Lin D, Koob G F, Markou A
Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA.
Psychopharmacology (Berl). 1999 Aug;145(3):283-94. doi: 10.1007/s002130051060.
Withdrawal from chronic amphetamine administration is characterized by deficits in reward that resemble some symptoms of depression. Nevertheless, the effects of long-term administration and withdrawal from other drugs, such as fluoxetine, that have the potential to elevate mood in depressed individuals have not been characterized.
The purpose of this study was to characterize the effects of withdrawal from chronic amphetamine or fluoxetine administration on central reward function. Furthermore, the effects of acute or chronic pretreatment with fluoxetine on responsiveness to an acute amphetamine challenge were examined to identify potential interactions between the two drugs.
A rate-independent discrete-trial threshold procedure was used to characterize self-stimulation behavior in rats prepared with bipolar electrodes in the medial forebrain bundle.
Elevations in intracranial self-stimulation (ICSS) thresholds, reflecting a decrease in the reward value of the stimulation, were associated with withdrawal from various chronic amphetamine treatment regimens (1-5 mg/kg, three injections per day for 1, 2, 4 or 6 days). The magnitude and duration of threshold elevations were proportional to the duration and dose of amphetamine treatment prior to withdrawal. In contrast, no alterations in ICSS thresholds were associated with withdrawal from chronic fluoxetine treatment (5 mg/kg/day for 15 days). While neither acute nor chronic administration of fluoxetine alone altered ICSS thresholds, chronic pretreatment with fluoxetine blocked the threshold-lowering effect of acute amphetamine administration (4 mg/kg), but acute pretreatment did not. Amphetamine-induced decreases in response latency, a measure of motor performance, were not affected by either chronic or acute fluoxetine pretreatment.
The results of these experiments suggest that chronic fluoxetine treatment may induce adaptive changes in serotonergic transmission that, in themselves, do not alter the function of central reward processes, but may alter the ability of amphetamine to potentiate ICSS reward. In addition, the lack of change in ICSS thresholds during withdrawal from the chronic fluoxetine treatment regimen used suggests that withdrawal from all mood-altering drugs may not necessarily produce changes in central reward functions.
长期服用苯丙胺后停药的特征是奖赏功能缺陷，类似于抑郁症的一些症状。然而，长期服用和停用其他药物（如氟西汀）对有潜在改善抑郁个体情绪作用的影响尚未得到描述。
本研究的目的是描述长期服用苯丙胺或氟西汀后停药对中枢奖赏功能的影响。此外，研究了急性或慢性给予氟西汀预处理对急性苯丙胺激发反应性的影响，以确定两种药物之间的潜在相互作用。
采用与速率无关的离散试验阈值程序来描述在内侧前脑束植入双极电极的大鼠的自我刺激行为。
颅内自我刺激（ICSS）阈值升高，反映刺激奖赏价值降低，与停用各种慢性苯丙胺治疗方案（1-5mg/kg，每天注射三次，持续1、2、4或6天）有关。阈值升高的幅度和持续时间与停药前苯丙胺治疗的持续时间和剂量成正比。相比之下，停用慢性氟西汀治疗（5mg/kg/天，持续15天）未导致ICSS阈值改变。虽然单独急性或慢性给予氟西汀均未改变ICSS阈值，但氟西汀慢性预处理可阻断急性苯丙胺给药（4mg/kg）引起的阈值降低作用，而急性预处理则无此作用。苯丙胺引起的反应潜伏期缩短（一种运动性能指标）不受慢性或急性氟西汀预处理的影响。
这些实验结果表明，慢性氟西汀治疗可能诱导5-羟色胺能传递的适应性变化，这些变化本身不会改变中枢奖赏过程的功能，但可能改变苯丙胺增强ICSS奖赏的能力。此外，在使用的慢性氟西汀治疗方案停药期间ICSS阈值缺乏变化表明，停用所有改变情绪的药物不一定会导致中枢奖赏功能改变。
