Molander Anna, Lidö Helga Höifödt, Löf Elin, Ericson Mia, Söderpalm Bo
Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, Box 410, 405 30 Gothenburg, Sweden.
Alcohol Alcohol. 2007 Jan-Feb;42(1):11-8. doi: 10.1093/alcalc/agl085. Epub 2006 Nov 9.
Previous findings from our group indicate that accumbal glycine receptors (GlyRs) are involved in mediating the dopamine (DA) activating effects of ethanol (EtOH), and that administration of glycine locally into the nucleus accumbens (nAc) reduces EtOH consumption in EtOH high-preferring rats.
The present study examines the influence of a systemically administered glycine reuptake inhibitor, Org 25935, on EtOH preference and intake, in male Wistar rats with an EtOH preference >60% (during continuous access to a bottle of EtOH, 6% v/v, and a bottle of water), called EP>60 rats, as well as in animals with an EtOH preference <60%, called EP<60 rats. Org 25935 is an inhibitor of the glycine transporter 1 (GlyT1) protein with negligible action on the glycine transporter 2 (GlyT2) protein.
Both EP>60 and EP<60 rats were limited to drink 2.5 h/day. Org 25935 or vehicle was administered intraperitoneally approximately 40 min before the rats were presented to a choice of drinking EtOH or water.
Org 25935 decreased EtOH intake and EtOH preference, as compared with vehicle, whereas water intake was unaffected. This effect was dose-dependent, developed gradually and was sustained for up to 40 days, also after introduction of an alcohol deprivation period.
It is suggested that Org 25935, and possibly also other GlyT1 inhibitors, can represent a new pharmacological treatment principle for alcohol dependence or abuse.
我们小组之前的研究结果表明，伏隔核甘氨酸受体（GlyRs）参与介导乙醇（EtOH）的多巴胺（DA）激活作用，并且向伏隔核（nAc）局部注射甘氨酸可减少乙醇高偏好大鼠的乙醇摄入量。
本研究考察了系统给予甘氨酸再摄取抑制剂Org 25935对乙醇偏好和摄入量的影响，实验对象为乙醇偏好>60%（在持续接触一瓶6% v/v乙醇和一瓶水的情况下）的雄性Wistar大鼠，即乙醇偏好>60%大鼠（EP>60大鼠），以及乙醇偏好<60%的动物，即乙醇偏好<60%大鼠（EP<60大鼠）。Org 25935是甘氨酸转运体1（GlyT1）蛋白的抑制剂，对甘氨酸转运体2（GlyT2）蛋白的作用可忽略不计。
EP>60大鼠和EP<60大鼠均限制每天饮水2.5小时。在大鼠面临乙醇或水的饮水选择前约40分钟，腹腔注射Org 25935或赋形剂。
与赋形剂相比，Org 25935降低了乙醇摄入量和乙醇偏好，而水的摄入量未受影响。这种作用具有剂量依赖性，逐渐显现且可持续长达40天，在引入酒精剥夺期后也是如此。
提示Org 25935以及其他可能的GlyT1抑制剂可代表一种治疗酒精依赖或滥用的新药理学原则。
