title: Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity.
abstract: OBJECTIVE
  Marijuana and alcohol are most widely abused drugs among women of reproductive age. Neurocognitive deficits have been reported in children whose mothers used marijuana during pregnancy. Maternal consumption of ethanol is known to cause serious developmental deficits
  
  
  METHODS
  Infant rats and mice received systemic injections of Delta(9)-tetrahydrocannabinol (THC; 1-10mg/kg) or the synthetic cannabinoid WIN 55,212-2 (1-10mg/kg), alone or in combination with subtoxic and toxic ethanol doses, and apoptotic neurodegeneration was studied in the brains
  
  
  RESULTS
  Acute administration of THC (1-10mg/kg), the principal psychoactive cannabinoid of marijuana, markedly enhanced proapoptotic properties of ethanol in the neonatal rat brain. THC did not induce neurodegeneration when administered alone. Neuronal degeneration became disseminated and severe when THC was combined with a mildly intoxicating ethanol dose (3gm/kg), with the effect of this drug combination resembling the massive apoptotic death observed when administering ethanol alone at much higher doses. The detrimental effect of THC was mimicked by the synthetic cannabinoid WIN 55,212-2 (1-10mg/kg) and counteracted by the CB(1) receptor antagonist SR141716A (0.4mg/kg). THC enhanced the proapoptotic effect of the GABA(A) agonist phenobarbital and the N-methyl-D-aspartate receptor antagonist dizocilpine. Interestingly, infant CB(1) receptor knock-out mice were less susceptible to the neurotoxic effect of ethanol. Furthermore, the CB(1) receptor antagonist SR141716A ameliorated neurotoxicity of ethanol
  
  
  CONCLUSIONS
  These observations indicate that CB(1) receptor activation modulates GABAergic and glutamatergic neurotransmission and primes the developing brain to suffer apoptotic neuronal death.
authors: Department of Pediatric Neurology and Neuroscience Research Center, Humboldt University, Berlin, Germany.
authors: Henrik H
authors: HH
authors: Hansen
authors: Birte
authors: B
authors: Krutz
authors: Marco
authors: M
authors: Sifringer
authors: Vanya
authors: V
authors: Stefovska
authors: Petra
authors: P
authors: Bittigau
authors: Fritz
authors: F
authors: Pragst
authors: Giovanni
authors: G
authors: Marsicano
authors: Beat
authors: B
authors: Lutz
authors: Chrysanthy
authors: C
authors: Ikonomidou
mesh_terms: D000375:Aging / Q000502:physiology*; D020268:Alcohol-Induced Disorders, Nervous System / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D048588:Benzoxazines / Q000819:agonists / Q000633:toxicity; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000503:physiopathology; D002186:Cannabinoids / Q000819:agonists* / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002492:Central Nervous System Depressants / Q000819:agonists / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000819:agonists / Q000633:toxicity; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D000431:Ethanol / Q000819:agonists* / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D018755:GABA Agonists / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000819:agonists / Q000633:toxicity; D009281:Naphthalenes / Q000819:agonists / Q000633:toxicity; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000819:agonists* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D009025:Morpholines; D009281:Naphthalenes; D009498:Neurotoxins; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol