Mignon Laurence, Wolf William A
Department of Pharmacology and Experimental Therapeutics, Loyola University, Stritch School of Medicine, Maywood, IL 60153, USA.
Psychopharmacology (Berl). 2002 Aug;163(1):85-94. doi: 10.1007/s00213-002-1121-3. Epub 2002 Jul 13.
In animal models of reduced dopamine transmission, such as haloperidol-induced catalepsy or monoamine-depleted animals, serotonin (5-hydroxytryptamine; 5-HT) 5-HT(1A) agonists appear to enhance motor activity. However, the exact mechanism remains unclear.
The objective of the present study was to demonstrate that 5-HT(1A) agonists can increase locomotor activity by activation of postsynaptic 5-HT(1A) heteroreceptors without the involvement of somatodendritic 5-HT(1A) autoreceptors which are known to regulate 5-HT neuronal activity.
The effects of the 5-HT(1A) full agonist R-(+)-8-hydroxy-2-(di- n-propylamino)tertralin ( R-(+)-8-OHDPAT) on locomotor activity in reserpinized (i.e., monoamine-depleted) rats were studied.
The present data demonstrate that R-(+)-8-OHDPAT significantly increased locomotor activity in monoamine-depleted animals at a dose as low as 0.01 mg/kg. The partial 5-HT(1A) agonist/D(2) antagonist buspirone (3 mg/kg) also elevated locomotor activity. The effects of these 5-HT(1A) compounds were found to be similar to the locomotor-stimulating effect of the dopamine precursor 3,4-dihydroxyphenylalanine (150 mg/kg, 15 min after 50 mg/kg benserazide). The 5-HT(1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635; 0.2 mg/kg) blocked the R-(+)-8-OHDPAT (0.03 mg/kg)-mediated increase in locomotion. Blockade of 5-HT synthesis with DL- p-chlorophenylalanine (pCPA), a tryptophan hydroxylase inhibitor, prior to reserpinization did not affect R-(+)-8-OHDPAT-induced locomotion.
The present data indicate that R-(+)-8-OHDPAT can increase motor activity in monoamine-depleted rats through postsynaptic 5-HT(1A) receptors and not necessarily through 5-HT(1A) autoreceptor-mediated alterations in 5-HT synthesis and release. A potential mechanism of 5-HT(1A)-mediated modulation of non-monoaminergic motor circuits in the brain is discussed. Taken together, the results suggest that 5-HT(1A) agonists would provide a novel approach to the amelioration of antipsychotic-induced side effects and the symptomatic treatment of Parkinson's disease.
在多巴胺传递减少的动物模型中，如氟哌啶醇诱导的僵住症或单胺耗竭的动物，血清素（5-羟色胺；5-HT）5-HT(1A)激动剂似乎能增强运动活性。然而，确切机制仍不清楚。
本研究的目的是证明5-HT(1A)激动剂可通过激活突触后5-HT(1A)异受体来增加运动活性，而不涉及已知可调节5-HT神经元活性的树突体5-HT(1A)自身受体。
研究了5-HT(1A)完全激动剂R-(+)-8-羟基-2-(二正丙基氨基)四氢萘（R-(+)-8-OHDPAT）对利血平化（即单胺耗竭）大鼠运动活性的影响。
目前的数据表明，R-(+)-8-OHDPAT在低至0.01mg/kg的剂量下就能显著增加单胺耗竭动物的运动活性。部分5-HT(1A)激动剂/ D(2)拮抗剂丁螺环酮（3mg/kg）也能提高运动活性。发现这些5-HT(1A)化合物的作用与多巴胺前体3,4-二羟基苯丙氨酸（150mg/kg，在50mg/kg苄丝肼后15分钟）的运动刺激作用相似。5-HT(1A)拮抗剂N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-2-吡啶基-环己烷甲酰胺马来酸盐（WAY 100635；0.2mg/kg）可阻断R-(+)-8-OHDPAT（0.03mg/kg）介导的运动增加。在利血平化之前用色氨酸羟化酶抑制剂DL-对氯苯丙氨酸（pCPA）阻断5-HT合成并不影响R-(+)-8-OHDPAT诱导的运动。
目前的数据表明，R-(+)-8-OHDPAT可通过突触后5-HT(1A)受体增加单胺耗竭大鼠的运动活性，而不一定通过5-HT(1A)自身受体介导的5-HT合成和释放改变。讨论了5-HT(1A)介导的大脑中非单胺能运动回路调节的潜在机制。综上所述，结果表明5-HT(1A)激动剂将为改善抗精神病药物引起的副作用和帕金森病的症状治疗提供一种新方法。
