Threlfell Sarah, Sammut Stephen, Menniti Frank S, Schmidt Christopher J, West Anthony R
Department of Neuro-science, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064.
J Pharmacol Exp Ther. 2009 Mar;328(3):785-95. doi: 10.1124/jpet.108.146332. Epub 2008 Dec 4.
The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium-sized spiny projection neurons (MSNs), apparently playing a critical role in the regulation of both cGMP and cAMP signaling cascades. Genetic disruption or pharmacological inhibition of PDE10A reverses behavioral abnormalities associated with subcortical hyperdopaminergia. Here, we investigate the effect of PDE10A inhibition on the activity of MSNs using single-unit extracellular recordings performed in the dorsal striatum of anesthetized rats. Antidromic stimulation of the substantia nigra pars reticulata was used to identify striatonigral (SNr+) MSNs. Intrastriatal infusion of the selective PDE10A inhibitors papaverine or TP-10 [2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid] by reverse microdialysis did not affect spontaneous firing but robustly increased measures of cortically evoked spike activity in a stimulus intensity-dependent manner. Systemic administration of TP-10 also increased cortically evoked spike activity in a stimulus intensity- and dose-dependent manner. A robust increase in cortically evoked activity was apparent in SNr- MSNs (primarily striatopallidal). It is interesting that TP-10 administration did not affect cortically evoked activity in SNr+ MSNs. However, TP-10 administration increased the incidence of antidromically activated (i.e., SNr+) MSNs. These findings indicate that inhibition of striatal PDE10A activity increases the responsiveness of MSNs to depolarizing stimuli. Furthermore, given the lack of effect of TP-10 on SNr+ MSNs, we speculate that PDE10A inhibition may have a greater facilitatory effect on corticostriatal synaptic activity in striatopallidal MSNs. These data support further investigation of selective targeting of PDE signaling pathways in MSN subpopulations because this may represent a promising novel approach for treating brain disorders involving dysfunctional glutamatergic and dopaminergic neurotransmission.
环核苷酸磷酸二酯酶10A（PDE10A）在纹状体中等大小棘状投射神经元（MSN）中高度表达，显然在cGMP和cAMP信号级联反应的调节中起关键作用。PDE10A的基因破坏或药理学抑制可逆转与皮质下多巴胺能亢进相关的行为异常。在此，我们使用在麻醉大鼠背侧纹状体中进行的单单位细胞外记录来研究PDE10A抑制对MSN活动的影响。通过对黑质网状部进行逆向刺激来识别纹状体黑质（SNr+）MSN。通过逆向微透析向纹状体内注入选择性PDE10A抑制剂罂粟碱或TP-10 [2-{4-[-吡啶-4-基-1-(2,2,2-三氟乙基)-1H-吡唑-3-基]-苯氧基甲基}-喹啉琥珀酸] 对自发放电没有影响，但以刺激强度依赖性方式显著增加了皮质诱发的棘波活动指标。TP-10的全身给药也以刺激强度和剂量依赖性方式增加了皮质诱发的棘波活动。在SNr- MSN（主要是纹状体苍白球）中，皮质诱发活动明显大幅增加。有趣的是，给予TP-10并不影响SNr+ MSN中的皮质诱发活动。然而，给予TP-10增加了逆向激活（即SNr+）MSN的发生率。这些发现表明，抑制纹状体PDE10A活性可增加MSN对去极化刺激的反应性。此外，鉴于TP-10对SNr+ MSN没有影响，我们推测PDE10A抑制可能对纹状体苍白球MSN中的皮质纹状体突触活动具有更大的促进作用。这些数据支持进一步研究在MSN亚群中选择性靶向PDE信号通路，因为这可能代表一种有前景的新型方法来治疗涉及谷氨酸能和多巴胺能神经传递功能障碍的脑部疾病。
