Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
European Child & Adolescent Psychiatry
Published in: European Child & Adolescent Psychiatry 10/2014

01-10-2014 | Review

Neuronal substrates and functional consequences of prenatal cannabis exposure

Authors: Daniela Calvigioni, Yasmin L. Hurd, Tibor Harkany, Erik Keimpema

Published in: European Child & Adolescent Psychiatry | Issue 10/2014

Login to get access

Abstract

Cannabis remains one of the world’s most widely used substance of abuse amongst pregnant women. Trends of the last 50 years show an increase in popularity in child-bearing women together with a constant increase in cannabis potency. In addition, potent herbal “legal” highs containing synthetic cannabinoids that mimic the effects of cannabis with unknown pharmacological and toxicological effects have gained rapid popularity amongst young adults. Despite the surge in cannabis use during pregnancy, little is known about the neurobiological and psychological consequences in the exposed offspring. In this review, we emphasize the importance of maternal programming, defined as the intrauterine presentation of maternal stimuli to the foetus, in neurodevelopment. In particular, we focus on cannabis-mediated maternal adverse effects, resulting in direct central nervous system alteration or sensitization to late-onset chronic and neuropsychiatric disorders. We compare clinical and preclinical experimental studies on the effects of foetal cannabis exposure until early adulthood, to stress the importance of animal models that permit the fine control of environmental variables and allow the dissection of cannabis-mediated molecular cascades in the developing central nervous system. In sum, we conclude that preclinical experimental models confirm clinical studies and that cannabis exposure evokes significant molecular modifications to neurodevelopmental programs leading to neurophysiological and behavioural abnormalities.
Literature
1.
2.
European Monitoring Centre for Drugs and Drug Addiction E (2013) European drug report. Trends and Development
3.
European Monitoring Centre for Drugs and Drug Addiction E (2013) Synthetic cannabinoids in Europe
4.
European Monitoring Centre for Drugs and Drug Addiction E (2012) Legal topic overviews: possession of cannabis for personal use
5.
Grotenhermen F (2004) Pharmakologie, Toxikologie und therapeutisches Potential. 2nd edn. Hans Huber, Göttingen
6.
Atwood BK et al (2010) JWH018, a common constituent of ‘Spice’ herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol 160(3):585–593PubMedPubMedCentralCrossRef
7.
Atwood BK et al (2011) CP47, 497-C8 and JWH073, commonly found in ‘Spice’ herbal blends, are potent and efficacious CB(1) cannabinoid receptor agonists. Eur J Pharmacol 659(2–3):139–145PubMedPubMedCentralCrossRef
8.
Zawilska JB, Wojcieszak J (2013) Spice/K2 drugs: more than innocent substitutes for marijuana. Int J Neuropsychopharmacol 17(3):509–525
9.
Fantegrossi WE et al (2013) Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Delta-THC: mechanism underlying greater toxicity. Life Sci 97(1):45–54
10.
SAMHSA (2011) Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings
11.
SAMHSA (2013) 2012 National Survey on Drug Use and Health (NSDUH)
12.
Wingo PA et al (2011) Recent changes in the trends of teen birth rates, 1981–2006. J Adolesc Health 48(3):281–288PubMedCrossRef
13.
SAMHSA (2010) Pregnant teen admissions to substance abuse treatment: 1992 and 2007
14.
15.
Jutras-Aswad D et al (2009) Neurobiological consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome. Eur Arch Psychiatry Clin Neurosci 259(7):395–412PubMedCrossRef
16.
Fried PA (2002) Conceptual issues in behavioral teratology and their application in determining long-term sequelae of prenatal marihuana exposure. J Child Psychol Psychiatry 43(1):81–102PubMedCrossRef
17.
18.
Driscoll CD, Streissguth AP, Riley EP (1990) Prenatal alcohol exposure: comparability of effects in humans and animal models. Neurotoxicol Teratol 12(3):231–237PubMedCrossRef
19.
20.
Linnet KM et al (2003) Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence. Am J Psychiatry 160(6):1028–1040PubMedCrossRef
21.
Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(Suppl 3):511–533PubMedPubMedCentralCrossRef
