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Short- and long-term consequences of prenatal exposure to the cannabinoid agonist WIN55,212-2 on rat glutamate transmission and cognitive functions

  • Basic Neurosciences, Genetics and Immunology - Review Article
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Abstract

The aim of the present review is to summarize integrated neurochemical, morphological and neurobehavioral evidence, in particular from our laboratory, which emphasize the short- and long-term consequences of prenatal exposure to the cannabinoid receptor agonist WIN55,212-2 on rat glutamate transmission and cognitive functions. The results obtained provide evidence that maternal exposure to WIN55,212-2 induces an impairment of cognitive capacities in the offspring. This impairment is associated with alterations of cortical and hippocampal glutamate outflow, cortical neuron morphology and hippocampal long-term potentiation. These findings are in line with clinical data showing that the consumption of marijuana by women during pregnancy has negative consequences on the cognitive functions of their children. Thus, although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of glutamate transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported.

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References

  • Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58:315–348

    Article  PubMed  CAS  Google Scholar 

  • Ang ESBC, Haydar TF, Gluncic V, Rakic P (2003) Four-dimensional migratory coordinates of GABAergic interneurons in the developing mouse cortex. J Neurosci 23:5805–5815

    PubMed  CAS  Google Scholar 

  • Antonelli T, Tanganelli S, Tomasini MC, Finetti S, Trabace L, Steardo L, Sabino V, Carratu MR, Cuomo V, Ferraro L (2004) Long-term effects on cortical glutamate release induced by prenatal exposure to the cannabinoid receptor agonist (R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1, 2, 3-de]-1, 4-benzoxazin-6-yl]-1-naphthalenylmethanone: an in vivo microdialysis study in the awake rat. Neuroscience 124:367–375

    Article  PubMed  CAS  Google Scholar 

  • Antonelli T, Tomasini MC, Tattoli M, Cassano T, Tanganelli S, Finetti S, Mazzoni E, Trabace L, Steardo L, Cuomo V, Ferraro L (2005) Prenatal exposure to the CB1 receptor agonist WIN 55, 212-2 causes learning disruption associated with impaired cortical NMDA receptor function and emotional reactivity changes in rat offspring. Cereb Cortex 15:2013–2020

    Article  PubMed  Google Scholar 

  • Antonelli T, Tomasini MC, Tattoli M, Cassano T, Finetti S, Mazzoni E, Trabace L, Carratù MR, Cuomo V, Tanganelli S, Ferraro L (2006) Prenatal exposure to the cannabinoid receptor agonist WIN 55, 212-2 and carbon monoxide reduces extracellular glutamate levels in primary rat cerebral cortex cell cultures. Neurochem Int 49:568–576

    Article  PubMed  CAS  Google Scholar 

  • Benagiano V, Lorusso L, Flace P, Girolamo F, Rizzi A, Sabatini R, Auteri P, Bosco L, Cagiano R, Ambrosi G (2007) Effects of prenatal exposure to the CB-1 receptor agonist WIN 55212-2 or CO on the GABAergic neuronal systems of rat cerebellar cortex. Neuroscience 149:592–601

    Article  PubMed  CAS  Google Scholar 

  • Berghuis P, Dobszay MB, Wang X, Spano S, Ledda F, Sousa KM, Schulte G, Ernfors P, Mackie K, Paratcha G, Hurd YL, Harkany T (2005) Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor. Proc Natl Acad Sci USA 102:19115–19120

    Article  PubMed  CAS  Google Scholar 

  • Bernard C, Milh M, Morozov YM, Ben-Ari Y, Freund TF, Gozlan H (2005) Altering cannabinoid signaling during development disrupts neuronal activity. Proc Natl Acad Sci USA 102:9388–9393

    Article  PubMed  CAS  Google Scholar 

  • Berrendero F, Sepe N, Ramos JA, Di Marzo V, Fernández-Ruiz JJ (1999) Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period. Synapse 33:181–191

    Article  PubMed  CAS  Google Scholar 

  • Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

    Article  PubMed  CAS  Google Scholar 

  • Campolongo P, Trezza V, Cassano T, Gaetani S, Morgese MG, Ubaldi M, Soverchia L, Antonelli T, Ferraro L, Massi M, Ciccocioppo R, Cuomo V (2007) Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict Biol 12:485–495

    Article  PubMed  CAS  Google Scholar 

  • Castaldo P, Magi S, Gaetani S, Cassano T, Ferraro L, Antonelli T, Amoroso S, Cuomo V (2007) Prenatal exposure to the cannabinoid receptor agonist WIN 55, 212–2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex. Neuropharmacology 53:369–378

