Abstract
Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212–2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212–2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212–2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease.
Similar content being viewed by others
References
Abboussi O, Tazi A, Paizanis E, El Ganouni S (2014) Chronic exposure to WIN55, 212–2 affects more potently spatial learning and memory in adolescents than in adult rats via a negative action on dorsal hippocampal neurogenesis. Pharmacol Biochem Behav 120:95–102
Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13(13):93–110
Bambico FR, Nguyen N-T, Katz N, Gobbi G (2010) Chronic exposure to cannabinoids during adolescence but not during adulthood impairs emotional behaviour and monoaminergic neurotransmission. Neurobiol Dis 37(3):641–655
Bockaert J, Claeysen S, Bécamel C, Dumuis A, Marin P (2006) Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 326(2):553–572
Bossong MG, Niesink RJ (2010) Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol 92(3):370–385
Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G (2007) Eng W-s, Gibson R, Ryan C, Connolly B, Patel S et al: [18F] MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci 104(23):9800–9805
Casadio P et al. (2011) Cannabis use in young people: the risk for schizophrenia. Neurosci Biobehav Rev 35(8):1779–1787
Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 51(3):347–372
Chen G, Kittler JT, Moss SJ, Yan Z (2006) Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens. J Neurosci 26(9):2513–2521
Costantino L, Barlocco D (2012) Designed multiple ligands: basic research vs clinical outcomes. Curr Med Chem 19(20):3353–3387
David, I., Effets anxiolytiques/antidépresseurs et neurogéniques des ligands du récepteur 5-HT4 chez la Souris: rôle de la protéine β-arrestin 1, 2013, Université Paris Sud-Paris XI.
Degenhardt L, Coffey C, Romaniuk H, Swift W, Carlin JB, Hall WD, Patton GC (2013) The persistence of the association between adolescent cannabis use and common mental disorders into young adulthood. Addiction 108(1):124–133
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090):1946–1949
Fernandez-Espejo E, Viveros M-P, Núñez L, Ellenbroek BA, de Fonseca FR (2009) Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology 206(4):531–549
Gross, G. and K. Drescher, The role of dopamine D3 receptors in antipsychotic activity and cognitive functions, in Novel antischizophrenia treatments 2012, Springer. p. 167–210.Haadsma-svensson SR, svensson KA: PNU99194a: A preferential dopamine D3 receptor antagonist. CNS Drug Reviews 1998, 4(1):42–53.
Gross G, Wicke K, Drescher KU (2013) Dopamine D3 receptor antagonism—still a therapeutic option for the treatment of schizophrenia. Naunyn Schmiedeberg's Arch Pharmacol 386(2):155–166
Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11(2):563–583
Joyce JN, Millan MJ (2005) Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today 10(13):917–925
Kim K-M, Valenzano KJ, Robinson SR, Yao WD, Barak LS, Caron MG (2001) Differential regulation of the dopamine D2and D3 receptors by G protein-coupled receptor kinases and β-arrestins. J Biol Chem 276(40):37409–37414
King MV, Marsden CA, Fone KC (2008) A role for the 5-HT1A, 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol Sci 29(9):482–492
Köfalvi A, Rodrigues RJ, Ledent C, Mackie K, Vizi ES, Cunha RA, Sperlágh B (2005) Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis. J Neurosci 25(11):2874–2884
Kroeze WK, Roth BL (2012) Polypharmacological drugs: magic shotguns for psychiatric diseases. Polypharmacology in Drug Discovery 133-148
Lamirault L, Simon H (2001) Enhancement of place and object recognition memory in young adult and old rats by RS 67333, a partial agonist of 5-HT4 receptors. Neuropharmacology 41(7):844–853
Laszy J, Laszlovszky I, Gyertyán I (2005) Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology 179(3):567–575
Lau T, Schloss P (2008) The cannabinoid CB1 receptor is expressed on serotonergic and dopaminergic neurons. Eur J Pharmacol 578(2):137–141
Leweke FM, Schneider M (2011) Chronic pubertal cannabinoid treatment as a behavioral model for aspects of schizophrenia: effects of the atypical antipsychotic quetiapine. Int J Neuropsychopharmacol 14(01):43–51
Liu M-T, Kuan Y-H, Wang J, Hen R, Gershon MD (2009) 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J Neurosci 29(31):9683–9699
Luedtke RR, Mach RH (2003) Progress in developing D3 dopamine receptor ligands as potential therapeutic agents for neurological and neuropsychiatric disorders. Curr Pharm Des 9(8):643–671
Matsumoto M et al. (2001) Evidence for involvement of central 5-HT4 receptors in cholinergic function associated with cognitive processes: behavioral, electrophysiological, and neurochemical studies. J Pharmacol Exp Ther 296(3):676–682
Mendez-David I, David DJ, Darcet F, Wu MV, Kerdine-Römer S, Gardier AM, Hen R (2014) Rapid anxiolytic effects of a 5-HT4 receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology 39(6):1366–1378
Meneses A (1998) Physiological, pathophysiological and therapeutic roles of 5-HT systems in learning and memory. Rev Neurosci 9(4):275–290
Millan MJ, Di Cara B, Dekeyne A, Panayi F, De Groote L, Sicard D, Cistarelli L, Billiras R, Gobert A (2007) Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis. J Neurochem 100(4):1047–1061
Morphy R, Rankovic Z (2006) The physicochemical challenges of designing multiple ligands. J Med Chem 49(16):4961–4970
Neves SR, Ram PT, Iyengar R (2002) G protein pathways. Science 296(5573):1636–1639
O’Shea M, Singh ME, McGregor IS, Mallet PE (2004) Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats. J Psychopharmacol 18(4):502–508
Orsetti M et al. (2003) Acquisition, retention, and recall of memory after injection of RS67333, a 5-HT4 receptor agonist, into the nucleus basalis magnocellularis of the rat. Learn Mem 10(5):420–426
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors. Eur J Pharmacol 463(31):3–33
Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, Boyfield I, Branch CL, Cilia J, Coldwell MC (2000) Pharmacological actions of a novel, high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-a. J Pharmacol Exp Ther 294(3):1154–1165
Saykin AJ et al. (1991) Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry 48(7):618–624
Schneider M, Koch M (2003) Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmacology 28(10):1760–1769
Schneider M, Koch M (2007) The effect of chronic peripubertal cannabinoid treatment on deficient object recognition memory in rats after neonatal mPFC lesion. Eur Neuropsychopharmacol 17(3):180–186
Schreiner AM, Dunn ME (2012) Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychopharmacol 20(5):420
Stone WS, Hsi X (2011a) Declarative memory deficits and schizophrenia: problems and prospects. Neurobiol Learn Mem 96(4):544–552
Stone WS, Hsi X (2011b) Declarative memory deficits and schizophrenia: problems and prospects. Neurobiol Learn Mem 96(4):544–552
Trezza V, Campolongo P, Manduca A, Morena M, Palmery M, Vanderschuren LJ, Cuomo V (2012) Altering endocannabinoid neurotransmission at critical developmental ages: impact on rodent emotionality and cognitive performance. Front Behav Neurosci 6:02
UNODC - United Nations Office on Drugs and Crime: World Drug Report 2013:20–48.
Zarrindast MR, Dorrani M, Lachinani R, Rezayof A (2010) Blockade of dorsal hippocampal dopamine receptors inhibits state-dependent learning induced by cannabinoid receptor agonist in mice. Neurosci Res 67(1):25–32
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Abboussi, O., Said, N., Fifel, K. et al. Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence. Metab Brain Dis 31, 321–327 (2016). https://doi.org/10.1007/s11011-015-9753-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-015-9753-2