Orexin and cannabinoid systems modulate long-term potentiation of the hippocampus CA1 area in anesthetized rats

Document Type : Original Article


1 Department of Physiology, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran

2 Department of Physiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

3 Nanobiotechnology Research Centre, Baqiyatallah University of Medical Sciences, Tehran, Iran

4 Department of Psychiatry, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran



Objective(s): Long-term potentiation (LTP) is a kind of synaptic plasticity and has a key role in learning and memory. Endocannabinoids and orexins are the endogenous systems that can modulate synaptic plasticity. Given that new studies have shown an interaction between cannabinoid and orexin systems in the brain, we decided to examine this interaction between the two systems on LTP induction in rat’s hippocampus.
Materials and Methods: Twenty-eight male Wistar rats were used for evaluating the effects of co-administrating of cannabinoid-1 receptor (CB1R) antagonist (AM251) and orexin-2 receptor (OX2R) antagonist (TCS OX2 29) on the induction of LTP in the Schaffer collateral-CA1 synapses of rat hippocampus. The drugs were microinjected into the CA1 area of rat hippocampus 30 min before inducing of LTP.
Results: Results showed that sole administration of the antagonists inhibited LTP, with respect to the control group. Also, co-administrating of them reduced LTP as compared to the control group, but not significantly more than that when the antagonists were solely microinjected into the CA1. Nonetheless, the inhibitory effect of concurrent administration of the antagonists on LTP lasted until the end of the recording. 
Conclusion: These results propose that endogenous cannabinoids and orexins play a role in the expression of LTP, at least by CA1-CB1Rs and CA1-OX2Rs, respectively. Finally, there is no interaction between CB1R and OX2R on the induction of LTP in the Schaffer collateral-CA1 synapses; therefore, these two systems possibly act through common signaling pathways in the hippocampus’s CA1 region.


