Table 1.

right brain regions – medial PFC, DLPFC and ventrolateral PFC

Age†	Cohort‡	Category	Results/outcomes	Exposure details	Ref.
*Fetus*
17–22 GW	–	Growth	Reduced foot length and bodyweight	≥0.4 J/day	[48]
18–22 GW	–	Dopamine signaling	Decreased D2 mRNA in amygdala of males only	≥0.4 J/day	[152]
18–22 GW	–	Endorphin signaling	Decreased opioid peptide (PENK) and receptor (κ) in caudal putamen and thalamus, respectively; increased opioid receptor (µ) in the amygdala	–	[74]
*Neonatal*
Neonatal	OPPS	Neurobehavior	Increased tremors, exaggerated startles and diminished responsiveness to light	–	[46]
Neonatal	MHPCD	Growth	Decreased body length	≥1 J/day, first Trim	[49]
Neonatal	–	Growth Neurobehavior	No effect on birthweight, length or gestational age No effect	– –	[54]
Neonatal	VIPS	Growth	No effect on birthweight, preterm delivery or abruptio placentae	–	[35]
Neonatal	–	Growth Behavior	No effect on birthweight, length or gestational age More irritable, less responsive to calming, increased jitters and startles	– –	[52]
Neonatal	NBDPS	Growth	No effect on birthweight, gestational age or preterm delivery	–	[40]
1 mo	–	Behavior	Less irritable, more alert, more robust autonomic and motor systems, more autonomically stable and increased orientation	≥2.86 J/day	[54]
*Toddler*
8 mo	MHPCD	Growth	No effect	–	[49]
9 mo	MHPCD	Mental/motor skills	Delayed mental development	≥1 J/day, third Trim	[26]
1 y	OPPS	Mental/motor skills	No effect	–	[55]
1 y	–	Mental/motor skills	Decreased motor scores, no effect on mental development	≥0.5 J/day, first Trim	[149]
19 mo	MHPCD	Mental/motor skills	No effect	–	[26]
2 y	OPPS	Mental/motor skills	No effect	–	[55]
3 y	MHPCD	Intelligence Cognition	No effect on overall IQ for entire cohort For African–Americans: decrease in short-term memory and verbal reasoning	– ≥1 J/day, first/second Trim	[57]
3 y	MHPCD	Sleep and arousal	Lowered sleep efficiency, more nocturnal arousals and more awake time after sleep onset	–	[153]
*Childhood*
4 y	–	Sustained attention	Increased number of omission errors	First Trim	[45]
4 y	MHPCD	Motor skills	No effect on balance and coordination skills	–	[154]
5–6 y	OPPS	Cognition and language	No effect	–	[155]
6 y	MHPCD	Growth	No effect	–	[156]
6 y	OPPS	Memory Attention Behavior	No effect Increased number of omission errors Described as more impulsive and hyperactive	≥0.86 J/day	[58]
6 y	MHPCD	Impulsivity Sustained attention	Decrease in errors of omission Lower overall composite score	Second Trim	[60]
6 y	MHPCD	Intelligence Cognition	Lower overall composite score Lower verbal reasoning, quantitative reasoning and short-term memory	≥1 J/day, first/second Trim	[59]
9–12 y	OPPS	Reading and language	No effect in regards to reading or language	–	[68]
9–12 y	OPPS	Intelligence Executive function	No effect in terms of full scale IQ Impulse control and visual hypothesis aspects are negatively impacted	– > 0.86 J/day	[63]
*Adolescence*
10 y	MHPCD	Behavior and emotion Behavior and emotion	Fewer internalizing problems, although not correlated with teacher’s report Predicted lower scores in design memory and screening index	≥0.4 J/day second Trim ≥0.89 J/day, first Trim	[47]
10 y	MHPCD	Learning and memory Sustained attention	Predicted lower scores in design memory and screening index Increase in errors of commission	≥0.89 J/day, first Trim ≥0.89 J/day, second Trim	[47]
10 y	MHPCD	Depression	Increased levels of depressive symptoms	>0.89 J/day, first/third Trim	[64]
12 y	–	Psychotic symptoms	No effect	–	[66]
10–14 y	–	Volumetric MRI	No effect on cortical gray matter volume, white matter volume, cerebral spinal fluid or parenchymal volume	–	[69]
10 y 14 y	MHPCD	Behavior and cognition Delinquent behaviors	Negatively associated with depressive symptoms, IQ, learning and memory Increased delinquent behaviors	≥0.89 J/day, first/second Trim ≥0.89 J/day	[61]
13–16 y	OPPS	Sustained attention	Decreased stability of attention over time	≥0.86 J/day	[71]
13–16 y	OPPS	Growth	No changes in weight, height or puberty symptoms	–	[157]
13–16 y	OPPS	Visual memory	Lower scores in abstract designs and Peabody spelling	≥0.86 J/day	[27]
16 y	MHPCD	Fine motor coordination Visual–motor coordination	Various light deficits in processing speed and interhemispheric motor coordination Slight increase in visual–motor coordination	≥2 J/mo	[158]
*Young adult*
18–22 y	OPPS	Response inhibition Response inhibition by fMRI Intelligence Working memory by fMRI	Slightly more errors of commission Increased bilateral PFC activity, right premotor cortex activity; decreased activity in left cerebellum No effect Increased activity in left medial PFC, inferior frontal gyrus and left cerebellum; decreased activity in	– – – –	[72] [73]

Prenatal Marijuana Exposure Studies in Humans

†Exposed offspring study age.
‡Specified conditions of prenatal exposure.
DLPFC: Dorsolateral prefrontal cortex; GW: Gestation week(s); J: Joint; MHPCD: Maternal Health Practices and Child Development Project; mo: Month(s); NBDPS: National Birth Defects Prevention Study; OPPS: Ottawa Prenatal Prospective Study; PENK: Proenkephalin; PFC: Prefrontal cortex; Trim: Trimester; VIPS: Vaginal Infections and Prematurity Study; y: Year(s).

