Reduced effect of NMDA glutamate receptor antagonist on ethanol-induced ataxia and striatal glutamate levels in mice lacking ENT1.
Alcohol-sensitive type 1 equilibrative nucleotide transporter (ENT1) is known to regulate glutamate signaling in the striatum as well as ethanol intoxication. However, it was unclear whether altered extracellular glutamate levels in ENT1(-/-) mice contribute to ethanol-induced behavioral changes. Here we report that altered glutamate signaling in ENT1(-/-) mice is implicated in the ethanol-induced locomotion and ataxia by NMDA receptor antagonist, CGP37849. ENT1(-/-) mice appear less intoxicated following sequential treatment with CGP37849 and ethanol, compared to ENT1(+/+) littermates on the rotarod. These results indicate that inhibiting NMDA glutamate receptors is critical to regulate the response and susceptibility of alcohol related behaviors. Interestingly, a microdialysis experiment showed that the ventral striatum of ENT1(-/-) mice is less sensitive to the glutamate-reducing effect of the NMDA receptor antagonist compared to the dorsal striatum. Our findings suggest that differential glutamate neurotransmission in the striatum regulates ethanol intoxication.
Nam
Hyung Wook
HW
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Lee
Moonnoh R
MR
Hinton
David J
DJ
Choi
Doo-Sup
DS
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics*; D000431:Ethanol / Q000633:toxicity*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D033721:Equilibrative Nucleoside Transporter 1; D016194:Receptors, N-Methyl-D-Aspartate; C498476:SLC29A1 protein, mouse; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D000431:Ethanol; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate