Dekeyne A, Millan M J
Institut de Recherches Servier, Centre de Recherches de Croissy, Phychopharmacology Department, Croissy-sur-Seine, Paris, France.
Behav Pharmacol. 2003 Sep;14(5-6):391-407. doi: 10.1097/01.fbp.0000089141.24369.07.
Though drug discrimination techniques have proven invaluable in characterizing the interoceptive properties of drugs of abuse, antipsychotics and anxiolytics, with the exception of some fragmentary data with tricyclic agents, surprisingly few studies have been undertaken with antidepressants. Nevertheless, the preferential dopamine (DA) reuptake inhibitor, bupropion, elicits a robust discriminative stimulus in rodents. Moreover, in rats trained on a two-lever FR-10 schedule for food reward, the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, and the noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, elicit discriminative stimuli at doses that selectively elevate extracellular levels of 5-HT and NA, respectively. In generalization tests, mixed inhibitors of 5-HT and NA reuptake, such as venlafaxine, substitute for both citalopram and reboxetine, while SSRIs substitute for citalopram but not for reboxetine. Intriguingly, selective NARIs appear to substitute both for reboxetine and for citalopram though, owing to long-term instability of the citalopram cue, the latter observation will require confirmation. Bupropion and the atypical antidepressant, mirtazapine - a 5-HT2/alpha2-adrenoceptor (AR) antagonist devoid of affinity for 5-HT and NA reuptake sites - substitute for neither citalopram nor reboxetine, indicating that 'antidepressant' effects per se do not account for their interoceptive properties. Moreover, mirtazapine abolishes the citalopram cue, an action mimicked by the selective 5-HT2C antagonist, SB242,084. The discriminative stimulus elicited by reboxetine is blocked by the alpha1-AR antagonist, prazosin. In contrast, it is not significantly attenuated by the alpha2-AR antagonist, RX821,002, nor by betaxolol or ICI118,551, antagonists at alpha1- and alpha2-ARs, respectively. These observations indicate that 5-HT2C receptors and alpha1-ARs contribute to the discriminative stimulus properties of SSRIs and NARIs, respectively. The present article reviews the literature devoted to the discriminative stimulus properties of antidepressant agents as training drugs, focusing in particular upon novel data with citalopram and reboxetine. In addition, several open questions and future research directions are evoked. It would be of considerable interest to extend such drug discrimination studies to other classes of antidepressants or potential antidepressants, including venlafaxine, mirtazapine and antagonists at neuropeptide (corticotropin releasing factor1 and neurokinin1) receptors.
尽管药物辨别技术已被证明在表征滥用药物、抗精神病药物和抗焦虑药物的内感受特性方面具有极高价值，但除了一些关于三环类药物的零散数据外，令人惊讶的是，针对抗抑郁药开展的研究极少。然而，选择性多巴胺（DA）再摄取抑制剂安非他酮在啮齿动物中能引发强烈的辨别性刺激。此外，在以双杠杆FR - 10程序进行食物奖励训练的大鼠中，选择性5 - 羟色胺（5 - HT）再摄取抑制剂（SSRI）西酞普兰以及去甲肾上腺素（NA）再摄取抑制剂（NARI）瑞波西汀，分别在能选择性提高细胞外5 - HT和NA水平的剂量下引发辨别性刺激。在泛化测试中，5 - HT和NA再摄取的混合抑制剂，如文拉法辛，可替代西酞普兰和瑞波西汀，而SSRI类药物可替代西酞普兰，但不能替代瑞波西汀。有趣的是，尽管由于西酞普兰线索的长期不稳定性，后一观察结果有待证实，但选择性NARI类药物似乎既能替代瑞波西汀，也能替代西酞普兰。安非他酮和非典型抗抑郁药米氮平——一种对5 - HT和NA再摄取位点无亲和力的5 - HT2/α2 - 肾上腺素能受体（AR）拮抗剂——既不能替代西酞普兰，也不能替代瑞波西汀，这表明“抗抑郁”作用本身并不能解释它们的内感受特性。此外，米氮平可消除西酞普兰线索，选择性5 - HT2C拮抗剂SB242,084也有类似作用。瑞波西汀引发的辨别性刺激可被α1 - AR拮抗剂哌唑嗪阻断。相比之下，它并未被α2 - AR拮抗剂RX821,002、β - 肾上腺素能受体阻滞剂倍他洛尔或α1 - 和α2 - AR拮抗剂ICI118,551显著减弱。这些观察结果表明，5 - HT2C受体和α1 - AR分别促成了SSRI和NARI的辨别性刺激特性。本文综述了关于抗抑郁药作为训练药物的辨别性刺激特性的文献，特别关注了有关西酞普兰和瑞波西汀的新数据。此外，还提出了几个未解决的问题和未来的研究方向。将此类药物辨别研究扩展到其他抗抑郁药或潜在抗抑郁药类别，包括文拉法辛、米氮平和神经肽（促肾上腺皮质激素释放因子1和神经激肽1）受体拮抗剂，将会非常有趣。