Hall W, Solowij N. Adverse effects of cannabis. Lancet 352(9140), 1611-1616 (1998).
Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals and humans. Addiction 91(11), 1585-1614 (1996).
Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur. J. Pharmacol. 359(1), 1-18 (1998).
Mackie K, Stella N. Cannabinoid receptors and endocannabinoids: evidence for new players. AAPSJ. 8(2), E298-E306 (2006).
Piomelli D. The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci. 4(11), 873-884 (2003).
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83(3), 1017-1066 (2003).
Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol. Sci. 28(2), 83-92 (2007).
•• Overview of the endocannabinoid pathways controlling neuronal specification during brain development.
Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89(1), 309-380 (2009).
Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat. Med. 14(9), 923-930 (2008) .
Osei-Hyiaman D, Harvey-White J, Batkai S, Kunos G. The role of the endocannabinoid system in the control of energy homeostasis. Int. J. Obes. (Lond.) 30(Suppl. 1), S33-S38 (2006).
Tam J, Vemuri VK, Liu J et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J. Clin. Invest. 120(8), 2953-2966 (2010).
Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat. Rev. Drug Discov. 7(5), 438-455 (2008).
Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58(3), 389-462 (2006).
Arevalo-Martin A, Vela JM, Molina-Holgado E, Borrell J, Guaza C. Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J. Neurosci. 23(7), 2511-2516 (2003).
Cravatt BF, Lichtman AH. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr. Opin. Chem. Biol. 7(4), 469-475 (2003).
Barnes MP. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert Opin. Pharmacother. 7(5), 607-615 (2006).
Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin. Emerg. Drugs 14(1), 43-65 (2009).
Maida V, Ennis M, Irani S, Corbo M, Dolzhykov M. Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J. Support Oncol. 6(3), 119-124 (2008).
Zutt M, Hanssle H, Emmert S, Neumann C, Kretschmer L. [Dronabinol for supportive therapy in patients with malignant melanoma and liver metastases]. Hautarzt 57(5), 423-427 (2006).
Ahn K, Johnson DS, Cravatt BF. Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert Opin. Drug Discov. 4(7), 763-784 (2009).
Hutchings DE, Martin BR, Gamagaris Z, Miller N, Fico T. Plasma concentrations of Δ-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats. Life Sci. 44(11), 697-701 (1989).
Perez-Reyes M, Wall ME. Presence of Δ9-tetrahydrocannabinol in human milk. N. Engl. J. Med. 307(13), 819-820 (1982).
Mehmedic Z, Chandra S, Slade D et al. Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J. Forensic. Sci. 55(5), 1209-1217 (2010).
Galve-Roperh I, Palazuelos J, Aguado T, Guzman M. The endocannabinoid system and the regulation of neural development: potential implications in psychiatric disorders. Eur. Arch. Psychiatry Clin. Neurosci. 259(7), 371-382 (2009).
Harkany T, Keimpema E, Barabas K, Mulder J. Endocannabinoid functions controlling neuronal specification during brain development. Mol. Cell Endocrinol. 286(1-2 Suppl. 1), S84-S90 (2008).
Richardson GA, Day NL, Goldschmidt L. Prenatal alcohol, marijuana, and tobacco use: infant mental and motor development. Neurotoxicol. Teratol. 17(4), 479-487 (1995).
Fried PA, Watkinson B, Gray R. Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 25(4), 427-436 (2003).
Jutras-Aswad D, Dinieri JA, Harkany T, Hurd YL. Neurobiological consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome. Eur. Arch. Psychiatry Clin. Neurosci. 259(7), 395-412 (2009).
•• A comprehensive review on prenatal marijuana exposure, impacted neurotransmitter systems and neuropsychiatric outcomes.
Schneider M. Cannabis use in pregnancy and early life and its consequences: animal models. Eur. Arch. Psychiatry Clin. Neurosci. 259(7), 383-393 (2009).
•• Recent and detailed review of animal models of perinatal cannabis exposure, including natural cannabis preparations and Δ-9-tetrahydrocannabinol and synthetic cannabinoid agonists.
Navarro M, Rubio P, De Fonseca FR. Behavioural consequences of maternal exposure to natural cannabinoids in rats. Psychopharmacology (Berl.) 122(1), 1-14 (1995).
Campolongo P, Trezza V, Palmery M, Trabace L, Cuomo V. Developmental exposure to cannabinoids causes subtle and enduring neurofunctional alterations. Int. Rev. Neurobiol. 85, 117-133 (2009).
•• Recent and detailed review on animal studies summarizing behavioral alterations exhibited by offspring of mothers exposed to cannabis.
Trezza V, Cuomo V, Vanderschuren LJ. Cannabis and the developing brain: insights from behavior. Eur. J. Pharmacol. 585(2-3), 441-452 (2008).
Yonkers KA, Gotman N, Kershaw T, Forray A, Howell HB, Rounsaville BJ. Screening for prenatal substance use: development of the Substance Use Risk Profile-Pregnancy scale. Obstet. Gynecol. 116(4), 827-833 (2010).
Ebrahim SH, Gfroerer J. Pregnancy-related substance use in the United States during 1996-1998. Obstet. Gynecol. 101(2), 374-379 (2003).
Shiono PH, Klebanoff MA, Nugent RP et al. The impact of cocaine and marijuana use on low birth weight and preterm birth: a multicenter study. Am. J. Obstet. Gynecol. 172(1 Pt 1), 19-27 (1995).
Moore DG, Turner JD, Parrott AC et al. During pregnancy, recreational drug-using women stop taking ecstasy (3,4-methylenedioxy-N-methylamphetamine) and reduce alcohol consumption, but continue to smoke tobacco and cannabis: initial findings from the Development and Infancy Study. J. Psychopharmacol. 24(9), 1403-1410 (2010).
Hingson R, Alpert JJ, Day N et al. Effects of maternal drinking and marijuana use on fetal growth and development. Pediatrics 70(4), 539-546 (1982).
Linn S, Schoenbaum SC, Monson RR, Rosner R, Stubblefield PC, Ryan KJ. The association of marijuana use with outcome of pregnancy. Am. J. Public Health 73(10), 1161-1164 (1983).
Van Gelder MM, Reefhuis J, Caton AR, Werler MM, Druschel CM, Roeleveld N. Maternal periconceptional illicit drug use and the risk of congenital malformations. Epidemiology 20(1), 60-66 (2009).
Van Gelder MM, Reefhuis J, Caton AR, Werler MM, Druschel CM, Roeleveld N. Characteristics of pregnant illicit drug users and associations between cannabis use and perinatal outcome in a population-based study. Drug Alcohol Depend. 109(1-3), 243-247 (2010).
El Marroun H, Tiemeier H, Steegers EA et al. Intrauterine Cannabis Exposure Affects Fetal Growth Trajectories: The Generation R Study. J. Am. Acad. Child Adolesc. Psychiatry (2009).
