Tatarczyńska Ewa, Kłodzińska Aleksandra, Chojnacka-Wójcik Ewa
Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Pol J Pharmacol. 2002 Nov-Dec;54(6):615-23.
Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the forced swimming test in rats. No interaction was observed between fluoxetine and 5-HT1A/5-HT1B receptor antagonists.
临床数据表明，5-羟色胺1A/5-羟色胺1B/β-肾上腺素能受体拮抗剂吲哚洛尔与选择性5-羟色胺再摄取抑制剂（SSRI）联合使用，可能会缩短临床起效时间，并可能增强难治性抑郁症治疗的有益效果。目前正在动物模型中评估SSRI与5-羟色胺受体配体联合给药对检测抗抑郁样活性的影响；然而，所得结果并不一致。本研究的目的是在大鼠强迫游泳试验（波索尔特试验）中，研究5-羟色胺1A拮抗剂（WAY 100635）、5-羟色胺1B拮抗剂（SB 216641和GR 127935）或吲哚洛尔与帕罗西汀或氟西汀（SSRI）联合给药的效果。单独给药时，帕罗西汀（10和20mg/kg）、氟西汀（10和20mg/kg）、WAY 100635（0.1和1mg/kg）、SB 216641（2mg/kg）、GR 127935（10和20mg/kg）和吲哚洛尔（4和8mg/kg）并未缩短大鼠在该试验中的不动时间。有趣的是，单独给予4mg/kg剂量的SB 216641可显著缩短该试验中的不动时间。帕罗西汀（20mg/kg）与WAY 100635或吲哚洛尔联合使用未显示出显著的相互作用；另一方面，当帕罗西汀与SB 216641（2mg/kg）或GR 127935（10和20mg/kg）联合给药时，该组合在大鼠强迫游泳试验中显示出显著的抗不动作用。该试验中的主动行为并不反映总体活动增加，因为5-羟色胺1B拮抗剂与帕罗西汀联合给药并未改变在旷场试验中测得的大鼠运动活动。氟西汀与所有使用的拮抗剂联合给药均未影响大鼠在强迫游泳试验中的行为。所得结果似乎表明，阻断5-羟色胺1B受体而非5-羟色胺1A受体，可促进帕罗西汀在大鼠强迫游泳试验中的抗抑郁样作用。未观察到氟西汀与5-羟色胺1A/5-羟色胺1B受体拮抗剂之间的相互作用。
