 0.05. ***: P b 0.001 compared to the control group. ##: P b 0.01 compared to the MK-801 and AM251 groups. $$$: P b 0.001 compared to the MK-801 group.

experiments that were performed with an antagonist/inverse agonist of the CB1 receptor (Riedel and Davies, 2005). Acute exposure to the major psychoactive component of marijuana (9-THC) or synthetic cannabinoid compounds disrupts spatial and cognitive performance tasks in animals (Lichtman et al., 1995; Hampson and Deadwyler, 1999) and humans (Heishman et al., 1997; Hoffman et al., 2007). Similarly, it has been reported that, while cannabinoid receptor agonists impair memory formation, antagonists reverse these deficits or act as memory enhancers (Riedel and Davies, 2005). Our results were in agreement with the cognitive effects of NMDAR antagonist drugs in animals and provided strong support for the proposal that decreases in NMDAR function can decrease memory and learning performance. Both competitive and noncompetitive NMDA antagonists transiently impair spatial learning in rats (Morris et al., 1990). In addition, the systemic administration of MK-801 impairs reversal learning in weanling rats (Chadman et al., 2006). The concentration of the MK-801 dose has a significant impact on the type of effects. It has been reported that a low dose of MK-801 (0.03 mg/kg) was not enough to disrupt memory formation, but it was able to cause state dependency for the task (Ceretta et al., 2008). A growing body of evidence has suggested that the endocannabinoid system modulates several forms of synaptic plasticity that are believed to underlie learning and memory (Haj-Dahmane and Shen, 2014; Wang et al., 2014; Lovelace et al., 2014). Several studies have indicated that cannabinoids oppose glutamatergic NMDAR function through various mechanisms, such as the presynaptic reduction of Glu release into the synaptic cleft (Brown et al., 2003; Melis et al., 2004; Li et al., 2010) or the inhibition of postsynaptic cannabinoid receptors, the signaling pathways of which may interfere with those of NMDARs (Liu et al., 2009; Hampson et al., 2011; Sánchez-Blázquez et al., 2014). The blockade of CB1 receptors by AM251 has been shown to produce a significant increase in extracellular Glu (Xi et al., 2006). Consistent with this report, the blockade of LTP by cannabinoid agonists results from a decrease in the probability of Glu release through presynaptic receptors (Misner and Sullivan, 1999; Hoffman et al., 2007). Moreover, it has been reported that cannabinoids reduce hippocampal LTP, which is related to NMDAR function and which has been implicated in learning and memory processes (Sánchez-Blázquez et al., 2014). In addition to other interactions that may occur between the endocannabinoid and Glu systems, the CB1–NMDAR association establishes a new scenario in which the CB1 directly interacts with the NMDAR to reduce its activity (Sánchez-Blázquez et al., 2014). Cannabinoids reduce primary calcium influx through activated NMDARs and the subsequent release of calcium from endogenous stores (Sensi and Jeng, 2004; Zhuang et al., 2005; Hampson et al., 2011; Liu et al., 2009; Li et al.,