Zuckerman B, Frank DA, Hingson R et al. Effects of maternal marijuana and cocaine use on fetal growth. N. Engl. J. Med. 320(12), 762-768 (1989).
Fried PA, Watkinson B, Gray R. Neurocognitive consequences of marihuana - a comparison with pre-drug performance. Neurotoxicol. Teratol. 27(2), 231-239 (2005).
Goldschmidt L, Richardson GA, Cornelius MD, Day NL. Prenatal marijuana and alcohol exposure and academic achievement at age 10. Neurotoxicol. Teratol. 26(4), 521-532 (2004).
Noland JS, Singer LT, Short EJ et al. Prenatal drug exposure and selective attention in preschoolers. Neurotoxicol. Teratol. 27(3), 429-438 (2005).
Fried PA, Makin JE. Neonatal behavioural correlates of prenatal exposure to marihuana, cigarettes and alcohol in a low risk population. Neurotoxicol. Teratol. 9(1), 1-7 (1987).
Richardson GA, Ryan C, Willford J, Day NL, Goldschmidt L. Prenatal alcohol and marijuana exposure: effects on neuropsychological outcomes at 10 years. Neurotoxicol. Teratol. 24(3), 309-320 (2002).
Hurd YL, Wang X, Anderson V, Beck O, Minkoff H, Dow-Edwards D. Marijuana impairs growth in mid-gestation fetuses. Neurotoxicol. Teratol. 27(2), 221-229 (2005).
Day N, Cornelius M, Goldschmidt L, Richardson G, Robles N, Taylor P. The effects of prenatal tobacco and marijuana use on offspring growth from birth through 3 years of age. Neurotoxicol. Teratol. 14(6), 407-414 (1992).
Bendersky M, Alessandri S, Gilbert P, Lewis M. Characteristics of pregnant substance abusers in two cities in the northeast. Am. J. Drug Alcohol Abuse 22(3), 349-362 (1996).
Fried PA, Watkinson B, Dillon RF, Dulberg CS. Neonatal neurological status in a low-risk population after prenatal exposure to cigarettes, marijuana, and alcohol. J. Dev. Behav. Pediatr. 8(6), 318-326 (1987).
De Moraes Barros MC, Guinsburg R, De Araujo Peres C, Mitsuhiro S, Chalem E, Laranjeira RR. Exposure to marijuana during pregnancy alters neurobehavior in the early neonatal period. J. Pediatr. 149(6), 781-78 (2006).
Richardson GA, Day N, Taylor P. The effect of prenatal alcohol, marijuana, and tobacco exposure on neonatal behavior. Infant Behav. Dev. 12, 199-209 (1989).
Dreher MC, Nugent K, Hudgins R. Prenatal marijuana exposure and neonatal outcomes in Jamaica: an ethnographic study. Pediatrics 93(2), 254-260 (1994).
Fried PA, Watkinson B. 12- and 24-month neurobehavioural follow-up of children prenatally exposed to marihuana, cigarettes and alcohol. Neurotoxicol. Teratol. 10(4), 305-313 (1988).
Fried PA, Watkinson B. 36- and 48-month neurobehavioral follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol. J. Dev. Behav. Pediatr. 11(2), 49-58 (1990).
Day NL, Richardson GA, Goldschmidt L et al. Effect of prenatal marijuana exposure on the cognitive development of offspring at age three. Neurotoxicol. Teratol. 16(2), 169-175 (1994).
Fried PA, Watkinson B, Gray R. A follow-up study of attentional behavior in 6-year-old children exposed prenatally to marihuana, cigarettes, and alcohol. Neurotoxicol. Teratol. 14(5), 299-311 (1992).
Goldschmidt L, Richardson GA, Willford J, Day NL. Prenatal marijuana exposure and intelligence test performance at age 6. J. Am. Acad. Child Adolesc. Psychiatry 47(3), 254-263 (2008).
Leech SL, Richardson GA, Goldschmidt L, Day NL. Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds. Neurotoxicol. Teratol. 21(2), 109-118 (1999).
Day NL, Leech SL, Goldschmidt L. The effects of prenatal marijuana exposure on delinquent behaviors are mediated by measures of neurocognitive functioning. Neurotoxicol. Teratol. 33(1), 129-136 (2011).
• Study from the Maternal Health Practices and Child Development Study (MHPCD) cohort showed that adolescents with heavy prenatal marijuana exposure (PME) are almost twice as likely to exhibit delinquent behaviors compared with nonexposed teens.
Goldschmidt L, Day NL, Richardson GA. Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol. Teratol. 22(3), 325-336 (2000).
Fried PA, Watkinson B, Gray R. Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 20(3), 293-306 (1998).
Gray KA, Day NL, Leech S, Richardson GA. Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age. Neurotoxicol. Teratol. 27(3), 439-448 (2005).
Fried PA. Conceptual issues in behavioral teratology and their application in determining long-term sequelae of prenatal marihuana exposure. J. Child. Psychol. Psychiatry 43(1), 81-102 (2002).
Zammit S, Thomas K, Thompson A et al. Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring. Br. J. Psychiatry 195(4), 294-300 (2009).
Stone KC, Lagasse LL, Lester BM et al. Sleep problems in children with prenatal substance exposure: the Maternal Lifestyle study. Arch. Pediatr. Adolesc. Med. 164(5), 452-456 (2010).
Fried PA, Watkinson B, Siegel LS. Reading and language in 9- to 12-year olds prenatally exposed to cigarettes and marijuana. Neurotoxicol. Teratol. 19(3), 171-183 (1997).
Rivkin MJ, Davis PE, Lemaster JL et al. Volumetric MRI study of brain in children with intrauterine exposure to cocaine, alcohol, tobacco, and marijuana. Pediatrics 121(4), 741-750 (2008).
Fried PA, Smith AM. 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), 1-11 (2001).
Fried PA, Watkinson B. Differential effects on facets of attention in adolescents prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 23(5), 421-430 (2001).
Smith AM, Fried PA, Hogan MJ, Cameron I. Effects of prenatal marijuana on response inhibition: an fMRI study of young adults. Neurotoxicol. Teratol. 26(4), 533-542 (2004).
•• The first functional MRI study on PME individuals demonstrating that altered neuronal activity is retained well into young adulthood.
Smith AM, Fried PA, Hogan MJ, Cameron I. Effects of prenatal marijuana on visuospatial working memory: an fMRI study in young adults. Neurotoxicol. Teratol. 28(2), 286-295 (2006).
Wang X, Dow-Edwards D, Anderson V, Minkoff H, Hurd YL. Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use. Pharmacogenomics J. 6(4), 255-264 (2006).
•• Along with [152] it is one of the only two human studies to date that describe changes in neurotransmitter signaling by as early as midgestation in response to PME.
Huizink AC. Moderate use of alcohol, tobacco and cannabis during pregnancy: new approaches and update on research findings. Reprod. Toxicol. 28(2), 143-151 (2009).
Spano MS, Ellgren M, Wang X, Hurd YL. Prenatal cannabis exposure increases heroin seeking with allostatic changes in limbic enkephalin systems in adulthood. Biol. Psychiatry 61(4), 554-563 (2007).
