THE BENZODIAZEPINE INVERSE AGONIST RO19-4603 EXERTS PROLONGED AND SELECTIVE SUPPRESSION OF ETHANOL INTAKE IN ALCOHOL-PREFERRING (P) RATS
THE BENZODIAZEPINE INVERSE AGONIST RO19-4603 EXERTS PROLONGED AND SELECTIVE SUPPRESSION OF ETHANOL INTAKE IN ALCOHOL-PREFERRING (P) RATS
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DOI：
10.1007/bf02245073
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发表时间：
1994-07-01
影响因子：
3.4
通讯作者：
LI, TK
中科院分区：
文献类型：
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作者：
JUNE, HL;MURPHY, JM;LI, TK
研究了苯二氮卓类（BDZ）反向激动剂R 019 -4603拮抗乙醇（EtOH）摄入量的时间过程，在嗜醇（P）大鼠（n = 7）中进行了24小时连续自由选择乙醇（10% v/v）、水和食物的研究。液体摄入量稳定数周后，向动物注射吐温-80溶剂溶液或R 019 -4603（0.075、0.150和0.30 mg/kg）。乙醇和水的摄入量在8-和24小时的时间间隔进行了测定。R 019 -4603在每种测试剂量下均导致EtOH饮用量显著衰减。0.075、0.150和0.30 mg/kg R 019 -4603给药后8小时内的EtOH摄入量分别降低约36、74和57%。24小时间隔内的摄入量与溶剂对照条件相似。然而，给药后32 h，0.075、0.150和0.30 mg/kg剂量组的EtOH摄入量分别降低至约27、31和29%。为进一步确认R 019 -4603剂量-反应效应的可靠性及其对EtOH的选择性，对最高剂量条件（0.30 mg/kg）进行了两次检测。第二个0.30 mg/kg剂量条件产生的效应特征与初始给药相似;给药后8 h，摄入量降至对照水平的60%，给药后32 h摄入量降至对照水平的约46%。与水相比，这些减少明显具有选择性，因为饮水显示出补偿性增加，这抵消了EtOH消耗的减少。剂量反应比较表明，0.150 mg/kg接近最大有效剂量，因为0.30 mg/kg剂量的R 019 -4603未导致EtOH摄入量额外减少。此外，与较低剂量不同，0.30 mg/kg剂量未能产生饮水量的可靠代偿性增加。结果表明，R 019 -4603单次急性给药对维持24小时连续自由接触EtOH的P大鼠的EtOH摄入产生长期和选择性抑制。虽然目前尚不清楚配体的什么性质可以解释观察到的对EtOH摄入的影响，但这些发现沿着我们以前的工作，清楚地表明R 019 -4603可能会改变促进EtOH自我给药的神经元过程。GABA（A）-BDZ受体复合物的神经传递可能在介导EtOH强化中起重要作用。
The time course of the benzodiazepine (BDZ) inverse agonist R019-4603 in antagonizing ethanol (EtOH) intake was investigated in alcohol-preferring (P) rats (n = 7) maintained on 24-h continuous free-choice access to EtOH (10% v/v), water, and food. After fluid intakes had stabilized over several weeks, animals were injected with Tween-80 vehicle solution or R019-4603 (0.075, 0.150, and 0.30 mg/kg). EtOH and water intakes were determined at 8- and 24-h intervals. R019-4603 caused a marked attenuation of EtOH drinking with each of the doses tested. EtOH intake during the 8-h following 0.075, 0.150, and 0.30 mg/kg R019-4603 was decreased by approximately 36, 74, and 57%, respectively. Intakes during the 24-h interval were similar to the vehicle control condition. However, 32 h post-drug administration, EtOH intakes were reduced to approximately 27, 31, and 29% following the 0.075, 0.150 and 0.30 mg/kg doses, respectively. To further confirm the reliability of the R019-4603 dose-response effect, and its selectivity for EtOH, the highest dose condition (0.30 mg/kg) was tested twice. The second 0.30 mg/kg dose condition exerted a profile of effects similar to the initial treatment; 8 h following administration, intake was decreased to 60% of the control level, and 32 h post-drug administration intake was decreased to approximately 46% of the controls. These decreases were evidently selective in comparison with water, since water drinking showed compensatory increases which paralleled the decreased EtOH consumption. Dose-response comparisons indicated that 0.150 mg/kg approaches the maximum effective dose, since the 0.30 mg/kg dose of R019-4603 did not produce an additional decrease in EtOH intake. Furthermore, unlike the lower doses, the 0.30 mg/kg dose failed to yield reliable compensatory increases in water drinking. The results demonstrated that a single acute administration of R019-4603 produces prolonged and selective suppression of EtOH intake in P rats maintained on 24-h continuous free access to EtOH. While it is not clear at present what properties of the ligand might explain the observed effects on EtOH intake, these findings along with our previous work, clearly suggest that R019-4603 may modify neuronal processes that promote EtOH self-administration. Neural transmission at the GABA(A)-BDZ receptor complex may play an important role in mediating EtOH reinforcement.