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 INTERPRETATION: These observations indicate that CB(1) receptor activation modulates GABAergic and glutamatergic neurotransmission and primes the developing brain to suffer apoptotic neuronal death.
Subject(s)
Aging/physiology , Alcohol-Induced Disorders, Nervous System/chemically induced , Brain/drug effects , Brain/growth & development , Cannabinoids/agonists , Ethanol/agonists , Neurotoxins/agonists , Alcohol-Induced Disorders, Nervous System/metabolism , Alcohol-Induced Disorders, Nervous System/physiopathology , Animals , Animals, Newborn , Benzoxazines/agonists , Benzoxazines/toxicity , Brain/physiopathology , Cannabinoids/toxicity , Cell Death/drug effects , Cell Death/physiology , Central Nervous System Depressants/agonists , Central Nervous System Depressants/toxicity , Dose-Response Relationship, Drug , Dronabinol/agonists , Dronabinol/toxicity , Drug Resistance/drug effects , Drug Resistance/physiology , Drug Synergism , Ethanol/toxicity , Excitatory Amino Acid Antagonists/toxicity , GABA Agonists/toxicity , Mice , Mice, Knockout , Morpholines/agonists , Morpholines/toxicity , Naphthalenes/agonists , Naphthalenes/toxicity , Nerve Degeneration/chemically induced , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Neurotoxins/toxicity , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/antagonists & inhibitorsABSTRACT
Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways.