    Article  PubMed  CAS  Google Scholar 

  • Dahl RE, Scher MS, Williamson DE, Robles N, Day N (1995) A longitudinal study of prenatal marijuana use. Effects on sleep and arousal at age 3 years. Arch Pediatr Adolesc Med 149:145–150

    PubMed  CAS  Google Scholar 

  • Day NL, Richardson GA, Goldschmidt L, Robles N, Taylor PM, Stoffer DS, Cornelius MD, Geva D (1994) Effect of prenatal marijuana exposure on the cognitive development of offspring at age three. Neurotoxicol Teratol 16:169–175

    Article  PubMed  CAS  Google Scholar 

  • English DR, Hulse GK, Milne E, Holman CD, Bower CI (1997) Maternal cannabis use and birth weight: a meta-analysis. Addiction 92:1553–1560

    Article  PubMed  CAS  Google Scholar 

  • Fernández-Ruiz JJ, Berrendero F, Hernández ML, Romero J, Ramos JA (1999) Role of endocannabinoids in brain development. Life Sci 65(6–7):725–736

    Google Scholar 

  • Fernández-Ruiz J, Berrendero F, Hernández ML, Ramos JA (2000) The endogenous cannabinoid system and brain development. Trends Neurosci 23:14–20

    Article  PubMed  Google Scholar 

  • French ED, Dillon K, Wu X (1997) Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 8:649–652

    Article  PubMed  CAS  Google Scholar 

  • Fride E (2008) Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development. J Neuroendocrinol 20(Suppl 1):75–81

    Article  PubMed  CAS  Google Scholar 

  • Fride E, Mechoulam R (1996) Developmental aspects of anandamide: ontogeny of response and prenatal exposure. Psychoneuroendocrinology 21(2):157–172

    Article  PubMed  CAS  Google Scholar 

  • Fried PA (1982) Marihuana use by pregnant women and effects on offspring: an update. Neurobehav Toxicol Teratol 4(4):451–454

    PubMed  CAS  Google Scholar 

  • Fried PA (2002) Adolescents prenatally exposed to marijuana: examination of facets of complex behaviors and comparisons with the influence of in utero cigarettes. J Clin Pharmacol 42:97S–102S

    PubMed  CAS  Google Scholar 

  • Fried PA, Makin JE (1987) Neonatal behavioural correlates of prenatal exposure to marihuana, cigarettes and alcohol in a low risk population. Neurotoxicol Teratol 9:1–7

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, Smith AM (2001) A literature review of the consequences of prenatal marihuana exposure. An emerging theme of a deficiency in aspects of executive function. Neurotoxicol Teratol 23:1–11

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, Watkinson B (1988) 12- and 24-month neurobehavioural follow-up of children prenatally exposed to marihuana, cigarettes and alcohol. Neurotoxicol Teratol 10:305–313

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, Watkinson B (1990) 36- and 48-month neurobehavioral follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol. J Dev Behav Pediatr 11:49–58

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, Watkinson B (2000) Visuoperceptual functioning differs in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 22:11–20

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, O’Connell CM, Watkinson B (1992) 60- and 72-month follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol: cognitive and language assessment. J Dev Behav Pediatr 13:383–391

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, Watkinson B, Gray R (1999) Growth from birth to early adolescence in offspring prenatally exposed to cigarettes and marijuana. Neurotoxicol Teratol 21:513–525

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, Watkinson B, Gray R (2003) Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 25:427–436

    Article  PubMed  CAS  Google Scholar 

  • Galve-Roperh I, Aguado T, Rueda D, Velasco G, Guzmán M (2006) Endocannabinoids: a new family of lipid mediators involved in the regulation of neural cell development. Curr Pharm Des 12:2319–2325

    Article  PubMed  CAS  Google Scholar 

  • García-Gil L, de Miguel R, Muñoz RM, Cebeira M, Villanua MA, Ramos JA, Fernández-Ruiz JJ (1997) Perinatal delta(9)-tetrahydrocannabinol exposure alters the responsiveness of hypothalamic dopaminergic neurons to dopamine-acting drugs in adult rats. Neurotoxicol Teratol 19:477–487

    Article  PubMed  Google Scholar 

  • García-Gil L, Ramos JA, Rubino T, Parolaro D, Fernández-Ruiz JJ (1998) Perinatal delta9-tetrahydrocannabinol exposure did not alter dopamine transporter and tyrosine hydroxylase mRNA levels in midbrain dopaminergic neurons of adult male and female rats. Neurotoxicol Teratol 20(5):549–553

    Google Scholar 

  • Garcia-Gil L, de Miguel R, Romero J, Perez A, Ramos JA, Fernández-Ruiz JJ (1999) Perinatal delta9-tetrahydrocannabinol exposure augmented the magnitude of motor inhibition caused by GABA(B), but not GABA(A), receptor agonists in adult rats. Neurotoxicol Teratol 21:277–283