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2010; Sánchez-Blázquez et al., 2014). This report of the direct effects of CB1 receptor activation on NMDA-triggered calcium release implicates endocannabinoids in the control of hippocampal cellular plasticity through the modulation of the NMDAR-mediated calcium conductance (Hampson et al., 2011). 5. Conclusion These findings suggested that a Glu-related mechanism might underlie the antagonism of cannabinoids by AM251 on learning and memory. However, future investigations are essential for a better understanding of the neurobiological mechanisms of action and the probable interaction of these two systems. The finding of an interaction between the cannabinoid and Glu receptors has important implications for the control of synaptic transmission and for novel therapeutic strategies. A greater understanding of the mechanisms underlying the cannabinoid and Glu receptor interactions may aid in the development of novel treatments for diseases related to learning and memory. Acknowledgments The authors would like to express their gratitude to the staff of the Neurophysiology Research Center for helping us to carry out this project. This research was supported by a grant (Grant number: 89004581124) of the Hamadan University of Medical Sciences, Hamadan, Iran. References Brown TM, Brotchie JM, Fitzjohn SM. Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake. J Neurosci 2003;23:11073–7. Carlson G, Wang Y, Alger BE. Endocannabinoids facilitate the induction of LTP in the hippocampus. Nat Neurosci 2002;5(8):723–4. Ceretta AP, Camera KC, Mello CF, Maribel AR. Arcaine and MK-801 make recall statedependent in rats. Psychopharmacology (Berl) 2008;201:405–11. Chadman KK, Watson DJ, Stanton ME. NMDA receptor antagonism impairs reversal learning in developing rats. Behav Neurosci 2006;120(5):1071–83. [PubMed: 17014258]. Collins DR, Pertwee RG, Davies SN. The action of synthetic cannabinoids on the induction of long-term potentiation in the rat hippocampal slice. Eur J Pharmacol 1994;259(3):R7–8. de Oliveira Alvares L, Genro BP, Vaz Breda R, Pedroso MF, Da Costa JC, Quillfeldt JA. AM251, a selective antagonist of the CB1 receptor, inhibits the induction of longterm potentiation and induces retrograde amnesia in rats. Brain Res 2006;1075(1): 60–7. Ferraro L, Tomasini MC, Beggiato S, Gaetani S, Cassano T, Cuomo V, et al. Short- and long-term consequences of prenatal exposure to the cannabinoid agonist WIN55,212-2 on rat glutamate transmission and cognitive functions. J Neural Transm 2009;116:1017–27. Gold PE. The use of avoidance training in studies of modulation of memory storage. Behav Neural Biol 1986;46:87–98. Haj-Dahmane S, Shen RY. Chronic stress impairs α1-adrenoceptor-induced endocannabinoid-dependent synaptic plasticity in the dorsal raphe nucleus. J Neurosci 2014;34(44):14560–70. http://dx.doi.org/10.1523/JNEUROSCI. 1310-14. 2014. [Oct 29]. Hampson RE, Deadwyler SA. Cannabinoids, hippocampal function and memory. Life Sci 1999;65:715–23. Hampson RE, Miller F, Palchik G, Deadwyler SA. Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: implications for endocannabinoid control of hippocampal neural plasticity. Neuropharmacology 2011;60(6):944–52. Heishman SJ, Arasteh K, Stitzer ML. Comparative effects of alcohol and marijuana on mood, memory, and performance. Pharmacol Biochem Behav 1997;58:93–101. Hoffman AF, Oz M, Yang R, Litchman AH. Opposing actions of chronic Delta9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learn Mem 2007;14:63–74. Lashgari R, Motamed F, Zahedi Asl S, Shahidi S, Komaki A. Behavioral and electrophysiological studies of chronic oral administration of L-type calcium channel blocker verapamil on learning and memory in rats. Behav Brain Res 2009;171:324–8. Levin ED. Neurotransmitter interaction and cognitive function. Switzerland: Birkhauser Verlag; 2006. p. 6. Li Q, Yan H, Wilson WA, Swartzwelder HS. Modulation of NMDA and AMPA-mediated synaptic transmission by CB1 receptors in frontal cortical pyramidal cells. Brain Res 2010;1342:127–37. Lichtman AH, Dimen KR, Martin BR. Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. Psychopharmacology (Berl) 1995;119: 282–90. Lin QS, Yang Q, Liu DD, Sun Z, Dang H, Liang J, et al. Hippocampal endocannabinoids play an important role in induction of long-term potentiation and regulation of contextual fear memory formation. Brain Res Bull 2011;86(3–4):139–45.

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Effects of cannabinoid and glutamate receptor antagonists and their interactions on learning and memory in male rats.

Despite previous findings on the effects of cannabinoid and glutamatergic systems on learning and memory, the effects of the combined stimulation or t...
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