Overstreet David H, Knapp Darin J, Moy Sheryl S, Breese George R
Department of Psychiatry, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, CB #7178, Chapel Hill, NC 27599-7178, USA.
Psychopharmacology (Berl). 2003 Jun;167(4):344-52. doi: 10.1007/s00213-003-1425-y. Epub 2003 Apr 4.
Repeated withdrawals from chronic forced ethanol exposure sensitize animals to withdrawal-induced deficits in social interaction behavior. The deficits in social interaction behavior following withdrawal from continuous ethanol exposure can be reduced following acute treatments with 5-HT(2C) antagonists or 5-HT(1A) agonists.
The present study investigated whether prior treatment with these serotonergic agents during early withdrawals in rats subjected to repeated withdrawals from ethanol exposure would ameliorate the social interaction deficits observed following the final withdrawal.
Sprague-Dawley rats were exposed to three cycles of 5 days forced ethanol (7%, w/v), with 2 days of control diet after the first and second cycles. Drugs were administered IP 4 h after removal of ethanol on the first and second cycles but not the third in one group and 4.5 h after removal of ethanol on the third cycle in another. The social interaction test was performed 5 h after removal of ethanol on the third cycle. Drugs tested included SB-242084, a 5-HT(2C) antagonist; buspirone, a 5-HT(1A) partial agonist; WAY-100635, a 5-HT(1A) antagonist; ketanserin, a 5-HT(2A) antagonist; ritanserin, a mixed 5-HT(2A/2C) antagonist; and Ro-601075, a 5-HT(2C) agonist.
Both SB-242084 and buspirone reduced ethanol withdrawal-induced deficits in social interaction when given either acutely 30 min before the test or at 4 h after withdrawal from the first and second cycles. WAY-100635 and ketanserin were completely ineffective regardless of mode of treatment. In contrast, the 5-HT(2C) agonist, Ro-601075, accentuated the withdrawal-induced deficit in social interaction behavior in rats exposed to either 4.5 or 7% ethanol diet.
These results support the utility of 5-HT(1A) agonists and 5-HT(2C) antagonists in reducing anxiety-like behavior induced by ethanol withdrawal and reducing the adaptive changes associated with repeated withdrawals.
长期强迫性乙醇暴露后反复戒断会使动物对戒断诱导的社交互动行为缺陷敏感。连续乙醇暴露戒断后社交互动行为的缺陷，在急性给予5-HT(2C)拮抗剂或5-HT(1A)激动剂后可减轻。
本研究调查了在反复乙醇暴露的大鼠早期戒断期间预先用这些血清素能药物治疗，是否会改善末次戒断后观察到的社交互动缺陷。
将Sprague-Dawley大鼠暴露于三个周期的5天强迫性乙醇（7%，w/v），在第一个和第二个周期后给予2天对照饮食。一组在第一个和第二个周期去除乙醇后4小时腹腔注射药物，但第三个周期不注射；另一组在第三个周期去除乙醇后4.5小时注射。在第三个周期去除乙醇后5小时进行社交互动测试。测试的药物包括5-HT(2C)拮抗剂SB-242084、5-HT(1A)部分激动剂丁螺环酮、5-HT(1A)拮抗剂WAY-100635、5-HT(2A)拮抗剂酮色林、5-HT(2A/2C)混合拮抗剂利坦色林和5-HT(2C)激动剂Ro-601075。
在测试前30分钟急性给药或在第一个和第二个周期戒断后4小时给药时，SB-242084和丁螺环酮均可减少乙醇戒断诱导的社交互动缺陷。无论治疗方式如何，WAY-100635和酮色林均完全无效。相反，5-HT(2C)激动剂Ro-601075在暴露于4.5%或7%乙醇饮食的大鼠中加剧了戒断诱导的社交互动行为缺陷。
这些结果支持5-HT(1A)激动剂和5-HT(2C)拮抗剂在减少乙醇戒断诱导的焦虑样行为以及减少与反复戒断相关的适应性变化方面的效用。
