Dekeyne Anne, Gobert Alain, Auclair Agnès, Girardon Sylvie, Millan Mark J
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
Psychopharmacology (Berl). 2002 Jul;162(2):156-67. doi: 10.1007/s00213-002-1070-x. Epub 2002 May 1.
The differential reinforcement of low-rate 72-s (DRL 72-s) schedule, in which rats must withhold a response for at least 72 s to obtain a reward (generally water), is an attractive procedure for the characterisation of potential antidepressant agents. Indeed, several antidepressants have been shown to improve efficiency (ratio of reinforcement rate to response rate) in this model, either by decreasing response rates and/or by increasing reinforcement rates.
Herein, we compared the actions of antidepressants known to inhibit serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) reuptake in a food-rewarded DRL 72-s schedule.
Rats trained in a food-rewarded DRL 72-s schedule and showing stable baseline performance were administered with drugs i.p. once a week. In independent experiments, the influence of drugs on food intake, spontaneous locomotor activity and extracellular levels of monoamines in the frontal cortex was evaluated.
In confirmation of previous studies, the tricyclic agent imipramine (10.0 mg/kg) and the "atypical" agent mianserin (40.0 mg/kg) significantly increased efficiency. In analogy, the selective NE reuptake inhibitors (NARIs) desipramine (20.0 mg/kg), nortriptyline (2.5 mg/kg) and reboxetine (0.63 mg/kg) all displayed marked enhancements in efficiency. In contrast, the selective 5-HT reuptake inhibitors (SSRIs) citalopram (10.0 mg/kg), fluvoxamine (10.0 mg/kg) and paroxetine (10.0 mg/kg) all significantly decreased efficiency. The mixed 5-HT/NE reuptake inhibitors (SNRIs) venlafaxine (2.5 mg/kg, 10.0 mg/kg) and S33005 (0.16-10.0 mg/kg), likewise, did not increase efficiency. Further, the DA reuptake inhibitors (DARIs) bupropion (0.16-10.0 mg/kg) and GBR12935 (0.63-10.0 mg/kg) had no effect on DRL 72-s performance. All drug classes exerted a similar, mild inhibitory influence on food intake and locomotor behaviour. Imipramine, mianserin and NARIs markedly increased extracellular levels of NE, and SSRIs elevated levels of 5-HT, while SSRIs augmented levels of both.
The present experimental procedure demonstrates, in analogy to imipramine and mianserin, robust and consistent increases in efficiency with NARIs. Their effects may be distinguished from a decrease in efficiency elicited by SSRIs, and a lack of activity of SNRIs and DARIs. While the reasons underlying the ineffectiveness of SSRIs (in contrast to previous studies) remain to be clarified, these data underline the importance of adrenergic mechanisms in the control of behaviour under conditions of delayed responding. Further, they support the interest of DRL 72-s procedures for the characterisation of diverse classes of antidepressant agent.
低速率72秒差异强化（DRL 72 - s）程序中，大鼠必须抑制反应至少72秒才能获得奖励（通常是水），这是一种用于鉴定潜在抗抑郁药的有吸引力的方法。实际上，几种抗抑郁药已被证明可通过降低反应速率和/或提高强化速率来提高该模型中的效率（强化速率与反应速率之比）。
在此，我们比较了已知抑制5-羟色胺（5-HT）、去甲肾上腺素（NE）和/或多巴胺（DA）再摄取的抗抑郁药在食物奖励DRL 72 - s程序中的作用。
对在食物奖励DRL 72 - s程序中训练且基线表现稳定的大鼠，每周腹腔注射一次药物。在独立实验中，评估药物对食物摄入量、自发运动活性和额叶皮质中单胺细胞外水平的影响。
正如先前研究所证实的，三环类药物丙咪嗪（10.0毫克/千克）和“非典型”药物米安色林（40.0毫克/千克）显著提高了效率。类似地，选择性NE再摄取抑制剂（NARI）地昔帕明（20.0毫克/千克）、去甲替林（2.5毫克/千克）和瑞波西汀（0.63毫克/千克）均显著提高了效率。相反，选择性5-HT再摄取抑制剂（SSRI）西酞普兰（10.0毫克/千克）、氟伏沙明（10.0毫克/千克）和帕罗西汀（10.0毫克/千克）均显著降低了效率。同样，5-HT/NE再摄取抑制剂（SNRI）文拉法辛（2.5毫克/千克，10.0毫克/千克）和S33005（0.16 - 10.0毫克/千克）并未提高效率。此外，DA再摄取抑制剂（DARI）安非他酮（0.16 - 10.0毫克/千克）和GBR12935（0.63 - 10.0毫克/千克）对DRL 72 - s表现无影响。所有药物类别对食物摄入量和运动行为均有类似的轻度抑制作用。丙咪嗪、米安色林和NARI显著提高了NE的细胞外水平，而SSRI提高了5-HT的水平，同时SSRI也提高了两者的水平。
本实验程序表明，与丙咪嗪和米安色林类似，NARI能显著且持续地提高效率。它们的作用可与SSRI引起的效率降低以及SNRI和DARI缺乏活性相区分。虽然SSRI无效的原因（与先前研究相反）仍有待阐明，但这些数据强调了肾上腺素能机制在延迟反应条件下行为控制中的重要性。此外，它们支持DRL 72 - s程序在鉴定不同类别的抗抑郁药方面的价值。
