Cannabis use in pregnancy and early life and its consequences: animal models

  • Miriam SchneiderEmail author
Special Issue


Cannabinoid receptors and their endogenous ligands have been detected from the earliest stages of embryonic development. The endocannabinoid system appears to play essential roles in these early stages for neuronal development and cell survival, although its detailed involvement in fundamental developmental processes such as proliferation, migration and differentiation has not yet been completely understood. Therefore, it is not surprising that manipulations of the endocannabinoid system by cannabinoid exposure during early developmental stages can result in long-lasting neurobehavioural consequences. The present review will summarize the possible residual behavioural effects of cannabinoid administration during pre- and perinatal as well as early postnatal development, derived from animal studies.


Cannabinoids Prenatal Postnatal CB1 receptor Pregnancy Animal models 



Brain growth spurt




Conditioned place preference


CP 55,940


Elevated plus maze


Forced swim test


Gestational day


Postnatal day


Progressive ratio




Ultrasonic vocalization


WIN 55,212-2


  1. 1.
    Abel EL (1980) Prenatal exposure to cannabis: a critical review of effects on growth, development, and behavior. Behav Neural Biol 29:137–156PubMedCrossRefGoogle Scholar
  2. 2.
    Abel EL (1983) Marihuana, tobacco, alcohol and reproduction. CRC Press, Boca RatonGoogle Scholar
  3. 3.
    Abel EL, Day N, Dintcheff BA, Ernst CAS (1979) Inhibition of postnatal maternal performance in rats treated with marijuana extract during pregnancy. Bull Psychon Soc 4:353–359Google Scholar
  4. 4.
    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 15:2013–2020PubMedCrossRefGoogle Scholar
  5. 5.
    Biscaia M, Fernandez B, Higuera-Matas A, Miguens M, Viveros MP, Garcia-Lecumberri C, Ambrosio E (2008) Sex-dependent effects of periadolescent exposure to the c cannabinoid agonist CP-55, 940 on morphine self-administration behaviour and the endogenous opioid system. Neuropharmacology 54:863–873PubMedCrossRefGoogle Scholar
  6. 6.
    Biscaia M, Marin S, Fernandez B, Marco EM, Rubio M, Guaza C, Ambrosio E, Viveros MP (2003) Chronic treatment with CP 55, 940 during the peri-adolescent period differentially affects the behavioural responses of male and female rats in adulthood. Psychopharmacology 170:301–308PubMedCrossRefGoogle Scholar
  7. 7.
    Bolles RC, Woods PJ (1964) The ontogeny of behaviour in the albino rat. Anim Behav 12:427–441CrossRefGoogle Scholar
  8. 8.
    Bortolato M, Frau R, Orru M, Casti A, Aru GN, Fa M, Manunta M, Usai A, Mereu G, Gessa GL (2006) Prenatal exposure to a cannabinoid receptor agonist does not affect sensorimotor gating in rats. Eur J Pharmacol 531:166–170PubMedCrossRefGoogle Scholar
  9. 9.
    Campbell BA, Lytle LD, Fibiger HC (1969) Ontogeny of adrenergic arousal and cholinergic inhibitory mechanisms in the rat. Science 166:635–637PubMedCrossRefGoogle Scholar
  10. 10.
    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 12:485–495PubMedCrossRefGoogle Scholar
  11. 11.
    Dalterio SL (1986) Cannabinoid exposure: effects on development. Neurobehav Toxicol Teratol 8:345–352PubMedGoogle Scholar
  12. 12.
    Dobbing J, Sands J (1979) Comparative aspects of the brain growth spurt. Early Hum Dev 3:79–83PubMedCrossRefGoogle Scholar
  13. 13.
    Economidou D, Mattioli L, Ubaldi M, Lourdusamy A, Soverchia L, Hardiman G, Campolongo P, Cuomo V, Ciccocioppo R (2007) Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to Delta9-tetrahydrocannabinol. Toxicol Appl Pharmacol 223:73–85PubMedCrossRefGoogle Scholar
  14. 14.
    Ellgren M, Spano SM, Hurd YL (2007) Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats. Neuropsychopharmacology 32:607–615PubMedCrossRefGoogle Scholar
