Effects of NMDA glutamate receptor antagonist drugs on the volitional consumption of ethanol by a genetic drinking rat.
The ability of drugs that reduce NMDA receptor activity on the volitional consumption of ethanol in the genetic drinking rat, mHEP line, was investigated. After the consumption of ethanol solutions and water by each male or female mHEP rat had stabilized on its preferred concentration, different doses of LY 274614, a competitive NMDA antagonist, MK 801, a non-competitive NMDA antagonist, (+)-HA-966 or ACPC (1-aminocyclopropane-1-carboxylic acid), antagonists of the glycine site were administered daily for three days. The dose of 3.0 mg/kg i.p. LY 274614 reduced the consumption of ethanol by 64% compared to the pre-treatment baseline, while 0.3 mg/kg of MK 801 reduced consumption by 44%, 20 mg/kg (+)-HA-966 reduced consumption by 47% and 300 mg/kg of ACPC reduced consumption by 30%. These doses of LY 274614 and MK 801 reduced the ability of Sprague-Dawley rats to walk on a rotorod. Effects of these drugs on food intake were small except for the 20 mg/kg dose of (+)-HA-966. Therefore, the drugs did not have an anti-caloric effect and manipulations of the glutamatergic system through NMDA receptors may modify the consumption of ethanol. This interaction should be explored further for its therapeutic potential and to better understand the control by central neuronal systems of the consumption of ethanol.
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA. mcmillenb@mail.ecu.edu
Brian A
BA
McMillen
Paul W
PW
Joyner
Chandresh A
CA
Parmar
Will E
WE
Tyer
Helen L
HL
Williams
D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics; D020268:Alcohol-Induced Disorders, Nervous System / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014836:Volition / Q000187:drug effects / Q000502:physiology
D000598:Amino Acids, Cyclic; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C070935:LY 274614; D000431:Ethanol; C023863:1-aminocyclopropane-1-carboxylic acid; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C001369:1-hydroxy-3-amino-2-pyrrolidone