Main Subjects

1. Abraham WC. How long will long-term potentiation last? Philos Trans R Soc Lond B Biol Sci 2003; 358: 735-744.
2. Dolatabadi LK, Reisi P. Acute effect of cholecystokinin on short-term synaptic plasticity in the rat hippocampus. Res Pharm Sci 2014; 9: 331-336.
3. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993; 361: 31-9.
4. Maroso M, Szabo GG, Kim HK, Alexander A, Bui AD, Lee S-H, et al. Cannabinoid control of learning and memory through HCN channels. Neuron 2016; 89: 1059-1073.
5. Lu H-C, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry 2016; 79: 516-525.
6. 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: R7-R8.
7. Terranova JP, Michaud JC, Le Fur G, Soubrie P. Inhibition of long-term potentiation in rat hippocampal slices by anandamide and WIN55212-2: Reversal by SR141716 A, a selective antagonist of CB1 cannabinoid receptors. Naunyn Schmiedebergs Arch Pharmacol 1995; 352: 576-579.
8. de Oliveira Alvares L, Pasqualini Genro B, Vaz Breda R, Pedroso MF, Costa Da Costa J, Quillfeldt JA. AM251, a selective antagonist of the CB1 receptor, inhibits the induction of long-term potentiation and induces retrograde amnesia in rats. Brain Res 2006; 1075: 60-67.
9. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573-585.
10. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001; 435: 6-25.
11. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998; 18: 9996-10015.
12. Azizi F, Fartootzadeh R, Alaei H, Reisi P. Effects of concurrent blockade of OX2 and CB1 receptors in the ventral tegmental area on nicotine-induced place preference in rats. Neurosci Lett 2018; 684: 121-126.
13. Akbari E, Naghdi N, Motamedi F. The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides 2007; 28: 650-656.
14. Azizi F, Fartootzadeh R, Alaei H, Reisi P. Electrophysiological study of the response of ventral tegmental area non-dopaminergic neurons to nicotine after concurrent blockade of orexin receptor-2 and cannabinoid receptors-1. Brain Res 2019; 1719: 176-182.
15. Fartootzadeh R, Azizi F, Alaei H, Reisi P. Functional crosstalk of nucleus accumbens CB1 and OX2 receptors in response to nicotine-induced place preference. Neurosci Lett 2019; 698: 160-164.
16. Akbari E, Naghdi N, Motamedi F. Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task. Behav Brain Res 2006; 173: 47-52.
17. Akbari E, Motamedi F, Davoodi FG, Noorbakhshnia M, Ghanbarian E. Orexin-1 receptor mediates long-term potentiation in the dentate gyrus area of freely moving rats. Behav Brain Res 2011; 216: 375-380.
18. Ardeshiri MR, Hosseinmardi N, Akbari E. The effect of orexin 1 and orexin 2 receptors antagonisms in the basolateral amygdala on memory processing in a passive avoidance task. Physiol Behav 2017; 174: 42-48.
19. Khastar H, Garmabi B, Mehrjerdi FZ, Rahimi MT, Shamsaei N, Ali A-H, et al. Cyanocobalamin improves memory impairment via inhibition of necrosis and apoptosis of hippocampal cell death after transient global ischemia/reperfusion. Iran J Basic Med Sci 2021; 24: 160–166.
20. Adabizadeh M, Mehri S, Rajabpour M, Abnous K, Rashedinia M, Hosseinzadeh H. The effects of crocin on spatial memory impairment induced by hyoscine: Role of NMDA, AMPA, ERK, and CaMKII proteins in rat hippocampus. Iran J Basic Med Sci 2019; 22: 601–609.
21. Moghimi M, Parvardeh S, Zanjani TM, Ghafghazi S. Protective effect of α-terpineol against impairment of hippocampal synaptic plasticity and spatial memory following transient cerebral ischemia in rats. Iran J Basic Med Sci 2016; 19: 960-969.
22. Mackie K. Distribution of Cannabinoid Receptors in the Central and Peripheral Nervous System. In: Pertwee RG, editor. Cannabinoids. Berlin, Heidelberg: Springer Berlin Heidelberg; 2005: 168: 299-325.
23. Berrendero F, Flores A, Robledo P. When orexins meet cannabinoids: Bidirectional functional interactions. Biochem Pharmacol 2018; 157: 43-50.
24. Jäntti MH, Mandrika I, Kukkonen JP. Human orexin/hypocretin receptors form constitutive homo-and heteromeric complexes with each other and with human CB1 cannabinoid receptors. Biochem Biophys Res Commun 2014; 445: 486-490.
25. Taslimi Z, Haghparast A, Hassanpour-Ezatti M, Safari M-S. Chemical stimulation of the lateral hypothalamus induces conditioned place preference in rats: Involvement of OX1 and CB1 receptors in the ventral tegmental area. Behav Brain Res 2011; 217: 41-46.
26. Yazdi F, Jahangirvand M, Pirasteh AH, Moradi M, Haghparast A. Functional interaction between OX2 and CB1 receptors in the ventral tegmental area and the nucleus accumbens in response to place preference induced by chemical stimulation of the lateral hypothalamus. Pharmacol Biochem Behav 2015; 139: 39-46.
27. Fartootzadeh R, Alaei H, Reisi P. Mutual assistance of nucleus accumbens cannabinoid receptor-1 and orexin receptor-2 in response to nicotine: A single-unit study. Res Pharm Sci 2021; 16: 173–181.
28. Fartootzadeh R, Azizi F, Alaei H, Reisi P. Orexin type-2 receptor blockade prevents the nicotine-induced excitation of nucleus accumbens core neurons in rats: An electrophysiological perspective. Pharmacol Rep 2019; 71: 361-366.
29. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Academic Press; 7th ed 2007.
30. Sadeghi M, Reisi P, Radahmadi M. The effects of CCK-8S on spatial memory and long-term potentiation at CA1 during induction of stress in rats. Iran J Basic Med Sci 2017; 20: 1368-1376.
31. Zamani M, Radahmadi M, Reisi P. Therapeutic effects of exercise-accompanied escitalopram on synaptic potency and long-term plasticity in the hippocampal CA1 area in rats under chronic restraint stress. Iran J Basic Med Sci 2022; 25: 1460–1467.
32. Komaki A, Khalili A, Salehi I, Shahidi S, Sarihi A. Effects of exposure to an extremely low frequency electromagnetic field on hippocampal long-term potentiation in rat. Brain Res. 2014; 1564: 1-8.
33. Wayner MJ, Armstrong DL, Phelix CF, Oomura Y. Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo. Peptides 2004; 25: 991-996.
34. Selbach O, Doreulee N, Bohla C, Eriksson KS, Sergeeva OA, Poelchen W, et al. Orexins/hypocretins cause sharp wave- and theta-related synaptic plasticity in the hippocampus via glutamatergic, gabaergic, noradrenergic, and cholinergic signaling. Neuroscience 2004; 127: 519-528.
35. Carlson G, Wang Y, Alger BE. Endocannabinoids facilitate the induction of LTP in the hippocampus. Nat Neurosci 2002; 5: 723-724.
36. Hoffman AF, Oz M, Yang R, Lichtman AH, Lupica CR. Opposing actions of chronic Δ9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learn Mem 2007; 14: 63-74.
37. Slanina KA, Roberto M, Schweitzer P. Endocannabinoids restrict hippocampal long-term potentiation via CB1. Neuropharmacology 2005; 49: 660-668.
38. Abush H, Akirav I. Cannabinoids modulate hippocampal memory and plasticity. Hippocampus 2010; 20: 1126-1138.
39. Flores Á, Maldonado R, Berrendero F. Cannabinoid-hypocretin cross-talk in the central nervous system: What we know so far. Front Neurosci 2013; 7: 256.