Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity.
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.
Hansen
Henrik H
HH
Department of Pediatric Neurology and Neuroscience Research Center, Humboldt University, Berlin, Germany.
Krutz
Birte
B
Sifringer
Marco
M
Stefovska
Vanya
V
Bittigau
Petra
P
Pragst
Fritz
F
Marsicano
Giovanni
G
Lutz
Beat
B
Ikonomidou
Chrysanthy
C
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
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