Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity.
Ann Neurol.. 2008-07-01; 64(1): 42-52
DOI: 10.1002/ana.21287
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1. Ann Neurol. 2008 Jul;64(1):42-52.
Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity.
Hansen HH(1), Krutz B, Sifringer M, Stefovska V, Bittigau P, Pragst F, Marsicano
G, Lutz B, Ikonomidou C.
Author information:
(1)Department of Pediatric Neurology and Neuroscience Research Center, Humboldt
University, Berlin, Germany.
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
INTERPRETATION: These observations indicate that CB(1) receptor activation
modulates GABAergic and glutamatergic neurotransmission and primes the developing
brain to suffer apoptotic neuronal death.
DOI: 10.1002/ana.21287
PMID: 18067175 [Indexed for MEDLINE]