Grant K A, Waters C A, Green-Jordan K, Azarov A, Szeliga K T
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA.
Psychopharmacology (Berl). 2000 Oct;152(2):181-8. doi: 10.1007/s002130000510.
The current study was designed to extend our knowledge of the GABA(A) receptor system in mediating discriminative stimulus effects of ethanol in non-human primates.
To characterize the discriminative stimulus effects of ethanol, pentobarbital, midazolam, muscimol and morphine in male and female monkeys under different ethanol training conditions.
Adult male (n=8) and female (n=10) Macaca fascicularis monkeys were divided into four groups and trained to discriminate 1.0 g/kg ethanol (n=8) versus water or 2.0 g/kg ethanol (n=10) versus water in a 2x2 design with training dose and sex as main group factors. Solutions were administered intragastrically (20% ethanol w/v) and responding was maintained under a fixed-ratio schedule of food reinforcement. Dose-response determinations of ethanol, pentobarbital, midazolam, muscimol and morphine were made under the training condition of 30 min pretreatment interval. The ethanol pretreatment interval in training sessions was then increased to 60 min and the effects of ethanol, pentobarbital and midazolam were redetermined.
Training dose influenced the ED50 of ethanol to produce substitution under both pretreatment intervals and pentobarbital to produce substitution under the 30-min pretreatment training interval. There were no group differences in sensitivity to midazolam. The potency of the ligands to produce ethanol substitution was consistent across groups with midazolam>pentobarbital>ethanol. There were no sex differences in substitution of the ligands for ethanol. Blood ethanol concentrations at the onset of ethanol training sessions were higher in the 2.0 g/kg groups and under longer pretreatment times, but were not different on the basis of sex.
Pentobarbital and midazolam produce ethanol-like discriminative stimulus effects in male and female cynomolgus monkeys suggesting a significant GABA(A) component mediating the behavioral effects of ethanol. There was limited evidence that training dose of ethanol influenced substitution pattern of the GABA(A) ligands in cynomolgus monkeys, unlike previous findings in rats. Finally, there appear to be no sex differences in the profile of GABA(A) mechanisms involved in the discriminative stimulus effects of ethanol.
本研究旨在拓展我们对γ-氨基丁酸A（GABA(A)）受体系统在介导乙醇对非人类灵长类动物辨别性刺激效应方面的认识。
在不同乙醇训练条件下，表征乙醇、戊巴比妥、咪达唑仑、蝇蕈醇和吗啡对雄性和雌性猴子的辨别性刺激效应。
成年雄性（n = 8）和雌性（n = 10）食蟹猴被分为四组，采用2×2设计，以训练剂量和性别作为主要分组因素，训练它们辨别1.0 g/kg乙醇（n = 8）与水或2.0 g/kg乙醇（n = 10）与水。溶液通过胃内给药（20%乙醇w/v），反应在固定比率的食物强化时间表下维持。在30分钟预处理间隔的训练条件下，对乙醇、戊巴比妥、咪达唑仑、蝇蕈醇和吗啡进行剂量-反应测定。然后将训练过程中乙醇的预处理间隔增加到60分钟，并重新测定乙醇、戊巴比妥和咪达唑仑的效应。
训练剂量影响乙醇在两种预处理间隔下产生替代作用的半数有效剂量（ED50），以及戊巴比妥在30分钟预处理训练间隔下产生替代作用的ED50。对咪达唑仑的敏感性没有组间差异。各配体产生乙醇替代作用的效力在各组中一致，即咪达唑仑>戊巴比妥>乙醇。配体替代乙醇的作用没有性别差异。在2.0 g/kg组和较长预处理时间下，乙醇训练开始时的血乙醇浓度较高，但在性别上没有差异。
戊巴比妥和咪达唑仑在雄性和雌性食蟹猴中产生类似乙醇的辨别性刺激效应，表明存在一个重要的GABA(A)成分介导乙醇的行为效应。与先前在大鼠中的发现不同，有有限的证据表明乙醇的训练剂量会影响食蟹猴中GABA(A)配体的替代模式。最后，在乙醇辨别性刺激效应所涉及的GABA(A)机制方面，似乎不存在性别差异。