    Article  PubMed  CAS  Google Scholar 

  • Goldschmidt L, Day NL, Richardson GA (2000) Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol 22:325–336

    Article  PubMed  CAS  Google Scholar 

  • Goldschmidt L, Richardson GA, Cornelius MD, Day NL (2004) Prenatal marijuana and alcohol exposure and academic achievement at age 10. Neurotoxicol Teratol 26:521–532

    Article  PubMed  CAS  Google Scholar 

  • Goldschmidt L, Richardson GA, Willford J, Day NL (2008) Prenatal marijuana exposure and intelligence test performance at age 6. J Am Acad Child Adolesc Psychiatry 47:254–263

    Article  PubMed  Google Scholar 

  • Griffith DR, Azuma SD, Chasnoff IJ (1994) Three-year outcome of children exposed prenatally to drugs. J Am Acad Child Adolesc Psychiatry 33:20–27

    Article  PubMed  CAS  Google Scholar 

  • Hampson RE, Deadwyler SA (2000) Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats. J Neurosci 20:8932–8942

    PubMed  CAS  Google Scholar 

  • Hampson AJ, Bornheim LM, Scanziani M, Yost CS, Gray AT, Hansen BM, Leonoudakis DJ, Bickler PE (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 70:671–676

    Article  PubMed  CAS  Google Scholar 

  • Harkany T, Guzmán M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92

    Article  PubMed  CAS  Google Scholar 

  • Hayes JS, Lampart R, Dreher MC, Morgan L (1991) Five-year follow-up of rural Jamaican children whose mothers used marijuana during pregnancy. West Indian Med J 40:120–123

    PubMed  CAS  Google Scholar 

  • 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 11:563–583

    PubMed  CAS  Google Scholar 

  • Hernández ML, García-Gil L, Berrendero F, Ramos JA, Fernández-Ruiz JJ (1997) delta 9-Tetrahydrocannabinol increases activity of tyrosine hydroxylase in cultured fetal mesencephalic neurons. J Mol Neurosci 8:83–91

    Article  PubMed  Google Scholar 

  • Huizink AC, Mulder EJ (2006) Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev 30:24–41

    Article  PubMed  CAS  Google Scholar 

  • Insel TR, Hill JL, Mayor RB (1986) Rat pup ultrasonic isolation calls: possible mediation by the benzodiazepine receptor complex. Pharmacol Biochem Behav 24:1263–1267

    Article  PubMed  CAS  Google Scholar 

  • Kehne JH, McCloskey TC, Baron BM, Chi EM, Harrison BL, Whitten JP, Palfreyman MG (1991) NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations. Eur J Pharmacol 193:283–292

    Article  PubMed  CAS  Google Scholar 

  • Kozloski J, Hamzei-Sichani F, Yuste R (2001) Stereotyped position of local synaptic targets in neocortex. Science 293:868–872

    Article  PubMed  CAS  Google Scholar 

  • Leinekugel X, Khazipov R, Cannon R, Hirase H, Ben-Ari Y, Buzsáki G (2002) Correlated bursts of activity in the neonatal hippocampus in vivo. Science 296:2049–2052

    Article  PubMed  CAS  Google Scholar 

  • Luk KC, Kennady TE, Sadikot AF (2003) Glutamate promotes proliferation of striatal neuronal progenitors by an NMDA receptor-mediated mechanism. J Neurosci 23:2239–2255

    PubMed  CAS  Google Scholar 

  • Mackie K (2005) Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol 168:299–325

    Article  PubMed  CAS  Google Scholar 

  • Mailleux P, Vanderhaeghen JJ (1992) Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons. Neurosci Lett 148:173–176

    Article  PubMed  CAS  Google Scholar 

  • Mato S, Del Olmo E, Pazos A (2003) Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain. Eur J Neurosci 17:1747–1754

    Article  PubMed  Google Scholar 

  • Mereu G, Fà M, Ferraro L, Cagiano R, Antonelli T, Tattoli M, Ghiglieri V, Tanganelli S, Gessa GL, Cuomo V (2003) Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release. Proc Natl Acad Sci USA 100:4915–4920

    Article  PubMed  CAS  Google Scholar 

  • Navarro M, Rubio P, de Fonseca FR (1995) Behavioural consequences of maternal exposure to natural cannabinoids in rats. Psychopharmacology 122:1–14

    Article  PubMed  CAS  Google Scholar 

  • Navarro M, de Miguel R, Rodríguez de Fonseca F, Ramos JA, Fernández-Ruiz JJ (1996) Perinatal cannabinoid exposure modifies the sociosexual approach behavior and the mesolimbic dopaminergic activity of adult male rats. Behav Brain Res 75:91–98

    Article  PubMed  CAS  Google Scholar 

  • Parmentier-Batteur S, Jin K, Mao XO, Xie L, Greenberg DA (2002) Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci 22:9771–9775

    PubMed  CAS  Google Scholar 

  • Pattij T, Wiskerke J, Schoffelmeer AN (2008) Cannabinoid modulation of executive functions. Eur J Pharmacol 585:458–463

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (2000) Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Invest Drugs 9:1553–1571

    Article  CAS  Google Scholar 

  • Ranganathan M, D’Souza DC (2006) The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl) 188:425–444

    Article  CAS  Google Scholar 

  • Richardson GA, Day NL, Goldschmidt L (1995) Prenatal alcohol, marijuana, and tobacco use: infant mental and motor development. Neurotoxicol Teratol 17:479–487

    Article  PubMed  CAS  Google Scholar 

  • Richardson GA, Ryan C, Willford J, Day NL, Goldschmidt L (2002) Prenatal alcohol and marijuana exposure: effects on neuropsychological outcomes at 10 years. Neurotoxicol Teratol 24:309–320

    Article  PubMed  CAS  Google Scholar 

  • Rodríguez de Fonseca F, Cebeira M, Fernández-Ruiz JJ, Navarro M, Ramos JA (1991) Effects of pre- and perinatal exposure to hashish extracts on the ontogeny of brain dopaminergic neurons. Neuroscience 43:713–723

    Article  PubMed  Google Scholar 

  • Rodríguez de Fonseca F, Hernández ML, de Miguel R, Fernández-Ruiz JJ, Ramos JA (1992) Early changes in the development of dopaminergic neurotransmission after maternal exposure to cannabinoids. Pharmacol Biochem Behav 41:469–474

    Article  PubMed  Google Scholar 

  • Rodríguez de Fonseca F, Ramos JA, Bonnin A, Fernández-Ruiz JJ (1993) Presence of cannabinoid binding sites in the brain from early postnatal ages. Neuroreport 4:135–138

    PubMed  Google Scholar 

  • Sarne Y, Mechoulam R (2005) Cannabinoids: between neuroprotection and neurotoxicity. Curr Drug Targets CNS Neurol Disord 4:677–684

    Article  PubMed  CAS  Google Scholar 

  • Scher MS, Richardson GA, Coble PA, Day NL, Stoffer DS (1988) The effects of prenatal alcohol and marijuana exposure: disturbances in neonatal sleep cycling and arousal. Pediatr Res 24:101–105

    Article  PubMed  CAS  Google Scholar 

  • Smith AM, Fried PA, Hogan MJ, Cameron J (2004) Effects of prenatal marijuana on response inhibition: an fMRI study of young adults. Neurotoxicol Teratol 26:533–542

    Article  PubMed  CAS  Google Scholar 

  • Suárez I, Bodega G, Rubio M, Fernández-Ruiz JJ, Ramos JA, Fernández B (2004) Prenatal cannabinoid exposure down-regulates glutamate transporter expressions (GLAST and EAAC1) in the rat cerebellum. Dev Neurosci 26:45–53

    Article  PubMed  CAS  Google Scholar 

  • Vela G, Martín S, García-Gil L, Crespo JA, Ruiz-Gayo M, Fernández-Ruiz JJ, García-Lecumberri C, Pélaprat D, Fuentes JA, Ramos JA, Ambrosio E (1998) Maternal exposure to delta9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central mu opioid receptors in adult offspring female rats. Brain Res 807:101–109

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

These studies were supported by Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2005 and FIRB 2007) and by the “Fondazione Cassa di Risparmio di Ferrara”, Italy.

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Authors and Affiliations

  1. Pharmacology Section and BioPharmaNet TransLab, Department of Clinical and Experimental Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44100, Ferrara, Italy

    Luca Ferraro, M. C. Tomasini, S. Beggiato, S. Tanganelli & T. Antonelli

  2. Department of Pharmacology and Physiology, Sapienza University of Rome, Rome, Italy

    S. Gaetani & V. Cuomo

  3. Department of Biomedical Sciences, University of Foggia, Foggia, Italy

    T. Cassano

  4. Pharmacology Section, Department of Neuroscience, University Politecnica of Marche, Ancona, Italy

    S. Amoroso

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  1. Luca Ferraro
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Correspondence to S. Tanganelli.

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Ferraro, L., Tomasini, M.C., Beggiato, S. 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 116, 1017–1027 (2009). https://doi.org/10.1007/s00702-009-0230-0

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