  15. 15.
    Fenoglio KA, Chen Y, Baram TZ (2006) Neuroplasticity of the hypothalamic-pituitary- adrenal axis early in life requires recurrent recruitment of stress-regulating brain regions. J Neurosci 26:2434–2442PubMedCrossRefGoogle Scholar
  16. 16.
    Fernandez-Ruiz J, Berrendero F, Hernandez ML, Ramos JA (2000) The endogenous cannabinoid system and brain development. Trends Neurosci 23:14–20PubMedCrossRefGoogle Scholar
  17. 17.
    Fernandez-Ruiz JJ, Berrendero F, Hernandez ML, Romero J, Ramos JA (1999) Role of endocannabinoids in brain development. Life Sci 65:725–736PubMedCrossRefGoogle Scholar
  18. 18.
    Fride E (2004) The endocannabinoid-CB(1) receptor system in pre- and postnatal life. Eur J Pharmacol 500:289–297PubMedCrossRefGoogle Scholar
  19. 19.
    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 functions. Neurotoxicol Teratol 23:1–11PubMedCrossRefGoogle Scholar
  20. 20.
    Garoflos E, Stamatakis A, Rafrogianni A, Pondiki S, Stylianopoulou F (2008) Neonatal handling on the first postnatal day leads to increased maternal behavior and fos levels in the brain of the newborn rat. Dev Psychobiol 00:1–10Google Scholar
  21. 21.
    Gerdeman G, Lovinger DM (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol 85:468–471PubMedGoogle Scholar
  22. 22.
    Gonzalez B, de Miguel R, Martin S, Perez-Rosado A, Romero J, Garcia-Lecumberri C, Fernandez-Ruiz J, Ramos JA, Ambrosio E (2003) Effects of perinatal exposure to delta 9-tetrahydrocannabinol on operant morphine-reinforced behavior. Pharmacol Biochem Behav 75:577–584PubMedCrossRefGoogle Scholar
  23. 23.
    Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J (2000) Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci 899:274–282PubMedCrossRefGoogle Scholar
  24. 24.
    Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92PubMedCrossRefGoogle Scholar
  25. 25.
    Huang CC, Lo SW, Hsu KS (2001) Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J Physiol 532:731–748PubMedCrossRefGoogle Scholar
  26. 26.
    Hutchings DE, Martin BR, Gamagaris Z, Miller N, Fico T (1989) Plasma concentrations of delta-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats. Life Sci 44:697–701PubMedCrossRefGoogle Scholar
  27. 27.
    Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74PubMedCrossRefGoogle Scholar
  28. 28.
    Jakubovic A, Hattori T, McGeer PL (1973) Radioactivity in suckled rats after giving 14 C- tetrahydrocannabinol to the mother. Eur J Pharmacol 22:221–223PubMedCrossRefGoogle Scholar
  29. 29.
    Kawash GF, Yeung DL, Berg SD (1980) Effects of administration of cannabis resin during pregnancy on emotionality and learning in rats’ offspring. Percept Mot Skills 50:359–365PubMedGoogle Scholar
  30. 30.
    Kolb B, Whishaw IQ (1989) Plasticity in the neocortex: mechanisms underlying recovery from early brain damage. Prog Neurobiol 32:235–276PubMedCrossRefGoogle Scholar
  31. 31.
    Kumar AM, Haney M, Becker T, Thompson ML, Kream RM, Miczek K (1990) Effect of early exposure to delta-9-tetrahydrocannabinol on the levels of opioid peptides, gonadotropin-releasing hormone and substance P in the adult male rat brain. Brain Res 525:78–83PubMedCrossRefGoogle Scholar
  32. 32.
    Lesage J, Sebaai N, Leonhardt M, Dutriez-Casteloot I, Breton C, Deloof S, Vieau D (2006) Perinatal maternal undernutrition programs the offspring hypothalamo- pituitary-adrenal (HPA) axis. Stress 9:183–198PubMedCrossRefGoogle Scholar
  33. 33.
    Llorente R, Arranz L, Marco EM, Moreno E, Puerto M, Guaza C, De la Fuente M, Viveros MP (2007) Early maternal deprivation and neonatal single administration with a cannabinoid agonist induce long-term sex-dependent psychoimmunoendocrine effects in adolescent rats. Psychoneuroendocrinology 32:636–650PubMedCrossRefGoogle Scholar
