, Volume 236, Issue 7, pp 2235–2242 | Cite as

Effects of the synthetic cannabinoid 5F-AMB on anxiety and recognition memory in mice

  • Shiho Ito
  • Satoshi Deyama
  • Masaki Domoto
  • Tong Zhang
  • Hitoki Sasase
  • Akari Fukao
  • Hirohito Esaki
  • Eiichi Hinoi
  • Shuji Kaneko
  • Katsuyuki KanedaEmail author
Original Investigation



N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-l-valine methyl ester (5F-AMB) is a synthetic cannabinoid that has been distributed recently. Although inhalation of 5F-AMB produces adverse effects, such as impaired memory and disturbed consciousness, in humans, the psychopharmacological effects of 5F-AMB in rodents have not been investigated.


We first examined the effects of intraperitoneal and intracerebroventricular injections of 5F-AMB on anxiety-like behavior and locomotor activity in the open field (OF) test and recognition memory in the novel object recognition test (NOR) in C57BL/6J mice. We also examined whether a cannabinoid 1 (CB1) receptor antagonist AM251 blocks the effects of 5F-AMB. We next examined the effects of 5F-AMB infusion into the medial prefrontal cortex (mPFC), a brain region associated with anxiety and memory, on these tests.


Intraperitoneal injection of 5F-AMB (0.3 mg/kg) dramatically decreased locomotor activity in the OF, and this effect was partially reversed by AM251 (3 mg/kg). Intracerebroventricular infusion of 5F-AMB (10 nmol) produced an anxiolytic effect in the OF and impaired acquisition, but not retrieval, of recognition memory in the NOR, and these effects were blocked by co-infusion of AM251 (1.8 nmol). Bilateral intra-mPFC infusion of 5F-AMB (10 pmol/side) similarly produced impaired recognition memory acquisition, but no anxiolytic effect.


The results demonstrate that centrally administered 5F-AMB produces anxiolytic effect and impaired recognition memory acquisition via activation of CB1 receptors, while systemic 5F-AMB severely impaired locomotor activity. The mPFC is involved in 5F-AMB-induced impairment of recognition memory acquisition. However, other brain region(s) may contribute to the 5F-AMB-induced anxiolytic effect.


5F-AMB Synthetic cannabinoids Designer drug Medial prefrontal cortex 


Funding information

This study was supported by Grant-in-Aid for Scientific Research (C) (K.K., 15K06765, 18K06520) from the Japan Society for the Promotion of Science (JSPS); Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sport, Science, and Technology of Japan (S.K., 15K15182); grant from Suzuken Memorial Foundation (K.K.); and the Kurata Grant awarded by the Hitachi Global Foundation (K.K.), Hoansha Foundation (K.K.), and Smoking Research Foundation (K.K.).

Compliance with ethical standards

All experiments were performed with the approval of the Institutional Animal Care and Use Committee at Kanazawa University.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.


