Baumann M H, Rothman R B
Clinical Psychopharmacology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
Biol Psychiatry. 1998 Oct 1;44(7):578-91. doi: 10.1016/s0006-3223(98)00123-1.
Withdrawal from long-term cocaine use is accompanied by symptoms resembling major depression. Because acute cocaine affects serotonin (5-HT) neurons, and 5-HT dysfunction is implicated in the pathophysiology of depression, we evaluated the effects to 5-HT agonists in rats withdrawn from repeated injections of cocaine (15 mg/kg i.p., b.i.d., 7 days) or saline.
In the first study, prolactin (PRL) responses elicited by the 5-HT-releasing agent fenfluramine, the 5-HT1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the 5-HT2A/2C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) were examined as indices of postsynaptic 5-HT receptor function. In a second study, specific responses induced by 8-OH-DPAT, namely inhibition of brain 5-HT synthesis and stimulation of feeding, were examined as correlates of 5-HT1A autoreceptor function.
Prior treatment with cocaine did not modify fenfluramine-evoked PRL release; however, the PRL secretory response to 8-OH-DPAT was blunted and the PRL response to DOI was potentiated after chronic cocaine treatment. Cocaine exposure did not alter the inhibitory effect of 8-OH-DPAT on 5-HT synthesis. 8-OH-DPAT-induced feeding was influenced by prior cocaine, but this effect was secondary to pronounced baseline hyperphagia in the cocaine-treated group.
These data indicate that withdrawal from chronic cocaine renders specific subpopulations of postsynaptic 5-HT1A receptors subsensitive and 5-HT2A/2C receptors supersensitive. No evidence for cocaine-induced changes in 5-HT1A autoreceptor responsiveness was found. A survey of the literature reveals similarities in the profile of 5-HT dysfunction between rats withdrawn from cocaine and humans diagnosed with depression. We propose that withdrawal from chronic cocaine in rats may serve as a useful animal model of depressive disorders.
长期使用可卡因后戒断会出现类似重度抑郁症的症状。由于急性可卡因会影响血清素（5-HT）神经元，且5-HT功能障碍与抑郁症的病理生理学有关，我们评估了5-HT激动剂对反复注射可卡因（15毫克/千克腹腔注射，每日两次，共7天）或生理盐水后的大鼠的影响。
在第一项研究中，检测了5-HT释放剂芬氟拉明、5-HT1A激动剂（±）-8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）和5-HT2A/2C激动剂（±）-1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷盐酸盐（DOI）引发的催乳素（PRL）反应，以此作为突触后5-HT受体功能的指标。在第二项研究中，检测了8-OH-DPAT诱导的特定反应，即对脑5-HT合成的抑制和对进食的刺激，作为5-HT1A自身受体功能的相关指标。
预先用可卡因处理并未改变芬氟拉明诱发的PRL释放；然而，慢性可卡因处理后，对8-OH-DPAT的PRL分泌反应减弱，对DOI的PRL反应增强。可卡因暴露并未改变8-OH-DPAT对5-HT合成的抑制作用。8-OH-DPAT诱导的进食受到预先使用可卡因的影响，但这种影响继发于可卡因处理组明显的基线食欲亢进。
这些数据表明，慢性可卡因戒断会使突触后5-HT1A受体的特定亚群变得不敏感，而5-HT2A/2C受体变得超敏感。未发现可卡因诱导5-HT1A自身受体反应性改变的证据。对文献的调查揭示了可卡因戒断大鼠和被诊断为抑郁症的人类之间5-HT功能障碍特征的相似性。我们提出，大鼠慢性可卡因戒断可能作为抑郁症的一种有用动物模型。