  34. 34.
    Mechoulam R (1970) Marihuana chemistry. Science 168:1159–1166PubMedCrossRefGoogle Scholar
  35. 35.
    Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (2007) Cannabidiol—recent advances. Chem Biodivers 4:1678–1692PubMedCrossRefGoogle Scholar
  36. 36.
    Mereu G, Fa 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 100:4915–4920PubMedCrossRefGoogle Scholar
  37. 37.
    Mokler DJ, Robinson SE, Johnson JH, Hong JS, Rosecrans JA (1987) Neonatal administration of delta-9-tetrahydrocannabinol (THC) alters the neurochemical response to stress in the adult Fischer-344 rat. Neurotoxicol Teratol 9:321–327PubMedCrossRefGoogle Scholar
  38. 38.
    Moreira FA, Lutz B (2008) The endocannabinoid system: emotion, learning and addiction. Addict Biol 13:196–212PubMedCrossRefGoogle Scholar
  39. 39.
    Moreno M, Escuredo L, Munoz R, Rodriguez dF, Navarro M (2005) Long-term behavioural and neuroendocrine effects of perinatal activation or blockade of CB1 cannabinoid receptors. Behav Pharmacol 16:423–430PubMedCrossRefGoogle Scholar
  40. 40.
    Navarro M, Rubio P, de Fonseca FR (1995) Behavioural consequences of maternal exposure to natural cannabinoids in rats. Psychopharmacology 122:1–14PubMedCrossRefGoogle Scholar
  41. 41.
    Navarro M, Rubio T, Rodriguez de Fonseca F (1994) Sex-dimorphic psychomotor activation after perinatal exposure to (-)-D9-tetrahadrocannabinol. An ontogenic study in Wistar rats. Psychopharmacology 116:414–422PubMedCrossRefGoogle Scholar
  42. 42.
    Newsom RJ, Kelly SJ (2008) Perinatal delta-9-tetrahydrocannabinol exposure disrupts social and open field behavior in adult male rats. Neurotoxicol Teratol 30:213–219PubMedCrossRefGoogle Scholar
  43. 43.
    O’Shea M, Mallet PE (2005) Impaired learning in adulthood following neonatal delta9- THC exposure. Behav Pharmacol 16:455–461PubMedCrossRefGoogle Scholar
  44. 44.
    O’Shea M, McGregor IS, Mallet PE (2006) Repeated cannabinoid exposure during perinatal, adolescent or early adult ages produces similar longlasting deficits in object recognition and reduced social interaction in rats. J Psychopharmacol 20:611–621PubMedCrossRefGoogle Scholar
  45. 45.
    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 18:502–508PubMedCrossRefGoogle Scholar
  46. 46.
    Ojeda SR, Urbanski HF (1994) Puberty in the rat. In: Knobil E, Neill JD (eds) The physiology of reproduction. Raven Press, New York, pp 363–410Google Scholar
  47. 47.
    Pijlman FT, Rigter SM, Hoek J, Goldschmidt HM, Niesink RJ (2005) Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops. Addict Biol 10:171–180PubMedCrossRefGoogle Scholar
  48. 48.
    Pistis M, Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL (2004) Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biol Psychiatry 56:86–94PubMedCrossRefGoogle Scholar
  49. 49.
    Potter DJ, Clark P, Brown MB (2008) Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci 53:90–94PubMedCrossRefGoogle Scholar
  50. 50.
    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 Delta(9)-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126PubMedCrossRefGoogle Scholar
  51. 51.
    Rubino T, Vigano’ D, Realini N, Guidali C, Braida D, Capurro V, Castiglioni C, Cherubino F, Romualdi P, Candeletti S, Sala M, Parolaro D (2008) Chronic delta(9)- tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. Neuropsychopharmacology 33:2760–2771PubMedCrossRefGoogle Scholar
  52. 52.
    Rubio P, Rodriguez de Fonseca F, Martin-Calderon JL, del Arco I, Bartolome S, Villanua MA, Navarro M (1998) Maternal exposure to low doses of delta9- tetrahydrocannabinol facilitates morphine-induced place conditioning in adult male offspring. Pharmacol Biochem Behav 61:229–238PubMedCrossRefGoogle Scholar
  53. 53.
