Baumann M H, Becketts K M, Rothman R B
Clinical Psychopharmacology Section, National Institutes of Health, National Institutes on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.
Eur J Pharmacol. 1995 Aug 25;282(1-3):87-93. doi: 10.1016/0014-2999(95)00280-x.
The effects of repeated cocaine administration on serotonin (5-hydroxytryptamine, 5-HT) function were investigated by comparing the corticosterone response to 5-HT receptor agonists in cocaine-treated and vehicle-treated rats. Male rats were fitted with indwelling jugular catheters and received cocaine (15 mg/kg i.p., b.i.d.) or saline for 7 days. Rats were challenged with either saline, the 5-HT releaser fenfluramine (1.2 mg/kg i.v.), the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 50 micrograms/kg i.v.), or the 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 100 micrograms/kg i.v.) 42 h and 8 days after the final chronic treatment. Repeated blood samples were withdrawn immediately before and at 15, 30 and 60 min after acute challenge injections. All 5-HT receptor agonists increased plasma corticosterone, but the fenfluramine-induced rise in corticosterone was significantly attenuated in cocaine-treated rats withdrawn for 42 h. This blunted response to fenfluramine exhibited only partial recovery when examined at 8 days postchronic treatment. Corticosterone responses to 8-OH-DPAT and DOI were not affected by cocaine exposure. Our data suggest that chronic cocaine produces deficits in presynaptic 5-HT function, and alterations in 5-HT neurotransmission may underlie the dysphoria experienced by abstinent cocaine users. Neuroendocrine challenge tests should be performed in human addicts to evaluate potential 5-HT dysfunction associated with cocaine abuse.
通过比较可卡因处理组和溶剂处理组大鼠对5-羟色胺（5-羟色胺，5-HT）受体激动剂的皮质酮反应，研究了重复给予可卡因对5-HT功能的影响。雄性大鼠植入颈静脉留置导管，连续7天接受可卡因（15mg/kg腹腔注射，每日两次）或生理盐水。在末次慢性处理后42小时和8天时，用生理盐水、5-HT释放剂芬氟拉明（1.2mg/kg静脉注射）、5-HT1A受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT；50μg/kg静脉注射）或5-HT2A/2C受体激动剂1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷（DOI；100μg/kg静脉注射）对大鼠进行激发试验。在急性激发注射前及注射后15、30和60分钟立即采集多次血样。所有5-HT受体激动剂均增加血浆皮质酮，但在撤药42小时的可卡因处理大鼠中，芬氟拉明诱导的皮质酮升高显著减弱。在慢性处理后8天检查时，这种对芬氟拉明反应迟钝仅部分恢复。对8-OH-DPAT和DOI的皮质酮反应不受可卡因暴露的影响。我们的数据表明，慢性可卡因导致突触前5-HT功能缺陷，5-HT神经传递的改变可能是戒毒可卡因使用者所经历烦躁不安的基础。应在人类成瘾者中进行神经内分泌激发试验，以评估与可卡因滥用相关的潜在5-HT功能障碍。