  1. Alon MH, Saint-Fleur MO (2017) Synthetic cannabinoid induced acute respiratory depression: case series and literature review. Respir Med Case Rep 22:137–141Google Scholar
  2. Araque A, Castillo PE, Manzoni OJ, Tonini R (2017) Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124:13–24CrossRefGoogle Scholar
  3. Banister SD, Longworth M, Kevin R, Sachdev S, Santiago M, Stuart J, Mack JB, Glass M, McGregor IS, Connor M, Kassiou M (2016) Pharmacology of valinate and tert-leucinate synthetic cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues. ACS Chem Neurosci 7:1241–1254CrossRefGoogle Scholar
  4. Beiranvand A, Nasehi M, Zarrindast MR, Moghaddasi M (2016) 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 30:945–954CrossRefGoogle Scholar
  5. Berrendero F, Maldonado R (2002) Involvement of the opioid system in the anxiolytic-like effects induced by Δ9-tetrahydrocannabinol. Psychopharmacology 163:111–117CrossRefGoogle Scholar
  6. Chocyk A, Majcher-Maslanka I, Dudys D, Przyborowska A, Wedzony K (2013) Impact of early-life stress on the medial prefrontal cortex functions—a search for the pathomechanisms of anxiety and mood disorders. Pharmacol Rep 65:1462–1470CrossRefGoogle Scholar
  7. Deyama S, Ishikawa Y, Yoshikawa K, Shimoda K, Ide S, Satoh M, Minami M (2017) Resolvin D1 and D2 reverse lipopolysaccharide-induced depression-like behaviors through the mTORC1 signaling pathway. Int J Neuropsychopharmacol 20:575–584CrossRefGoogle Scholar
  8. Domoto M, Sasase H, Wada S, Ito S, Deyama S, Hinoi E, Kaneko S, Kaneda K (2018) The synthetic cannabinoid 5F-AMB changes the balance between excitation and inhibition of layer V pyramidal neurons in the mouse medial prefrontal cortex. Psychopharmacology 235:2367–2376CrossRefGoogle Scholar
  9. Dong Y, White FJ (2003) Dopamine D1-class receptors selectively modulate a slowly inactivating potassium current in rat medial prefrontal cortex pyramidal neurons. J Neurosci 23:2686–2695CrossRefGoogle Scholar
  10. Egerton A, Allison C, Brett RR, Pratt JA (2006) Cannabinoids and prefrontal cortical function: insights from preclinical studies. Neurosci Biobehav Rev 30:680–695CrossRefGoogle Scholar
  11. Franklin KBJ, Paxinos G (2007) The mouse brain in stereotaxic coordinates, 3rd edn. Elsevier, BurlingtonGoogle Scholar
  12. Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066CrossRefGoogle Scholar
  13. Gatch MB, Forester MJ (2014) Δ9-tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found K2/spice. Behav Pharmacol 25:750–757CrossRefGoogle Scholar
  14. Gatch MB, Forester MJ (2016) Δ9-tetrahydrocannabinol-like effects of novel synthetic cannabinoids in mice and rats. Psychopharmacology 233:1901–1910CrossRefGoogle Scholar
  15. Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Watanabe K, Suzuki O (2015) Postmortem distribution of AB-CHMINACA, 5-fluoro-AMB, and diphenidine in body fluids and solid tissues in a fatal poisoning case: usefulness of the adipose tissue for detection of the drugs in the unchanged forms. Forensic Toxicol 33:45–53CrossRefGoogle Scholar
  16. Kaneko S (2017) Motor vehicle collisions caused by the ‘super-strength’ synthetic cannabinoids, MAM-2201, 5F-PB-22, 5F-AB-PINACA, 5F-AMB and 5F-ADB in Japan experienced from 2012 to 2014. Forensic Toxicol 35:244–251CrossRefGoogle Scholar
  17. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89:309–380CrossRefGoogle Scholar
  18. Kruk-Slomka M, Biala G (2016) CB1 receptors in the formation of the different phases of memory-related processes in the inhibitory avoidance test in mice. Behav Brain Res 301:84–95CrossRefGoogle Scholar
  19. Kucewicz MT, Tricklebank MD, Bogacz R, Jones MW (2011) Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation. J Neurosci 31:15560–15568CrossRefGoogle Scholar
  20. Le Boisselier R, Alexandre J, Lelong-Boulouard V, Debruyne D (2017) Focus on cannabinoids and synthetic cannabinoids. Clin Pharmacol Ther 101:220–229CrossRefGoogle Scholar
  21. Lutz B, Marsicano G, Maldonado R, Hillard CJ (2015) The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci 16:705–718CrossRefGoogle Scholar
  22. Mishima K, Egashira N, Hirosawa N, Fujii M, Matsumoto Y, Iwasaki K, Fujiwara M (2001) Characteristics of learning and memory impairment induced by Δ9-tetrahydrocannabinol in rats. Jpn J Pharmacol 87:297–308CrossRefGoogle Scholar
