Scherkl R, Hashem A, Dreimann E, Neumayer H H, Frey H H
Department of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, F.R.G.
Arch Int Pharmacodyn Ther. 1990 May-Jun;305:172-82.
In previous studies, development of functional tolerance to the anticonvulsant effect of clonazepam and physical dependence on the drug have been demonstrated. In the present study, dogs were treated for 6 weeks with clonazepam 0.5 mg/kg b.i.d. Under methohexital anesthesia, cerebrospinal fluid samples were taken before treatment, at 3 days (acute effect), 4 and 5 weeks (tolerance) after the start of treatment, 2 and 8 days after withdrawal and 5 weeks after the end of treatment as another control. The following transmitters or metabolites were determined: HVA, VMA, 5-HIAA, GABA, PGE2, TXB2 and 6-keto PGF1 alpha. 5-HIAA levels showed a significant rise, indicating an increased activity of the serotonergic system in the brain during development both of tolerance and withdrawal. Dopaminergic activity was not altered during treatment, but was increased after cessation of treatment, as indicated by a significant increase in HVA concentrations.
在先前的研究中，已证实对氯硝西泮的抗惊厥作用产生功能性耐受以及对该药物产生身体依赖性。在本研究中，犬只以0.5毫克/千克的氯硝西泮每日两次治疗6周。在美索比妥麻醉下，于治疗前、治疗开始后3天（急性效应）、4周和5周（耐受）、撤药后2天和8天以及治疗结束后5周采集脑脊液样本作为另一对照。测定了以下递质或代谢物：高香草酸（HVA）、香草扁桃酸（VMA）、5-羟吲哚乙酸（5-HIAA）、γ-氨基丁酸（GABA）、前列腺素E2（PGE2）、血栓素B2（TXB2）和6-酮-前列腺素F1α（6-keto PGF1α）。5-羟吲哚乙酸水平显著升高，表明在耐受和撤药形成过程中大脑中血清素能系统的活性增强。治疗期间多巴胺能活性未改变，但治疗停止后升高，高香草酸浓度显著增加表明了这一点。