Spano MS, Fadda P, Fratta W, Fattore L. Cannabinoid-opioid interactions in drug discrimination and self-administration: effect of maternal, postnatal, adolescent and adult exposure to the drugs. Curr. Drug Targets 11(4), 450-461 (2010).
Fernandez-Ruiz J, Berrendero F, Hernandez ML, Ramos JA. The endogenous cannabinoid system and brain development. Trends Neurosci. 23(1), 14-20 (2000).
Colombo G, Rusconi F, Rubino T et al. Transcriptomic and proteomic analyses of mouse cerebellum reveals alterations in RasGRF1 expression following in vivo chronic treatment with Δ 9-tetrahydrocannabinol. J. Mol. Neurosci. 37(2), 111-122 (2009).
Castaldo P, Magi S, Cataldi M et al. Altered regulation of glutamate release and decreased functional activity and expression of GLT1 and GLAST glutamate transporters in the hippocampus of adolescent rats perinatally exposed to Δ(9)-THC. Pharmacol. Res. 61(4), 334-341 (2010).
Katona I, Urban GM, Wallace M et al. Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26(21), 5628-5637 (2006).
Huestis MA, Gorelick DA, Heishman SJ et al. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch. Gen. Psychiatry 58(4), 322-328 (2001).
Di Marzo V. Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight. Nat. Neurosci. 14(1), 9-15 (2011).
Liu J, Wang L, Harvey-White J et al. A biosynthetic pathway for anandamide. Proc. Natl Acad. Sci. USA 103(36), 13345-13350 (2006).
Simon GM, Cravatt BF. Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for α/β-hydrolase 4 in this pathway. J. Biol. Chem. 281(36), 26465-26472 (2006).
Cravatt BF, Lichtman AH. The enzymatic inactivation of the fatty acid amide class of signaling lipids. Chem. Phys. Lipids 121(1-2), 135-148 (2002).
Bisogno T, Howell F, Williams G et al. 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), 463-468 (2003).
Gao Y, Vasilyev DV, Goncalves MB et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J. Neurosci. 30(6), 2017-2024 (2010).
Ludanyi A, Eross L, Czirjak S et al. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J. Neurosci. 28(12), 2976-2990 (2008).
Dinh TP, Carpenter D, Leslie FM et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99(16), 10819-10824 (2002).
Marrs WR, Blankman JL, Horne EA et al. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat. Neurosci. 13(8), 951-957 (2010).
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284), 561-564 (1990).
Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441), 61-65 (1993).
Baker D, Pryce G, Davies WL, Hiley CR. In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol. Sci. 27(1), 1-4 (2006).
Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc. Natl Acad. Sci. USA 105(7), 2699-2704 (2008).
Pertwee RG. GPR55 : a new member of the cannabinoid receptor clan? Br. J. Pharmacol. 152(7), 984-986 (2007).
Ryberg E, Larsson N, Sjogren S et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152(7), 1092-1101 (2007).
Kreitzer FR, Stella N. The therapeutic potential of novel cannabinoid receptors. Pharmacol. Ther. 122(2), 83-96 (2009).
Mackie K. Signaling via CNS cannabinoid receptors. Mol. Cell Endocrinol. 286(1-2 Suppl 1), S60-65 (2008).
•• Overview of the signal transduction pathways downstream of cannabinoid receptors in the CNS.
Galve-Roperh I, Sanchez C, Cortes ML, Gomez Del Pulgar T, Izquierdo M, Guzman M. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med. 6(3), 313-319 (2000).
Guzman M, Galve-Roperh I, Sanchez C. Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol. Sci. 22(1), 19-22 (2001).
Berrendero F, Sepe N, Ramos JA, Di Marzo V, Fernandez-Ruiz JJ. 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(3), 181-191 (1999).
Keimpema E, Barabas K, Morozov YM et al. Differential subcellular recruitment of monoacylglycerol lipase generates spatial specificity of 2-arachidonoyl glycerol signaling during axonal pathfinding. J. Neurosci. 30(42), 13992-14007 (2010).
• Article that described temporal and spatial changes in monoglyceride lipase expression and in vitro evidence of a 2-arachidonoyl glycerol microgradient.
Paria BC, Dey SK. Ligand-receptor signaling with endocannabinoids in preimplantation embryo development and implantation. Chem. Phys. Lipids 108(1-2), 211-220 (2000).
Habayeb OM, Taylor AH, Bell SC, Taylor DJ, Konje JC. Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology 149(10), 5052-5060 (2008).
Trabucco E, Acone G, Marenna A et al. Endocannabinoid system in first trimester placenta: low FAAH and high CB1 expression characterize spontaneous miscarriage. Placenta 30(6), 516-522 (2009).
Mato S, Del Olmo E, Pazos A. Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain. Eur. J. Neurosci. 17(9), 1747-1754 (2003).
Wang X, Dow-Edwards D, Keller E, Hurd YL. Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain. Neuroscience 118(3), 681-694 (2003).
Mulder J, Aguado T, Keimpema E et al. Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proc. Natl Acad. Sci. USA 105(25), 8760-8765 (2008).
Wu CS, Zhu J, Wager-Miller J et al. Requirement of cannabinoid CB(1) receptors in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projections. Eur. J. Neurosci. 32(5), 693-706 (2010).
• Article that provided evidence of the involvement of CI^ cannabinoid receptor signaling in the developmental sensory neural circuit and interactions of corticothalamic and thalamocortical projections.
Vitalis T, Laine J, Simon A, Roland A, Leterrier C, Lenkei Z. The type 1 cannabinoid receptor is highly expressed in embryonic cortical projection neurons and negatively regulates neurite growth in vitro. Eur. J. Neurosci. 28(9), 1705-1718 (2008).
Morozov YM, Torii M, Rakic P. Origin, early commitment, migratory routes, and destination of cannabinoid type 1 receptor-containing interneurons. Cereb. Cortex 19(Suppl. 1), I78-I89 (2009).
Berghuis P, Rajnicek AM, Morozov YM et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316(5828), 1212-1216 (2007).
Morozov YM, Freund TF. Post-natal development of type 1 cannabinoid receptor immunoreactivity in the rat hippocampus. Eur. J. Neurosci. 18(5), 1213-1222 (2003).
Marin O, Rubenstein JL. A long, remarkable journey: tangential migration in the telencephalon. Nat. Rev. Neurosci. 2(11), 780-790 (2001).
Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD. Neuronal subtype specification in the cerebral cortex. Nat. Rev. Neurosci. 8(6), 427-437 (2007).
Shen Q, Wang Y, Dimos JT et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nat. Neurosci. 9(6), 743-751 (2006).
Aimone JB, Deng W, Gage FH. Adult neurogenesis: integrating theories and separating functions. Trends Cogn. Sci. 14(7), 325-337 (2010).
Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11(5), 339-350 (2010).
Mu Y, Lee SW, Gage FH. Signaling in adult neurogenesis. Curr. Opin. Neurobiol. 20(4), 416-423 (2010).
Aguado T, Monory K, Palazuelos J et al. The endocannabinoid system drives neural progenitor proliferation. FASEB J. 19(12), 1704-1706 (2005).
Aguado T, Palazuelos J, Monory K et al. The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J. Neurosci. 26(5), 1551-1561 (2006).
Guzman M, Sanchez C, Galve-Roperh I. Cannabinoids and cell fate. Pharmacol. Ther. 95(2), 175-184 (2002).
Goncalves MB, Suetterlin P, Yip P et al. A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner. Mol. Cell Neurosci. 38(4), 526-536 (2008) .
Galve-Roperh I, Aguado T, Palazuelos J, Guzman M. The endocannabinoid system and neurogenesis in health and disease. Neuroscientist 13(2), 109-114 (2007).
Aguado T, Romero E, Monory K et al. The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis. J. Biol. Chem. 282(33), 23892-23898 (2007).
Jiang W, Zhang Y, Xiao L et al. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J. Clin. Invest. 115(11), 3104-3116 (2005).
Marchalant Y, Brothers HM, Wenk GL. Cannabinoid agonist WIN-55,212-212 partially restores neurogenesis in the aged rat brain. Mol. Psychiatry 14(12), 1068-1069 (2009) .
Rueda D, Navarro B, Martinez-Serrano A, Guzman M, Galve-Roperh I. The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway. J. Biol. Chem. 277(48), 46645-46650 (2002).
Krebs-Kraft DL, Hill MN, Hillard CJ, McCarthy MM. Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior. Proc. Natl Acad. Sci. USA 107(47), 20535-20540 (2010) .
Arevalo-Martin A, Garcia-Ovejero D, Molina-Holgado E. The endocannabinoid 2-arachidonoylglycerol reduces lesion expansion and white matter damage after spinal cord injury. Neurobiol. Dis. 38(2), 304-312 (2010).
Arevalo-Martin A, Garcia-Ovejero D, Rubio-Araiz A, Gomez O, Molina-Holgado F, Molina-Holgado E. Cannabinoids modulate Olig2 and polysialylated neural cell adhesion molecule expression in the subventricular zone of post-natal rats through cannabinoid receptor 1 and cannabinoid receptor 2. Eur J. Neurosci. 26(6), 1548-1559 (2007).
Solbrig MV, Fan Y, Hermanowicz N, Morgese MG, Giuffrida A. A synthetic cannabinoid agonist promotes oligodendrogliogenesis during viral encephalitis in rats. Exp. Neurol. 226(1), 231-241 (2010).
Cayre M, Canoll P, Goldman JE. Cell migration in the normal and pathological postnatal mammalian brain. Prog. Neurobiol. 88(1), 41-63 (2009).
Goldman JE. Regulation of oligodendrocyte differentiation. Trends Neurosci. 15(10), 359-362 (1992).
Gomez O, Arevalo-Martin A, Garcia-Ovejero D et al. The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia 58(16), 1913-1927 (2010).
Berghuis P, Dobszay MB, Wang X et al. Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor. Proc. Natl Acad. Sci. USA 102(52), 19115-19120 (2005).
Oudin MJ, Gajendra S, Williams G, Hobbs C, Lalli G, Doherty P. Endocannabinoids regulate the migration of subventricular zone-derived neuroblasts in the postnatal brain. J. Neurosci. 31(11), 4000-4011 (2011).
Dodd J, Jessell TM. Axon guidance and the patterning of neuronal projections in vertebrates. Science 242(4879), 692-699 (1988).
Van Vactor D. Adhesion and signaling in axonal fasciculation. Curr. Opin. Neurobiol. 8(1), 80-86 (1998).
Watson S, Chambers D, Hobbs C, Doherty P, Graham A. The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation. Mol. Cell Neurosci. 38(1), 89-97 (2008).
Jones EG. Thalamic circuitry and thalamocortical synchrony. Philos. Trans R. Soc. Lond. B Biol. Sci. 357(1428), 1659-1673 (2002).
Temereanca S, Simons DJ. Functional topography of corticothalamic feedback enhances thalamic spatial response tuning in the somatosensory whisker/barrel system. Neuron 41(4), 639-651 (2004).
Theyel BB, Llano DA, Sherman SM. The corticothalamocortical circuit drives higher-order cortex in the mouse. Nat. Neurosci. 13(1), 84-88 (2010).
Hevner RF, Miyashita-Lin E, Rubenstein JL. Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: evidence that cortical and thalamic axons interact and guide each other. J. Comp. Neurol. 447(1), 8-17 (2002).
Molnar Z, Adams R, Blakemore C. Mechanisms underlying the early establishment of thalamocortical connections in the rat. J. Neurosci. 18(15), 5723-5745 (1998).
Molnar Z, Blakemore C. How do thalamic axons find their way to the cortex? Trends Neurosci. 18(9), 389-397 (1995).
Argaw A, Duff G, Zabouri N et al. Concerted action of CB1 cannabinoid receptor and deleted in colorectal cancer in axon guidance. J. Neurosci. 31(4), 1489-1499 (2011).
Astley SJ, Little RE. Maternal marijuana use during lactation and infant development at one year. Neurotoxicol. Teratol. 12(2), 161-168 (1990).
Long JZ, Nomura DK, Vann RE et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc. Natl Acad. Sci. USA 106(48), 20270-20275 (2009).
Straiker A, Mackie K. Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones. J. Physiol. 569(Pt 2), 501-517 (2005).
Wang X, Dow-Edwards D, Anderson V, Minkoff H, Hurd YL. In utero marijuana exposure associated with abnormal amygdala dopamine D2 gene expression in the human fetus. Biol Psychiatry 56(12), 909-915 (2004).
•• Along with [74], it is one of only two human studies to date that describe changes in neurotransmitter signaling by as early as midgestation in response to PME.
Dahl RE, Scher MS, Williamson DE, Robles N, Day N. A longitudinal study of prenatal marijuana use. Effects on sleep and arousal at age 3 years. Arch. Pediatr. Adolesc. Med. 149(2), 145-150 (1995).
Chandler LS, Richardson GA, Gallagher JD, Day NL. Prenatal exposure to alcohol and marijuana: effects on motor development of preschool children. Alcohol Clin. Exp. Res. 20(3), 455-461 (1996).
Fried PA, O'connell CM, Watkinson B. 60- and 72-month follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol: cognitive and language assessment. J. Dev. Behav. Pediatr. 13(6), 383-391 (1992).
Day NL, Richardson GA, Geva D, Robles N. Alcohol, marijuana, and tobacco: effects of prenatal exposure on offspring growth and morphology at age six. Alcohol Clin. Exp. Res. 18(4), 786-794 (1994).
Fried PA, James DS, Watkinson B. Growth and pubertal milestones during adolescence in offspring prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 23(5), 431-436 (2001).
Willford JA, Chandler LS, Goldschmidt L, Day NL. Effects of prenatal tobacco, alcohol and marijuana exposure on processing speed, visual-motor coordination, and interhemispheric transfer. Neurotoxicol. Teratol. 32(6), 580-588 (2010).

