Anxiety and depression, key symptoms of the cocaine withdrawal syndrome in human addicts, are considered the main factors that precipitate relapse in chronic cocaine addiction. Pharmacological therapeutic strategies should 1) decrease the cocaine-reinforcing effects and 2) decrease the adverse symptoms of cocaine withdrawal. Therefore, it requires improving the effect of effective therapy (mirtazapine) through combination with other (s) effective therapies (prazosin). This study sought to determine whether chronic dosing of mirtazapine plus prazosin during cocaine withdrawal reduced depression- and anxiety-like behaviors that characterize cocaine withdrawal in Wistar rats. Cocaine-pre-treated Wistar rats were subjected to a 60-day cocaine withdrawal period during which depression- and anxiety-like behaviors were evaluated in open field tests (OFT), the elevated plus-maze (EPM), the light–dark box test (LDT), the forced swimming test (FST), and spontaneous locomotor activity (SLA). We found 1) that chronic dosing of mirtazapine (30 mg/kg) + prazosin (1 mg/kg) decreased depression- and anxiety-like behaviors induced by 10 mg/kg of cocaine during the 60-day cocaine withdrawal. 2) prazosin enhanced the effect of mirtazapine on depression- and anxiety-like behaviors and 3) oxymetazoline blocked the prazosin-induced effect. Our results suggest that the pharmacological effect of mirtazapine on its target sites of action (α₂-adrenergic and 5-HT₁, 5-HT_2A and 5-HT₃ receptors) and of prazosin (α₁-adrenergic) within the brain may improve depression- and anxiety-like behaviors for long periods. Therefore, the findings support the use of a combination of mirtazapine + prazosin as a potentially effective therapy to reduce anxiety and depressive-like behavior during cocaine withdrawal.

焦虑和抑郁是人类可卡因成瘾者可卡因戒断综合征的关键症状，被认为是导致慢性可卡因成瘾复发的主要因素。药物治疗策略应该：1）减少可卡因的强化作用，2）减少可卡因戒断的不良症状。因此，需要通过与其他有效疗法（哌唑嗪）联合来提高有效疗法（米氮平）的效果。本研究旨在确定在可卡因戒断过程中长期服用米氮平加哌唑嗪是否可以减少Wistar大鼠可卡因戒断期间的抑郁和焦虑样行为。经过可卡因预处理的 Wistar 大鼠接受 60 天的可卡因戒断期，在此期间通过旷场测试 (OFT)、高架十字迷宫 (EPM)、明暗盒测试评估抑郁和焦虑样行为测试（LDT）、强迫游泳测试（FST）和自发运动活动（SLA）。我们发现 1) 长期服用米氮平 (30 mg/kg) + 哌唑嗪 (1 mg/kg) 可减少 60 天可卡因戒断期间由 10 mg/kg 可卡因引起的抑郁和焦虑样行为。 2) 哌唑嗪增强了米氮平对抑郁和焦虑样行为的作用，3) 羟甲唑啉阻断了哌唑嗪诱导的作用。我们的结果表明，米氮平对其靶作用位点（α _{2 -}肾上腺素能和 5-HT ₁、5-HT _2A和 5-HT ₃受体）和哌唑嗪（α _{1 -}肾上腺素能）在大脑内的药理作用可能长期改善类似抑郁和焦虑的行为。因此，研究结果支持使用米氮平+哌唑嗪的组合作为一种潜在有效的疗法，以减少可卡因戒断期间的焦虑和抑郁样行为。