  23. Morena M, Campolongo P (2014) The endocannabinoid system: an emotional buffer in the modulation of memory function. Neurobiol Learn Mem 112:30–43CrossRefGoogle Scholar
  24. Morici JF, Bekinschtein P, Weisstaub NV (2015) Medial prefrontal cortex role in recognition memory in rodents. Behav Brain Res 292:241–251CrossRefGoogle Scholar
  25. Onaivi ES, Green MR, Martin BR (1990) Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther 253:1002–1009Google Scholar
  26. Pezze MA, Marshall HJ, Fone KC, Cassaday HJ (2015) Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: role of the prelimbic cortex. Eur Neuropsychopharmacol 25:2145–2156CrossRefGoogle Scholar
  27. Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, Thompson MR, Dawson B, Mallet PE, Kashem MA, Matsuda-Matsumoto H, Iwazaki T, McGregor IS (2008) Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126CrossRefGoogle Scholar
  28. Resstel LB, Lisboa SF, Aguiar DC, Correa FM, Guimaraes FS (2008) Activation of CB1 cannabinoid receptors in the dorsolateral periaqueductal gray reduces the expression of contextual fear conditioning in rats. Psychopharmacology 198:405–411CrossRefGoogle Scholar
  29. Rubino T, Sala M, Vigano D, Braida D, Castiglioni C, Limonta V, Guidali C, Realini N, Parolaro D (2007) Cellular mechanisms underlying the anxiolytic effect of low doses of peripheral Δ9-tetrahydrocannabinol in rats. Neuropsychopharmacology 32:2036–2045CrossRefGoogle Scholar
  30. Rubino T, Guidali C, Vigano D, Realini N, Valenti M, Massi P, Parolaro D (2008a) CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour. Neuropharmacology 54:151–160CrossRefGoogle Scholar
  31. Rubino T, Realini N, Castiglioni C, Guidali C, Vigano D, Marras E, Petrosino S, Perletti G, Maccarrone M, Di Marzo V, Parolaro D (2008b) Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 18:1292–1301CrossRefGoogle Scholar
  32. Schneider M, Schomig E, Leweke FM (2008) Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats. Addict Biol 13:345–357CrossRefGoogle Scholar
  33. Schreiber S, Bader M, Lenchinski T, Meningher I, Rubovitch V, Katz Y, Cohen E, Gabet Y, Rotenberg M, Wolf EU, Pick CG (2018) Functional effects of synthetic cannabinoids versus Δ9-THC in mice on body temperature, nociceptive threshold, anxiety, cognition, locomotor/exploratory parameters and depression. Addict Biol in pressGoogle Scholar
  34. Shanks KG, Behonick GS (2016) Death after use of the synthetic cannabinoid 5F-AMB. Forensic Sci Int 262:e21–e24CrossRefGoogle Scholar
  35. Silva de Melo LC, Cruz AP, Rios Valentim SJ Jr, Marinho AR, Mendonca JB, Nakamura-Palacios EM (2005) Δ9-THC administered into the medial prefrontal cortex disrupts the spatial working memory. Psychopharmacology 183:54–64CrossRefGoogle Scholar
  36. Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R (2002) Behavioural and biochemical evidence for interactions between Δ9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578CrossRefGoogle Scholar
  37. Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH (2007) Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology 32:1032–1041CrossRefGoogle Scholar
  38. Vinals X, Moreno E, Lanfumey L, Cordomi A, Pastor A, de La Torre R, Gasperini P, Navarro G, Howell LA, Pardo L, Lluis C, Canela EI, McCormick PJ, Maldonado R, Robledo P (2015) Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors. PLoS Biol 13:e1002194CrossRefGoogle Scholar
  39. Wiley JL, Marusich JA, Lefever TW, Grabenauer M, Moore KN, Thomas BF (2013) Cannabinoids in disguise: Δ9-tetrahydrocannabinol-like effects of tetramethylcyclopropyl ketone indoles. Neuropharmacology 75:145–154CrossRefGoogle Scholar
  40. Witkowski G, Szulczyk B, Rola R, Szulczyk P (2008) D1 dopaminergic control of G protein-dependent inward rectifier K+ (GIRK)-like channel current in pyramidal neurons of the medial prefrontal cortex. Neuroscience 155:53–63CrossRefGoogle Scholar
  41. Zanettini C, Panlilio LV, Alicki M, Goldberg SR, Haller J, Yasar S (2011) Effects of endocannabinoid system modulation on cognitive and emotional behavior. Front Behav Neurosci 5:57CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  2. 2.Department of Molecular Pharmacology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan

Personalised recommendations