22.
23.
24.
Thompson BL, Levitt P, Stanwood GD (2009) Prenatal exposure to drugs: effects on brain development and implications for policy and education. Nat Rev Neurosci 10(4):303–312PubMedPubMedCentralCrossRef
25.
26.
Nielsen A et al (2006) Maternal smoking predicts the risk of spontaneous abortion. Acta Obstet Gynecol Scand 85(9):1057–1065PubMedCrossRef
27.
Abbott LC, Winzer-Serhan UH (2012) Smoking during pregnancy: lessons learned from epidemiological studies and experimental studies using animal models. Crit Rev Toxicol 42(4):279–303PubMedCrossRef
28.
El Marroun H et al (2014) Prenatal tobacco exposure and brain morphology: a prospective study in young children. Neuropsychopharmacology 39(4):792–800PubMedCrossRef
29.
Roy TS, Sabherwal U (1994) Effects of prenatal nicotine exposure on the morphogenesis of somatosensory cortex. Neurotoxicol Teratol 16(4):411–421PubMedCrossRef
30.
Roy TS et al (1998) Nicotine evokes cell death in embryonic rat brain during neurulation. J Pharmacol Exp Ther 287(3):1136–1144PubMed
31.
Bell SH et al (2010) The remarkably high prevalence of epilepsy and seizure history in fetal alcohol spectrum disorders. Alcohol Clin Exp Res 34(6):1084–1089PubMedCrossRef
32.
Grotenhermen F (2003) Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42(4):327–360PubMedCrossRef
33.
Hurd YL et al (2005) Marijuana impairs growth in mid-gestation fetuses. Neurotoxicol Teratol 27(2):221–229PubMedCrossRef
34.
Dinieri JA, Hurd YL (2012) Rat models of prenatal and adolescent cannabis exposure. Methods Mol Biol 829:231–242
35.
Day NL, Richardson GA (1991) Prenatal marijuana use: epidemiology, methodologic issues, and infant outcome. Clin Perinatol 18(1):77–91PubMed
36.
Fried PA, O’Connell CM (1987) A comparison of the effects of prenatal exposure to tobacco, alcohol, cannabis and caffeine on birth size and subsequent growth. Neurotoxicol Teratol 9(2):79–85PubMedCrossRef
37.
38.
Weiser M, Noy S (2005) Interpreting the association between cannabis use and increased risk for schizophrenia. Dialogues Clin Neurosci 7(1):81–85PubMedPubMedCentral
39.
Fried PA (1980) Marihuana use by pregnant women: neurobehavioral effects in neonates. Drug Alcohol Depend 6(6):415–424PubMedCrossRef
40.
Fried PA, Watkinson B, Gray R (1998) Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 20(3):293–306PubMedCrossRef
41.
Hofman A et al (2004) Growth, development and health from early fetal life until young adulthood: the Generation R Study. Paediatr Perinat Epidemiol 18(1):61–72PubMedCrossRef
42.
Jaddoe VW et al (2012) The generation R Study: design and cohort update 2012. Eur J Epidemiol 27(9):739–756PubMedCrossRef
43.
El Marroun H et al (2008) Demographic, emotional and social determinants of cannabis use in early pregnancy: the generation R study. Drug Alcohol Depend 98(3):218–226PubMedCrossRef
44.
El Marroun H et al (2009) Intrauterine cannabis exposure affects fetal growth trajectories: the generation R Study. J Am Acad Child Adolesc Psychiatry 48(12):1173–1181PubMedCrossRef
45.
Hadlock FP et al (1984) Sonographic estimation of fetal weight. The value of femur length in addition to head and abdomen measurements. Radiology 150(2):535–540PubMedCrossRef
46.
Zuckerman B et al (1989) Effects of maternal marijuana and cocaine use on fetal growth. N Engl J Med 320(12):762–768PubMedCrossRef
47.
Boito S et al (2002) Umbilical venous volume flow in the normally developing and growth-restricted human fetus. Ultrasound Obstet Gynecol 19(4):344–349PubMedCrossRef
48.
El Marroun H et al (2010) A prospective study on intrauterine cannabis exposure and fetal blood flow. Early Hum Dev 86(4):231–236PubMedCrossRef
49.
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(2):49–58PubMedCrossRef
50.
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(1):24–41PubMedCrossRef
51.
Richardson GA, Day NL, Goldschmidt L (1995) Prenatal alcohol, marijuana, and tobacco use: infant mental and motor development. Neurotoxicol Teratol 17(4):479–487PubMedCrossRef
52.
Wang X et al (2004) In utero marijuana exposure associated with abnormal amygdala dopamine D2 gene expression in the human fetus. Biol Psychiatry 56(12):909–915PubMedCrossRef
53.
Goldschmidt L et al (2004) Prenatal marijuana and alcohol exposure and academic achievement at age 10. Neurotoxicol Teratol 26(4):521–532PubMedCrossRef
