Markou A, Hauger R L, Koob G F
Department of Neuropharmacology CVN-7, Scripps Research Institute, La Jolla, CA 92037.
Psychopharmacology (Berl). 1992;109(3):305-14. doi: 10.1007/BF02245878.
Depression and anhedonia are two major symptoms of cocaine withdrawal in humans. Hence, pharmacological treatments effective in depression might also alleviate the symptoms of cocaine withdrawal. In the present study, the effects of acute and repeated administration of a tricyclic antidepressant, desmethylimipramine (DMI), were investigated in naive and cocaine-withdrawing rats. An animal model of cocaine withdrawal was used that employs the elevation in intracranial self-stimulation (ICSS) thresholds following the termination of prolonged periods of cocaine self-administration as a measure of an animal's "anhedonic" state. The influence of chronic DMI treatment on beta-adrenergic receptor binding and affinity was also correlated with the behavioral signs of cocaine withdrawal. Neither acute nor repeated DMI treatment influenced reward functions in rats that were not undergoing cocaine withdrawal. However, repeated DMI treatment significantly down-regulated beta-adrenergic receptors, and shortened the duration of the post-cocaine "anhedonia" (elevation in thresholds). Furthermore, the magnitude of the beta-adrenergic receptor down-regulation correlated significantly with the degree of effectiveness of DMI treatment in reversing the post-cocaine "anhedonia". However, chronic DMI treatment did reduce the amount of cocaine self-administered by the animals. The reversal of the post-cocaine anhedonia in this animal model of cocaine withdrawal by chronic DMI treatment demonstrates the potential usefulness of the model in identifying new pharmacotherapies for cocaine withdrawal. In addition, the results indicate that tricyclic antidepressants may be able to ameliorate some of the symptoms of cocaine withdrawal.
抑郁和快感缺失是人类可卡因戒断的两大主要症状。因此，对抑郁症有效的药物治疗也可能缓解可卡因戒断症状。在本研究中，研究了在未接触过可卡因和正在经历可卡因戒断的大鼠中，三环类抗抑郁药去甲丙咪嗪（DMI）急性和重复给药的效果。采用了一种可卡因戒断动物模型，该模型利用长时间可卡因自我给药终止后颅内自我刺激（ICSS）阈值的升高作为衡量动物“快感缺失”状态的指标。慢性DMI治疗对β-肾上腺素能受体结合和亲和力的影响也与可卡因戒断的行为体征相关。急性或重复DMI治疗均未影响未经历可卡因戒断的大鼠的奖赏功能。然而，重复DMI治疗显著下调了β-肾上腺素能受体，并缩短了可卡因后“快感缺失”（阈值升高）的持续时间。此外，β-肾上腺素能受体下调的程度与DMI治疗逆转可卡因后“快感缺失”的有效性程度显著相关。然而，慢性DMI治疗确实减少了动物自我给药的可卡因量。在这个可卡因戒断动物模型中，慢性DMI治疗逆转了可卡因后的快感缺失，证明了该模型在识别可卡因戒断新药物疗法方面的潜在有用性。此外，结果表明三环类抗抑郁药可能能够改善可卡因戒断的一些症状。