Websites
201. Substance Abuse and Mental Health Services Administration (2010). Results from the 2009 National Survey on Drug Use and Health Mental Health Findings (Center for Behavioral Health Statistics and Quality, NSDUH Series H-39, HHS Publication No.SMA 10-4609) www.oas.samhsa.gov/NSDUH/2k9NSDUH/MH/2k9MHResults.htm
202. Substance Abuse and Mental Health Services Administration: Substance Use among Women During Pregnancy and Following Childbirth. The NSDUH Report (2009) http://oas.samhsa.gov/2k9/135/PregWoSubUse.htm
203. United Nations Office on Drugs and Crime: United Nations Office on Drugs and Crime (UNODC), World Drug Report 2010 (United Nations Publication, Sales No. E. 10.XI.13) www.unodc.org/documents/wdr/WDR_2010/World_Drug_Report_2010_lo-res.pdf

Papers of special note have been highlighted as:
• of interest
•• of considerable interest

As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Author(s)

Chia-Shan Wu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital

Disclosures

Disclosure: Chia-Shan Wu, PhD, has disclosed no relevant financial relationships.

Christopher P. Jew

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Christopher P. Jew has disclosed no relevant financial relationships.

Hui-Chen Lu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Department of Pediatrics; Program in Developmental Biology; Department of Neuroscience, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Hui-Chen Lu, PhD, is supported by NIH grants: NS048884 (NINDS), DA029381 (NIDA) and HD065561 (NICHD).

Editor(s)

Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom

Disclosures

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosures

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosures

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain

Authors: Chia-Shan Wu, PhD; Christopher P. Jew; Hui-Chen Lu, PhD
CME Released: 7/1/2011
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 7/1/2012, 11:59 PM EST

Start Activity

Target Audience and Goal Statement

This activity is intended for primary care clinicians, obstetricians, neurologists, psychiatrists, pediatricians, and other healthcare providers advising pregnant women regarding the effects of prenatal marijuana exposure and/or caring for their offspring.

The goal of this activity is to review the interaction of prenatal exposure to marijuana with endocannabinoid effects on neural development.

Upon completion of this activity, participants will be able to:

Describe the epidemiology of prenatal exposure to marijuana, based on a review
Describe the neurodevelopmental effects of prenatal exposure to marijuana
Describe the effects of endocannabinoids on neural development and how prenatal exposure to marijuana influences these effects

Disclosures

Author(s)

Chia-Shan Wu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital

Disclosures

Disclosure: Chia-Shan Wu, PhD, has disclosed no relevant financial relationships.

Christopher P. Jew

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Christopher P. Jew has disclosed no relevant financial relationships.

Hui-Chen Lu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Department of Pediatrics; Program in Developmental Biology; Department of Neuroscience, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Hui-Chen Lu, PhD, is supported by NIH grants: NS048884 (NINDS), DA029381 (NIDA) and HD065561 (NICHD).

Editor(s)

Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom

Disclosures

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosures

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosures

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

Accreditation Statements

For Physicians

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Future Medicine Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test.

Follow these steps to earn CME/CE credit*:

Read the target audience, learning objectives, and author disclosures.
Study the educational content online or printed out.
Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape Education encourages you to complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage.

*The credit that you receive is based on your user profile.

processing....

