McMillen Brian A, Joyner Paul W, Parmar Chandresh A, Tyer Will E, Williams Helen L
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
Brain Res Bull. 2004 Sep 30;64(3):279-84. doi: 10.1016/j.brainresbull.2004.08.001.
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.
研究了降低NMDA受体活性的药物对遗传性嗜酒大鼠mHEP品系自愿摄入乙醇的影响。在每只雄性或雌性mHEP大鼠对乙醇溶液和水的摄入量在其偏好浓度上稳定后，每天给予不同剂量的竞争性NMDA拮抗剂LY 274614、非竞争性NMDA拮抗剂MK 801、甘氨酸位点拮抗剂(+)-HA-966或ACPC（1-氨基环丙烷-1-羧酸），持续三天。腹腔注射3.0mg/kg的LY 274614使乙醇摄入量比预处理基线降低了64%，而0.3mg/kg的MK 801使摄入量降低了44%，20mg/kg的(+)-HA-966使摄入量降低了47%，300mg/kg的ACPC使摄入量降低了30%。这些剂量的LY 274614和MK 801降低了Sprague-Dawley大鼠在转棒上行走的能力。除了20mg/kg剂量 的(+)-HA-966外，这些药物对食物摄入量的影响较小。因此，这些药物没有抗热量作用，通过NMDA受体对谷氨酸能系统的调控可能会改变乙醇的摄入量。这种相互作用的治疗潜力以及为更好地理解中枢神经系统对乙醇摄入的控制，都值得进一步探索。