    Rubio P, Rodriguez de Fonseca F, Munoz RM, Ariznavarreta C, Martin-Calderon JL, Navarro M (1995) Long-term behavioral effects of perinatal exposure to delta 9- tetrahydrocannabinol in rats: possible role of pituitary–adrenal axis. Life Sci 56:2169–2176PubMedCrossRefGoogle Scholar
  54. 54.
    Schneider M (2008) Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure. Addict Biol 13(2):253–263PubMedCrossRefGoogle Scholar
  55. 55.
    Schneider M, Drews E, Koch M (2005) Behavioral effects in adult rats of chronic prepubertal treatment with the cannabinoid receptor agonist WIN 55, 212–2. Behav Pharmacol 16:447–454PubMedCrossRefGoogle Scholar
  56. 56.
    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 28:1760–1769Google Scholar
  57. 57.
    Schneider M, Koch M (2005) Deficient social and play behavior in juvenile and adult rats after neonatal cortical lesion: effects of chronic pubertal cannabinoid treatment. Neuropsychopharmacology 30:944–957PubMedCrossRefGoogle Scholar
  58. 58.
    Schneider M, Schoemig E, Leweke FM (2008) Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats. Addict Biol 13:345–357PubMedCrossRefGoogle Scholar
  59. 59.
    Singh ME, McGregor IS, Mallet PE (2006) Perinatal exposure to delta(9)- tetrahydrocannabinol alters heroin-induced place conditioning and fos- immunoreactivity. Neuropsychopharmacology 31:58–69PubMedGoogle Scholar
  60. 60.
    Siviy SM, Harrison KA (2008) Effects of neonatal handling on play behavior and fear towards a predator odor in juvenile rats (Rattus norvegicus). J Comp Psychol 122:1–8PubMedCrossRefGoogle Scholar
  61. 61.
    Spano MS, Ellgren M, Wang X, Hurd YL (2007) Prenatal cannabis exposure increases heroin seeking with allostatic changes in limbic enkephalin systems in adulthood. Biol Psychiatry 61:554–563PubMedCrossRefGoogle Scholar
  62. 62.
    Stamatakis A, Pondiki S, Kitraki E, Diamantopoulou A, Panagiotaropoulos T, Raftogianni A, Stylianopoulou F (2008) Effect of neonatal handling on adult rat spatial learning and memory following acute stress. Stress 11:148–159PubMedGoogle Scholar
  63. 63.
    Trezza V, Campolongo P, Cassano T, Macheda T, Dipasquale P, Carratu MR, Gaetani S, Cuomo V (2008) Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: a longitudinal behavioral study in Wistar rats. Psychopharmacology (Berl) 198:529–537CrossRefGoogle Scholar
  64. 64.
    Vela G, Fuentes JA, Bonnin A, Fernandez-Ruiz J, Ruiz-Gayo M (1995) Perinatal exposure to delta 9-tetrahydrocannabinol (delta 9-THC) leads to changes in opioid- related behavioral patterns in rats. Brain Res 680:142–147PubMedCrossRefGoogle Scholar
  65. 65.
    Vela G, Martin S, Garcia-Gil L, Crespo JA, Ruiz-Gayo M, Fernandez-Ruiz JJ, Garcia-Lecumberri C, Pelaprat D, Fuentes JA, Ramos JA, Ambrosio E (1998) Maternal exposure to D9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central m opioid receptors in adult offspring female rats. Brain Res 807:101–109PubMedCrossRefGoogle Scholar
  66. 66.
    Viberg H, Ponten E, Eriksson P, Gordh T, Fredriksson A (2008) Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly. Toxicology 249:153–159PubMedCrossRefGoogle Scholar
  67. 67.
    Wang H, Xie H, Dey SK (2008) Loss of cannabinoid receptor CB1 induces preterm birth. PLoS ONE 3:e3320PubMedCrossRefGoogle Scholar
  68. 68.
    Zuardi AW (2008) Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr 30:271–280PubMedGoogle Scholar
  69. 69.
    Zuckerman B, Frank DA, Hingson R, Amaro H, Levenson SM, Kayne H, Parker S, Vinci R, Aboagye K, Fried LE (1989) Effects of maternal marijuana and cocaine use on fetal growth. N Engl J Med 320:762–768PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of PsychopharmacologyCentral Institute of Mental Health (ZI)MannheimGermany

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