Endocannabinoid System During Neural Development

Endocannabinoid signaling plays important roles in learning and memory, anxiety, depression, addiction, appetite and feeding behaviors, pain and neuroprotection.^[5,13] In the adult brain, eCBs are synthesized and released ‘on demand’ from postsynaptic neuronal compartments, where they act as retrograde messengers by engaging CB₁ cannabinoid receptors (CB₁R) on presynaptic terminals^[6,8,81] to attenuate neurotransmitter release in many excitatory and inhibitory synapses. Examples of eCB-dependent synaptic plasticity include depolarization-induced suppression of inhibition and excitation, metabotropic suppression of inhibition and excitation, and some forms of long-term depression.^[8] However, recent findings establish a strikingly different molecular organization of eCB signaling networks in the developing mammalian forebrain. The following subsections summarize the temporal and spatial distribution of various components of the endocannabinoid system in developing brains with an emphasis on the developmental profile of CB₁R as it is responsible for mediating most of the effects of THC.^[1,82]

Overview of the Endocannabinoid System

Endocannabinoids are amides, esters and ethers of long-chain polyunsaturated fatty acids. There are two major families of eCBs, acyl amides and acyl esters. Anandamide (arachidonoyl ethanolamide [AEA]) and 2-arachidonoyl glycerol (2-AG), respectively, are the prototypical members of each family. The enzymes that synthesize AEA are still uncertain, with at least four routes of AEA biosynthesis proposed to occur in brain homogenates.^[83] These enzymes include N-acyl-phosphatidyl-ethanolamine-specific phospholipase D, α,β-hydrolase domain-containing 4, glycerophosphodiesterase-1 and phosphatases such as PTPN22.^[5,84,85] These biosynthetic pathways demonstrate substantial overlap and may be able to substitute for one another. AEA is hydrolyzed to arachidonic acid and ethanolamine by fatty acid amide hydrolase (FAAH).^[15,86] 2-AG is synthesized by sn-1-selective diacylglycerol lipases α and β (DAGLα and DAGLβ).^[87] Recent data from genetic ablation of these two isoforms suggest DAGLα is the major CNS form in adult mice and is important for postsynaptic release of 2-AG to transiently suppress GABA-mediated transmission at inhibitory synapses in the hippocampus.^[88] Interestingly, DAGLα mRNA level is found to be decreased in the hippocampus of epileptic human patients, while DAGLβ isoform levels were unchanged, suggesting that under pathophysiological conditions, DAGLα is the affected isoform.^[89] However, it remains to be determined which DAGL isoform is responsible for 2-AG production in humans. 2-AG is hydrolyzed to arachidonic acid and glycerol by monoglyceride lipase (MAGL)^[90] and α/β-hydrolase domain-containing serine hydrolases (ABHD6/12).^[91]

The eCBs elicit diverse central and peripheral effects by activating the cannabinoid receptors: CB₁R and CB₂R,^[92,93] G-protein coupled receptor 55 (GPR55),^[94–97] the transient receptor potential of vanilloid type-1 (TRPV1) channel, the peroxisome proliferators-activated receptor (PPAR)α^[4] and at least two, as yet molecularly uncharacterized, receptors.^[98] The signal transduction mechanisms include Gi-mediated inhibition of adenylyl cyclase and modulation of ion channels. Cannabinoid signaling often inhibits voltage-dependent Ca²⁺ channels (N and P/Q type) or activates inwardly rectifying K⁺ channels.^[99] In addition, cannabinoids stimulate various signaling pathways involved in the regulation of cell fate, such as the MAP kinase family (ERK, JNK and p38), protein kinase B and the sphingolipid pathway.^[100,101]

Ontogeny of the Endocannabinoid System

Owing to their lipophilic nature, endocannabinoids are highly unstable and difficult to quantify, hence the paucity of data on endocannabinoid levels during development. The only available data comes from older studies employing mass spectrometry, where levels of AEA and 2-AG have been shown to vary substantially in rodent brains throughout prenatal development.^[78,102] AEA is present at low concentrations in the brain at midgestation and gradually increases through the perinatal period until adult levels are reached,^[102] whereas fetal 2-AG levels gradually increase through the prenatal period, with a surge occurring at birth.^[102,103] Notably, 2-AG concentrations (2–8 nmol/g tissue) are approximately 1000-fold higher than those of AEA (3–6 pmol/g tissue) throughout brain development.^[102] However, additional studies are required to substantiate these findings.

The ontogeny of the metabolizing enzymes and receptors of the endocannabinoid system has not been extensively characterized. Nevertheless, current data suggest that the endocannabinoid system exists from the earliest stage of pregnancy, in the preimplantation embryo and uterus,^[104] placenta^[105] and in the developing fetal brain,^[78] presenting multiple points of vulnerability to exogenous cannabis or cannabimimetic drug exposure throughout gestation. In the mouse, stimulation of CB₁R arrests the development of two-cell embryos into blastocytsts in culture.^[104] AEA is present in the pregnant uterus at relatively high levels (5–10 nmol/g tissue) that fluctuate with changes in the pregnancy status, with higher levels associated with a nonreceptive uterine environment.^[104] Indeed, low levels of the AEA-degrading enzyme FAAH and high levels of CB₁R expression in human placenta are associated with spontaneous miscarriage.^[106] Studies characterizing the endocannabinoid system in early human pregnancy (weeks 7–12 gestation) demonstrated that CB₂R and FAAH are expressed in relatively constant levels in trophoblasts in early gestation, but their cellular distribution changed from syncytiotrophoblast to the mesenchymal core of the villus.^[105]

In the developing mouse brain, CB₁R are expressed as early as day 11 postgestation (comparable with 5–6-week old human embryos), with gradually increasing levels of both mRNA and receptor density (revealed by radiolabeled agonist binding) throughout the prenatal period in the whole brain.^[78] CB₁R are abundantly expressed in corticolimbic areas of the fetal rodent brain.^[78] Pharmacological studies of the ability of the CB₁R agonist, WIN55212-2, to stimulate [³⁵S]GTPγS binding indicate that CB₁Rs are functionally active from early stages of development.^[107] In human fetal brains, CB₁Rs were detected at week 14 of gestation, with preferential expression in the cerebral cortex, hippocampus, caudate nucleus, putamen and cerebellar cortex. By week 20, intense expression is evident in CA2–CA3 of hippocampus and in the basal nuclear group of the amygdala.^[107,108]

