Nowak Przemyslaw, Bortel Aleksandra, Dabrowska Joanna, Biedka Izabela, Slomian Grzegorz, Roczniak Wojciech, Kostrzewa Richard M, Brus Ryszard
Department of Pharmacology, Medical University of Silesia, 41-808 Zabrze, Poland.
Neurotox Res. 2008 May-Jun;13(3-4):231-40. doi: 10.1007/BF03033506.
To explore a recently established association between histaminergic and dopaminergic neuronal phenotypic systems in brain, we determined the effect of the respective histaminergic H(3) receptor agonist and antagonist/inverse agonist, imetit and thioperamide, on L-DOPA - derived tissue and extracellular DA and metabolite levels in the striatum of 6-hydroxydopamine (6-OHDA) - lesioned rats (i.e., parkinsonian rats). We also examined the influence of histamine H(3) ligands on L-DOPA evoked behavioral responses (locomotor activity, number of rearings, stereotyped behavior and motor coordination). Using HPLC/ED and in vivo microdialysis technique imetit (5 mg/kg, i.p.) but not thioperamide (5 mg/kg, i.p.) was shown to attenuate an L-DOPA-evoked (15 mg/kg, i.p.; carbidopa, 30 min pretreatment) increase in extracellular DA in the neostriatum of 6-OHDA-lesioned rats. However, both imetit and thioperamide increased microdialysate levels of DOPAC and HVA, probably by enhancing intraneuronal DA utilization. As indicated by neurochemical analysis of the striatum imetit produced a decrease in tissue DA content. These findings support the hypothesis that central H(3) histaminergic receptors have a modulatory role in the storage, metabolism and release of DA derived from exogenous L-DOPA challenge. Furthermore, evidence from behavioral studies indicate that histamine H3 receptor blockade markedly improved motor coordination. Conversely, histamine H(3) receptor stimulation, being without effect on motor coordination, enhanced vertical activity in rats. From the above we conclude that the histamine H(3) agonism may augment motor dyskinesia in Parkinson's disease (PD) patients and presumably worsen L-DOPA therapy. Consequently, the histaminergic system represents a viable target for modulating the effectiveness of L-DOPA therapy in Parkinson's disease.
为了探究大脑中组胺能和多巴胺能神经元表型系统之间最近建立的关联，我们测定了相应的组胺能H(3)受体激动剂和拮抗剂/反向激动剂，即碘替丁和硫代乙酰胺，对6-羟基多巴胺（6-OHDA）损伤大鼠（即帕金森病大鼠）纹状体中左旋多巴衍生的组织和细胞外多巴胺及其代谢产物水平的影响。我们还研究了组胺H(3)配体对左旋多巴诱发的行为反应（运动活性、竖毛次数、刻板行为和运动协调性）的影响。使用高效液相色谱/电化学检测法和体内微透析技术，结果显示碘替丁（5mg/kg，腹腔注射）而非硫代乙酰胺（5mg/kg，腹腔注射）可减弱6-OHDA损伤大鼠新纹状体中左旋多巴诱发（15mg/kg，腹腔注射；卡比多巴，预处理30分钟）的细胞外多巴胺增加。然而，碘替丁和硫代乙酰胺均增加了3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的微透析液水平，可能是通过增强神经元内多巴胺的利用。纹状体的神经化学分析表明，碘替丁使组织多巴胺含量降低。这些发现支持以下假说：中枢H(3)组胺能受体在外源性左旋多巴激发的多巴胺的储存、代谢和释放中具有调节作用。此外，行为学研究证据表明，组胺H3受体阻断可显著改善运动协调性。相反，组胺H(3)受体刺激对运动协调性无影响，但增强了大鼠的垂直活动。综上所述，我们得出结论：组胺H(3)激动作用可能会加重帕金森病（PD）患者的运动障碍，并可能使左旋多巴治疗恶化。因此，组胺能系统是调节帕金森病左旋多巴治疗效果的一个可行靶点。
