Sprouse J, Braselton J, Reynolds L
Pfizer Central Research, Groton, CT 06340, USA.
Biol Psychiatry. 2000 Jun 15;47(12):1050-5. doi: 10.1016/s0006-3223(99)00322-4.
The ability of pindolol to block 5-HT(1A) autoreceptors on serotonin-containing neurons in the raphe nuclei is thought to underlie the clinical reports of enhanced efficacy and rate of improvement in depressed patients treated with pindolol/selective serotonin reuptake inhibitor (SSRI) combinations. Selectivity for somatodendritic 5-HT(1A) autoreceptors is a crucial requirement, as blockade of postsynaptic 5-HT(1A) sites may jeopardize the therapeutic response. Previous investigators have probed the effects of pindolol on serotonergic dorsal raphe cell firing in animal species; here we confirm their findings and extend them to include observations on postsynaptic 5-HT(1A) receptors in the hippocampus.
Extracellular single-unit recordings were made in rats using standard electrophysiologic techniques. Firing rates of serotonin-containing neurons in the dorsal raphe nucleus and CA3 hippocampal pyramidal neurons were monitored and the effects of pindolol given alone or in combination with an SSRI (fluoxetine) or a 5-HT(1A) antagonist (WAY-100,635) were determined.
Pindolol inhibited the firing rates of serotonergic dorsal raphe neurons in a dose-dependent manner. Recovery to baseline firing rates was gradual, but this inhibition could be acutely reversed by WAY-100,635. A range of pindolol doses failed to block the inhibitory effects of fluoxetine on dorsal raphe cell firing. In the hippocampus, pindolol also inhibited cell firing as a function of dose, although these effects were insensitive to WAY-100,635 treatment.
The ability of pindolol to inhibit serotonergic dorsal raphe cell firing is indicative of its agonist potential and is consistent with previous studies. The lack of observable antagonism of the SSRI-induced slowing of raphe unit activity casts doubt on the suitability of this mechanism of action to account for the positive findings in clinical studies utilizing pindolol/SSRI combinations. The 5-HT(1A)-independent inhibition of hippocampal CA3 cell firing by pindolol suggests that this compound invokes multiple pharmacologic actions, all of which need to be assimilated into any proposed mechanism of action.
吲哚洛尔阻断中缝核中含5-羟色胺（5-HT）神经元上的5-HT（1A）自身受体的能力，被认为是关于吲哚洛尔/选择性5-羟色胺再摄取抑制剂（SSRI）联合治疗的抑郁症患者疗效增强及改善率提高的临床报告的基础。对树突-胞体5-HT（1A）自身受体的选择性是一个关键要求，因为阻断突触后5-HT（1A）位点可能会危及治疗反应。既往研究人员已探究了吲哚洛尔对动物物种中5-羟色胺能背侧中缝核细胞放电的影响；在此我们证实了他们的发现，并将其扩展至包括对海马体中突触后5-HT（1A）受体的观察。
采用标准电生理技术在大鼠中进行细胞外单单位记录。监测背侧中缝核中含5-羟色胺神经元及海马体CA3区锥体神经元的放电率，并确定单独给予吲哚洛尔或与SSRI（氟西汀）或5-HT（1A）拮抗剂（WAY-100,635）联合给予时的效果。
吲哚洛尔以剂量依赖性方式抑制5-羟色胺能背侧中缝核神经元的放电率。恢复至基线放电率是渐进的，但这种抑制可被WAY-100,635急性逆转。一系列吲哚洛尔剂量未能阻断氟西汀对背侧中缝核细胞放电的抑制作用。在海马体中，吲哚洛尔也根据剂量抑制细胞放电，尽管这些作用对WAY-100,635治疗不敏感。
吲哚洛尔抑制5-羟色胺能背侧中缝核细胞放电的能力表明其具有激动剂潜能，且与既往研究一致。SSRI引起的中缝核单位活动减慢缺乏可观察到的拮抗作用，这使人怀疑这种作用机制是否适合解释在使用吲哚洛尔/SSRI联合治疗的临床研究中的阳性结果。吲哚洛尔对海马体CA3区细胞放电的不依赖5-HT（1A）的抑制作用表明，该化合物引发多种药理作用，所有这些作用都需要被纳入任何提出的作用机制中。
