Fornal C A, Martin F J, Metzler C W, Jacobs B L
Program in Neuroscience, Department of Psychology, Princeton University, Princeton, New Jersey, USA.
J Pharmacol Exp Ther. 1999 Oct;291(1):229-38.
Clinical studies have shown that pindolol can enhance the effects of antidepressant drugs, presumably by acting as an antagonist at somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors, which regulate the firing rate of central serotonergic neurons. The current study characterized the action of pindolol on the single-unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats. (+/-)-Pindolol produced a dose-dependent inhibition of neuronal activity after i.v. (ED(50) = 0.25 mg/kg) and s.c. (ED(50) = 1.23 mg/kg) administration. The active enantiomer (-)-pindolol (1 mg/kg i.v.) also suppressed neuronal activity (maximal decrease, 88%). Upon p.o. administration, (+/-)-pindolol (10 mg/kg) produced a marked, long-acting suppression of neuronal activity similar to that observed after s.c. administration. In all cases, the reduction in firing rate produced by pindolol was completely reversed by low doses of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cycloh exanecarboxamide (WAY-100635) (0.1 mg/kg i.v. or 0.2 mg/kg s.c.), a selective 5-HT(1A) antagonist. Systemic administration of (-)-tertatolol (1-5 mg/kg i.v.), another beta-adrenoceptor blocker/putative 5-HT(1A) antagonist, had no significant effect on neuronal activity. The ability of i.v. (+/-)-pindolol (0.1-1 mg/kg) to reverse the suppression of serotonergic neuronal activity produced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10 microg/kg i.v.), a selective 5-HT(1A) agonist, also was examined. (+/-)-Pindolol had no appreciable effect on the action of 8-OH-DPAT. In contrast, the 5-HT(1A) antagonist drugs WAY-100635 (0.1 mg/kg i.v. ), 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl benzamide (0.1 mg/kg, i.v.), N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylprop anamid e [(S)-WAY-100135] (0.5 mg/kg i.v.), and (-)-tertatolol (1-5 mg/kg i. v.) reversed the effect of 8-OH-DPAT to varying degrees. Overall, these results indicate that pindolol acts as an agonist rather than an antagonist at 5-HT(1A) autoreceptors in awake animals.
临床研究表明，吲哚洛尔可增强抗抑郁药的效果，这可能是通过作为躯体树突状5-羟色胺（5-HT）（1A）自身受体的拮抗剂来实现的，该自身受体可调节中枢5-羟色胺能神经元的放电频率。当前研究对吲哚洛尔对自由活动猫的中缝背核中5-羟色胺能神经元的单单位活动的作用进行了表征。静脉注射（ED50 = 0.25 mg/kg）和皮下注射（ED50 = 1.23 mg/kg）后，（±）-吲哚洛尔对神经元活动产生剂量依赖性抑制。活性对映体（-）-吲哚洛尔（1 mg/kg静脉注射）也抑制了神经元活动（最大降低88%）。口服给药后，（±）-吲哚洛尔（10 mg/kg）对神经元活动产生了明显的长效抑制，类似于皮下注射后观察到的情况。在所有情况下，吲哚洛尔产生的放电频率降低可被低剂量的N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]-乙基]-N-（2-吡啶基）环己烷甲酰胺（WAY-100635）（0.1 mg/kg静脉注射或0.2 mg/kg皮下注射）完全逆转，WAY-1是一种选择性5-HT（1A）拮抗剂。静脉注射（-）-替他洛尔（1 - 5 mg/kg），另一种β-肾上腺素能受体阻滞剂/假定的5-HT（1A）拮抗剂，对神经元活动无显著影响。还研究了静脉注射（±）-吲哚洛尔（0.1 - 1 mg/kg）逆转由选择性5-HT（1A）激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）（10 μg/kg静脉注射）产生的5-羟色胺能神经元活动抑制的能力。（±）-吲哚洛尔对8-OH-DPAT的作用没有明显影响。相比之下，5-HT（1A）拮抗剂药物WAY-100635（0.1 mg/kg静脉注射）、4-氟-N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]-N-2-吡啶基苯甲酰胺（0.1 mg/kg，静脉注射）、N-叔丁基-3-（4-（2-甲氧基苯基）哌嗪-1-基）-2-苯基丙酰胺[（S）-WAY-100135]（0.5 mg/kg静脉注射）和（-）-替他洛尔（1 - 5 mg/kg静脉注射）在不同程度上逆转了8-OH-DPAT的作用。总体而言，这些结果表明，在清醒动物中，吲哚洛尔在5-HT（1A）自身受体上起激动剂而非拮抗剂的作用。
