Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States.
ACS Chem Neurosci. 2013 May 15;4(5):747-60. doi: 10.1021/cn300234z. Epub 2013 Apr 1.
Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson's disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT1AR stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT1AR stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT1AR agonists for the treatment of dyskinesia.
越来越多的证据表明，5-羟色胺 1A 受体（5-HT1AR）激动剂对帕金森病（PD）患者长期接受左旋多巴治疗引起的运动障碍具有治疗价值。然而，5-HT1AR 刺激如何直接影响产生运动障碍的 D1 受体（D1R）表达纹状体苍白球通路仍知之甚少。为了直接研究这一点，一组半帕金森大鼠接受了系统注射载体+载体、载体+D1R 激动剂 SKF81297（0.8mg/kg）或 5-HT1AR 激动剂±8-OH-DPAT（1.0mg/kg）+SKF81297。通过 RT-PCR 检测大鼠异常不自主运动（AIMs）、旋转、纹状体前原啡肽（PPD）和谷氨酸脱羧酶（GAD；65 和 67）mRNA 的变化。在第二个实验中，半帕金森大鼠接受了纹状体内预处理载体（aCSF）、±8-OH-DPAT（7.5mM）或±8-OH-DPAT+5-HT1AR 拮抗剂 WAY100635（4.6mM），然后进行系统注射载体或 SKF81297，之后通过在体微透析测量 AIMs、旋转和纹状体外谷氨酸和黑质 GABA 外排。结果表明，系统和纹状体内 5-HT1AR 刺激可减少 D1R 激动剂诱导的 AIMs，而旋转增强。尽管±8-OH-DPAT 并未改变 D1R 激动剂诱导的纹状体 PPD mRNA 增加，但 D1R/5-HT1AR 激动剂组合增强了 GAD65 和 GAD67 mRNA。当局部应用时，±8-OH-DPAT 单独降低纹状体谷氨酸水平，而激动剂组合增加黑质 GABA 外排。因此，突触前 5-HT1AR 刺激可能会降低纹状体谷氨酸水平，从而减少 D1R 介导的运动障碍行为，但维持或增强纹状体突触后因子，最终增加黑质 GABA 水平和旋转活动。目前的研究结果为先前关于 5-HT1AR 激动剂治疗运动障碍的研究结果提供了一种新的机制解释。
