The effect of alpha-2 adrenergic receptors on memory retention deficit induced by rapid eye movement sleep deprivation

Document Type : Original Article


1 Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran

2 Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

3 Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran

4 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

5 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran


Objective(s): Evidence shows that sleep deprivation (SD) disrupts the formation of hippocampus-related memories. Moreover, α2 adrenergic receptors that are wildly expressed in the CA1 hippocampal region have a significant role in modulating both sleep and memory formation. In the present research, we wanted to investigate the effect of stimulation and blockage of CA1 α2 adrenergic receptors by clonidine (an agonist of α2 adrenergic receptor) and yohimbine (an antagonist of α2 adrenergic receptor), respectively, on memory retention impairment induced by REM SD (RSD) in rats.
Materials and Methods: Multiple platform apparatus were used to induce RSD, and the passive avoidance task was used to assess memory consolidation. Clonidine and yohimbine were injected intra-CA1.
Results: The results showed that RSD (for 24 and 36, but not 12 hr) decreased memory retention, with no effect on locomotion. Post-training intra-CA1 infusion of a subthreshold dose of yohimbine (0.001 μg/rat) did not alter, while clonidine (0.1 μg/rat) restored memory retention impairment induced by RSD (24 and 36 hr). Also, none of the interventions did not influence locomotor activity.
Conclusion: Our data strongly showed that CA1 α2 adrenergic receptors have a critical role in RSD-induced memory retention impairment.