54.
Fried PA, Watkinson B, Gray R (1992) A follow-up study of attentional behavior in 6-year-old children exposed prenatally to marihuana, cigarettes, and alcohol. Neurotoxicol Teratol 14(5):299–311PubMedCrossRef
55.
Goldschmidt L, Day NL, Richardson GA (2000) Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol 22(3):325–336PubMedCrossRef
56.
Leech SL et al (1999) Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds. Neurotoxicol Teratol 21(2):109–118PubMedCrossRef
57.
Trezza V, Cuomo V, Vanderschuren LJ (2008) Cannabis and the developing brain: insights from behavior. Eur J Pharmacol 585(2–3):441–452PubMedCrossRef
58.
59.
Smith AM et al (2006) Effects of prenatal marijuana on visuospatial working memory: an fMRI study in young adults. Neurotoxicol Teratol 28(2):286–295PubMedCrossRef
60.
Navarro M, Rubio P, de Fonseca FR (1995) Behavioural consequences of maternal exposure to natural cannabinoids in rats. Psychopharmacology 122(1):1–14PubMedCrossRef
61.
Mereu G et al (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(8):4915–4920PubMedPubMedCentralCrossRef
62.
Trezza V et al (2012) Altering endocannabinoid neurotransmission at critical developmental ages: impact on rodent emotionality and cognitive performance. Front Behav Neurosci 6:2PubMedCrossRef
63.
Szutorisz H et al (2014) Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation. Neuropsychopharmacology
64.
Day NL et al (1994) Effect of prenatal marijuana exposure on the cognitive development of offspring at age three. Neurotoxicol Teratol 16(2):169–175PubMedCrossRef
65.
Herkenham M (1992) Cannabinoid receptor localization in brain: relationship to motor and reward systems. Ann N Y Acad Sci 654:19–32PubMedCrossRef
66.
Matsuda LA et al (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284):561–564PubMedCrossRef
67.
Morgan NH, Stanford IM, Woodhall GL (2009) Functional CB2 type cannabinoid receptors at CNS synapses. Neuropharmacology 57(4):356–368PubMedCrossRef
68.
Lauckner JE et al (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci USA 105(7):2699–2704PubMedPubMedCentralCrossRef
69.
Sawzdargo M et al (1999) Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res 64(2):193–198PubMedCrossRef
70.
71.
Kaplan BL (2013) The role of CB1 in immune modulation by cannabinoids. Pharmacol Ther 137(3):365–374PubMedCrossRef
72.
den Boon FS et al (2012) Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc Natl Acad Sci USA 109(9):3534–3539CrossRef
73.
Van Sickle MD et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310(5746):329–332PubMedCrossRef
74.
Belue RC et al (1995) The ontogeny of cannabinoid receptors in the brain of postnatal and aging rats. Neurotoxicol Teratol 17(1):25–30PubMedCrossRef
75.
Oh HA et al (2013) Uncovering a role for endocannabinoid signaling in autophagy in preimplantation mouse embryos. Mol Hum Reprod 19(2):93–101PubMedCrossRef
76.
77.
Berrendero F et al (1998) Localization of mRNA expression and activation of signal transduction mechanisms for cannabinoid receptor in rat brain during fetal development. Development 125(16):3179–3188PubMed
78.
Bisogno T et al (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163(3):463–468PubMedPubMedCentralCrossRef
79.
Wang X et al (2003) Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain. Neuroscience 118(3):681–694PubMedCrossRef
80.
Devane WA et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090):1946–1949PubMedCrossRef
81.
Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388(6644):773–778PubMedCrossRef
82.
Hillard CJ, Campbell WB (1997) Biochemistry and pharmacology of arachidonylethanolamide, a putative endogenous cannabinoid. J Lipid Res 38(12):2383–2398PubMed
83.
Cravatt BF et al (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384(6604):83–87PubMedCrossRef
84.
85.
Gulyas AI et al (2004) Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20(2):441–458PubMedCrossRef
86.
Di Marzo V et al (1998) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 21(12):521–528PubMedCrossRef
87.
Harkany T et al (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28(2):83–92PubMedCrossRef
88.
Paria BC et al (2001) Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. J Biol Chem 276(23):20523–20528PubMedCrossRef
89.
90.