More recently, several specific antibodies against different endocannabinoid system components have become available, making it possible to examine the distribution of specific enzymes at the light- and electron-microscopic level. In particular, immunohistological studies using specific antibodies have mapped the temporal and spatial distribution of CB₁R, DAGLα/β and MAGL during neural development in mice.^{[103,109,110]} Similar to ligand binding and mRNA expression studies, CB₁R immunoreactivity can be detected by embryonic day (E)12.5, and is localized to reelin-expressing Cajal-Retzius cells and newly differentiated postmitotic glutamatergic neurons of the mouse telencephalon,^[111] and to the subpial area of the ganglionic eminence and marginal zone of the neocortex.^[112] From E13.5 to birth, abundant CB₁R immunoreactivity is detected in several long-range axonal tracts including corticofugal tracts such as corticothalamic (Figure 1) and corticospinal tracts.^[109,111] On the subcellular level, CB₁R is localized to somato-dendritic endosomes at E12.5 and then to developing axons of glutamatergic neurons at E13.5 and after this time.^[111] The ‘atypical’ pattern of CB₁R expression in long-range glutamatergic axons disappears after birth.^[110,111] During late gestation (E17–18), CB₁R immunoreactivity becomes detectable in axons and axonal growth cones of cholecystokinin (CCK)-positive GABAergic interneurons.^[113,114] The origin of these CB₁R containing interneurons has been traced to the caudal ganglionic eminence and pallial–subpallial boundary at E11–12. These cells undergo a complex long-distance migration, first radially to the marginal zone, then tangentially in the lateral-to-medial direction within the dorsal telencephalon, eventually reaching their final destination in the cortex, hippocampus and dentate gyrus where they migrate radially and differentiate into CB₁/CCK⁺ or CB₁/reelin/calretinin⁺ GABAergic interneurons.^[112]

Figure 1.

Enlarge

Expression Pattern of CB₁R, DAGLβ and MAGL in Developing Thalamocortical Axonal Tracts. (A) Embryonic brain slice highlighting the path of developing thalamocortical axons (green lines) and corticothalamic axons (blue lines) at E14.5. A thalamocortical axon reporter mice line (TCA^mGFP) was generated by crossing a Cre-reporter line containing a floxed ‘stop transcription’ sequence in front of membrane-anchored green fluorescent protein (mGFP) followed by an IRES-NLS-lacZ gene inserted into exon 2 of the Tau locus with RORα-Cre mice. (B) Thalamocortical axons extending toward the cortex are GFP labeled in TCA^mGFP reporter mice. (C) Using the TCA^mGFP mice, CB₁R is demonstrated to be localized to corticothalamic, but not thalamocortical, axons during brain development. (D–I) DAGLβ is localized mainly to GFP-labeled thalamocortical axons (dashed arrow in F), while MAGL is localized to both CB₁R-containing corticothalamic (arrow in I) and GFP-labeled thalamocortical axons (dashed arrow in I). (F, I) higher magnification of squared areas in (E) and (H). CB₁R: CB₁ cannabinoid receptor; cp: Cortical plate; DAGLβ: Diacylglycerol lipase β; ge: Ganglionic eminence; GFP: Green fluorescent protein; hc: Hippocampus; lv: Lateral ventricle; MAGL: Monoglyceride lipase; RORα: retinoic acid-receptor-related orphan receptor a; st: Striatum; TCA: Thalamocortical axon; th: Thalamus.

The overall protein levels of CB₁Rs are relatively constant throughout forebrain development, while DAGLα protein levels peak at E14.5/E16.5 and then dramatically decrease in neonates, furthermore MAGL transiently decreases around E18.5 (Figure 2).^[103] Similar to CB₁R, the distribution of DAGLα/β and MAGL are localized to long-range glutamatergic axons in the prenatal period (Figure 1).^[103,110] Interestingly, after E16.5, MAGL expression undergoes a dramatic change from cortical plate and long-range axon tracts to a restricted expression in perisomatic segments and proximal dendrites both in the late-gestational brain and at birth.^[103] This coincides with the surge in cortical and hippocampal 2-AG concentrations, suggesting that MAGL plays an essential role in determining 2-AG availability in the developing brain.

Figure 2.

Enlarge

Temporal Changes in the Expression of Endocannabinoid System Components During Development. DAGLα and MAGL are expressed starting at midgestation. Expression levels of DAGLα decrease from E18.5 onwards, while there is a transient decrease in MAGL expression levels around birth. CB₁R is expressed at relatively constant levels throughout brain development and, prenatally, is primarily localized to the corticofugal tract. The expression pattern undergoes a dramatic change after birth, with the adult-like distribution pattern in the cortex is apparent after P1. CB₁R: CB₁ cannabinoid receptor; DAGLα: Diacylglycerol lipase α; MAGL: Monoglyceride lipase; P1: Postnatal day 1.

Together, these expression studies indicate that components of the endocannabinoid system are expressed early in life and are positioned to modulate neuronal generation, differentiation, migration and neural circuit wiring during development.

« Back

Page 3 of 7

Involvement of Endocannabinoid Signaling in Neural Development

CME Information

Abstract and Introduction
Adverse Effect of Prenatal Exposure to Marijuana
Endocannabinoid System During Neural Development
Involvement of Endocannabinoid Signaling in Neural Development
Conclusion
Future Perspective
Executive Summary

References

Table 1.

CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain

Target Audience and Goal Statement

Disclosures

Author(s)

Chia-Shan Wu, PhD

Christopher P. Jew

Hui-Chen Lu, PhD

Editor(s)

Elisa Manzotti

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain: Endocannabinoid System During Neural Development

Endocannabinoid System During Neural Development

Overview of the Endocannabinoid System

Ontogeny of the Endocannabinoid System

Figure 1.

Figure 2.

Table of Contents

Table 1.

References

Faculty and Disclosures

Author(s)

Chia-Shan Wu, PhD

Christopher P. Jew

Hui-Chen Lu, PhD

Editor(s)

Elisa Manzotti

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain

Target Audience and Goal Statement

Disclosures

Author(s)

Chia-Shan Wu, PhD

Christopher P. Jew

Hui-Chen Lu, PhD

Editor(s)

Elisa Manzotti

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain: Endocannabinoid System During Neural Development

Endocannabinoid System During Neural Development

Overview of the Endocannabinoid System

Ontogeny of the Endocannabinoid System

Figure 1.

Figure 2.

Table of Contents