1. Eydipour Z, Nasehi M, Vaseghi S, Jamaldini SH, Zarrindast MR. The role of 5-HT4 serotonin receptors in the CA1 hippocampal region on memory acquisition impairment induced by total (TSD) and REM sleep deprivation (RSD). Physiol Behav 2020; 215:112788.
2. Javad-Moosavi BZ, Nasehi M, Vaseghi S, Jamaldini SH, Zarrindast MR. Activation and inactivation of nicotinic receptnors in the dorsal hippocampal region restored negative effects of total (TSD) and REM sleep deprivation (RSD) on memory acquisition, locomotor activity and pain perception. Neuroscience 2020; 433:200-211.
3. Norozpour Y, Nasehi M, Sabouri-Khanghah V, Torabi-Nami M, Zarrindast MR. The effect of CA1 alpha2 adrenergic receptors on memory retention deficit induced by total sleep deprivation and the reversal of circadian rhythm in a rat model. Neurobiol Learn Mem 2016; 133:53-60.
4. Javad-Moosavi BZ, Vaezi G, Nasehi M, Haeri-Rouhani SA, Zarrindast MR. Critical role of CA1 muscarinic receptors on memory acquisition deficit induced by total (TSD) and REM sleep deprivation (RSD). Prog Neuropsychopharmacol Biol Psychiatry 2017; 79:128-135.
5. de Bruin EJ, van Run C, Staaks J, Meijer AM. Effects of sleep manipulation on cognitive functioning of adolescents: A systematic review. Sleep Med Rev 2016; 32:45-57.
6. Havekes R, Vecsey CG, Abel T. The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity. Cell Signal 2012; 24:1251-1260.
7. Ertugrul A, Rezaki M. The neurobiology of sleep and its influence on memory. Turk Psikiyatri Derg 2004; 15:300-308.
8. Landmann N, Kuhn M, Maier JG, Spiegelhalder K, Baglioni C, Frase L, et al. REM sleep and memory reorganization: Potential relevance for psychiatry and psychotherapy. Neurobiol Learn Mem 2015; 122:28-40.
9. Kordestani-Moghadam P, Nasehi M, Khodagholi F, Vaseghi S, Zarrindast MR, Khani M. The fluctuations of metabotropic glutamate receptor subtype 5 (mGluR5) in the amygdala in fear conditioning model of male Wistar rats following sleep deprivation, reverse circadian and napping. Brain Res 2020; 1734:146739.
10. Kim Y, Elmenhorst D, Weisshaupt A, Wedekind F, Kroll T, McCarley RW, et al. Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain. J Sleep Res 2015; 24:549-558.
11. Uschakov A, Grivel J, Cvetkovic-Lopes V, Bayer L, Bernheim L, Jones BE, et al. Sleep-deprivation regulates alpha-2 adrenergic responses of rat hypocretin/orexin neurons. PLoS One 2011; 6:e16672.
12. Sirvio J, MacDonald E. Central alpha1-adrenoceptors: their role in the modulation of attention and memory formation. Pharmacol Ther 1999; 83:49-65.
13. Valizadegan F, Oryan S, Nasehi M, Zarrindast MR. Interaction between morphine and noradrenergic system of basolateral amygdala on anxiety and memory in the elevated plus-maze test based on a test-retest paradigm. Arch Iran Med 2013; 16:281-287.
14. Kim Y, Chen L, McCarley RW, Strecker RE. Sleep allostasis in chronic sleep restriction: the role of the norepinephrine system. Brain Res 2013; 1531:9-16.
15. MacDonald E, Kobilka BK, Scheinin M. Gene targeting--homing in on alpha 2-adrenoceptor-subtype function. Trends Pharmacol Sci 1997; 18:211-219.
16. Kable JW, Murrin LC, Bylund DB. In vivo gene modification elucidates subtype-specific functions of alpha(2)-adrenergic receptors. J Pharmacol Exp Ther 2000; 293:1-7.
17. Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 2005; 25:6716-6720.
18. Paxinos G, Watson C, Pennisi M, Topple A. Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 1985; 13:139-143.
19. Vaseghi S, Babapour V, Nasehi M, Zarrindast MR. Synergistic but not additive effect between ACPA and lithium in the dorsal hippocampal region on spatial learning and memory in rats: Isobolographic analyses. Chem Biol Interact 2019; 315:108895.
20. Machado RB, Hipolide DC, Benedito-Silva AA, Tufik S. Sleep deprivation induced by the modified multiple platform technique: quantification of sleep loss and recovery. Brain Res 2004; 1004:45-51.
21. Naseri MH, Hesami-Tackallou S, Torabi-Nami M, Zarrindast MR, Nasehi M. Involvement of the CA1 GABAA receptors in MK-801-induced anxiolytic-like effects: an isobologram analysis. Behav Pharmacol 2014; 25:197-205.
22. Nasehi M, Sahebgharani M, Haeri-Rohani A, Zarrindast MR. Effects of cannabinoids infused into the dorsal hippocampus upon memory formation in 3-days apomorphine-treated rats. Neurobiol Learn Mem 2009; 92:391-399.
23. Zarrindast MR, Farajzadeh Z, Rostami P, Rezayof A, Nourjah P. Involvement of the ventral tegmental area (VTA) in morphine-induced memory retention in morphine-sensitized rats. Behav Brain Res 2005; 163:100-106.
24. Malboosi N, Nasehi M, Hashemi M, Vaseghi S, Zarrindast MR. The neuroprotective effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1alpha, DeltafosB and CART genes in the hippocampus of male Wistar rats. Gene 2020; 742:144601.
25. Torabi-Nami M, Nasehi M, Zarrindast MR. Sleep loss and the brain vulnerability to neurodegeneration: behavioral, biochemical and neurohistopathological observations in a rat model. EXCLI J 2013; 12:347-372.
26. Dorokhov VB, Kozhedub RG, Arsen’ev GN, Kozhechkin SN, Ukraintseva Iu V, Kulikov MA, et al. [Sleep deprivation effect upon spatial memory consolidation in rats after one-day learning in a Morris water maze]. Zh Vyssh Nerv Deiat Im I P Pavlova 2011; 61:322-331.
27. Bridoux A, Laloux C, Derambure P, Bordet R, Monaca Charley C. The acute inhibition of rapid eye movement sleep by citalopram may impair spatial learning and passive avoidance in mice. J Neural Transm 2013; 120:383-389.
28. Ferry B, McGaugh JL. Involvement of basolateral amygdala alpha2-adrenoceptors in modulating consolidation of inhibitory avoidance memory. Learn Mem 2008; 15:238-243.
29. Silva RH, Abilio VC, Takatsu AL, Kameda SR, Grassl C, Chehin AB, et al. Role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice. Neuropharmacology 2004; 46:895-903.
30. Alzoubi KH, Rawashdeh NQ, Khabour OF, El-Elimat T, Albataineh H, Al-Zghool HM, et al. Evaluation of the effect of Moringa peregrina extract on learning and memory: Role of oxidative stress. J Mol Neurosci 2017; 63:355-363.
31. Liu YZ, Chen JK, Li ZP, Zhao T, Ni M, Li DJ, et al. High-salt diet enhances hippocampal oxidative stress and cognitive impairment in mice. Neurobiol Learn Mem 2014; 114:10-15.
32. Bridoux A, Laloux C, Derambure P, Bordet R, Monaca Charley C. The acute inhibition of rapid eye movement sleep by citalopram may impair spatial learning and passive avoidance in mice. J Neural Transm (Vienna) 2013; 120:383-389.
33. Beiranvand A, Nasehi M, Zarrindast MR, Moghaddasi M. Involvement of medial prefrontal cortex alpha-2 adrenoceptors on memory acquisition deficit induced by arachidonylcyclopropylamide, a cannabinoid CB1 receptor agonist, in rats; possible involvement of Ca2+ channels. J Psychopharmacol 2016; 30:945-954.
34. Li Y, Yu M, Zhao B, Wang Y, Zha Y, Li Z, et al. Clonidine preconditioning improved cerebral ischemia-induced learning and memory deficits in rats via ERK1/2-CREB/ NF-kappaB-NR2B pathway. Eur J Pharmacol 2018; 818:167-173.
35. Ellenbogen JM, Payne JD, Stickgold R. The role of sleep in declarative memory consolidation: passive, permissive, active or none? Curr Opin Neurobiol 2006; 16:716-722.
36. Ishikawa A, Kanayama Y, Matsumura H, Tsuchimochi H, Ishida Y, Nakamura S. Selective rapid eye movement sleep deprivation impairs the maintenance of long-term potentiation in the rat hippocampus. Eur J Neurosci 2006; 24:243-248.
37. Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol 2005; 493:99-110.
38. Gibbs ME, Summers RJ. Role of adrenoceptor subtypes in memory consolidation. Prog Neurobiol 2002; 67:345-391.
39. Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci 2009; 10:423-433.
40. Izquierdo I, Medina JH, Izquierdo LA, Barros DM, de Souza MM, Mello e Souza T. Short- and long-term memory are differentially regulated by monoaminergic systems in the rat brain. Neurobiol Learn Mem 1998; 69:219-224.
41. Bear MF, Singer W. Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 1986; 320:172-176.
42. Frey S, Bergado-Rosado J, Seidenbecher T, Pape HC, Frey JU. Reinforcement of early long-term potentiation (early-LTP) in dentate gyrus by stimulation of the basolateral amygdala: heterosynaptic induction mechanisms of late-LTP. J Neurosci 2001; 21:3697-3703.
43. Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 2003; 42:33-84.
44. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 2002; 3:591-605.
45. Aston-Jones G, Bloom FE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci 1981; 1:876-886.