Berghuis P et al (2007) Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316(5828):1212–1216PubMedCrossRef
91.
Argaw A et al (2011) Concerted action of CB1 cannabinoid receptor and deleted in colorectal cancer in axon guidance. J Neurosci 31(4):1489–1499PubMedCrossRef
92.
Harkany T et al (2008) Endocannabinoid functions controlling neuronal specification during brain development. Mol Cell Endocrinol 286((1-2 Suppl 1)):S84–S90PubMedCrossRef
93.
Keimpema E et al (2010) Differential subcellular recruitment of monoacylglycerol lipase generates spatial specificity of 2-arachidonoyl glycerol signaling during axonal pathfinding. J Neurosci 30(42):13992–14007PubMedPubMedCentralCrossRef
94.
Kim D, Thayer SA (2001) Cannabinoids inhibit the formation of new synapses between hippocampal neurons in culture. J Neurosci 21(10):RC146PubMed
95.
Burstein S et al (1994) Phospholipase participation in cannabinoid-induced release of free arachidonic acid. Biochem Pharmacol 48(6):1253–1264PubMedCrossRef
96.
Bari M et al (2006) New insights into endocannabinoid degradation and its therapeutic potential. Mini Rev Med Chem 6(3):257–268PubMedCrossRef
97.
Coutts AA et al (2001) Agonist-induced internalization and trafficking of cannabinoid CB1 receptors in hippocampal neurons. J Neurosci 21(7):2425–2433PubMed
98.
Mulder J et al (2008) Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proc Natl Acad Sci USA 105(25):8760–8765PubMedPubMedCentralCrossRef
99.
Puighermanal E et al (2009) Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci 12(9):1152–1158PubMedCrossRef
100.
Tanimura A et al (2010) The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron 65(3):320–327PubMedCrossRef
101.
Keimpema E et al (2013) Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. Proc Natl Acad Sci USA 110(5):1935–1940PubMedPubMedCentralCrossRef
102.
Kittler JT et al (2000) Large-scale analysis of gene expression changes during acute and chronic exposure to [Delta]9-THC in rats. Physiol Genomics 3(3):175–185PubMed
103.
Grigorenko E et al (2002) Assessment of cannabinoid induced gene changes: tolerance and neuroprotection. Chem Phys Lipids 121(1–2):257–266PubMedCrossRef
104.
Perez-Rosado A et al (2000) Prenatal Delta(9)-tetrahydrocannabinol exposure modifies proenkephalin gene expression in the fetal rat brain: sex-dependent differences. Brain Res Dev Brain Res 120(1):77–81PubMedCrossRef
105.
Gomez M, Hernandez M, Fernandez-Ruiz J (2007) The activation of cannabinoid receptors during early postnatal development reduces the expression of cell adhesion molecule L1 in the rat brain. Brain Res 1145:48–55PubMedCrossRef
106.
Quinn HR et al (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(5):1113–1126PubMedCrossRef
107.
108.
Campolongo P et al (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(3–4):485–495PubMedCrossRef
109.
Tortoriello G et al (2014) Miswiring the brain: Delta9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J 33(7):668–685PubMedCrossRef
110.
Morozov YM, Ben-Ari Y, Freund TF (2004) The spatial and temporal pattern of fatty acid amide hydrolase expression in rat hippocampus during postnatal development. Eur J Neurosci 20(2):459–466PubMedCrossRef
Metadata
Title
Neuronal substrates and functional consequences of prenatal cannabis exposure
Authors
Daniela Calvigioni
Yasmin L. Hurd
Tibor Harkany
Erik Keimpema
Publication date
01-10-2014
Publisher
Springer Berlin Heidelberg
Published in
European Child & Adolescent Psychiatry / Issue 10/2014
Print ISSN: 1018-8827
Electronic ISSN: 1435-165X
DOI
https://doi.org/10.1007/s00787-014-0550-y

Other articles of this Issue 10/2014

European Child & Adolescent Psychiatry 10/2014 Go to the issue

Review

Antenatal depression and children’s developmental outcomes: potential mechanisms and treatment options

Original Contribution

Maternal pre-pregnancy risk drinking and toddler behavior problems: the Norwegian Mother and Child Cohort Study

Review

Mechanisms underlying the effects of prenatal psychosocial stress on child outcomes: beyond the HPA axis

Review

Prenatal nicotine exposure and child behavioural problems

Original Contribution

Prenatal exposure to binge pattern of alcohol consumption: mental health and learning outcomes at age 11

Review

Fetal alcohol spectrum disorders