Zhang Han-Ting, Huang Ying, Mishler Kathleen, Roerig Sandra C, O'Donnell James M
Department of Pharmacology, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA.
Psychopharmacology (Berl). 2005 Oct;182(1):104-15. doi: 10.1007/s00213-005-0055-y. Epub 2005 Sep 29.
Type 4 phosphodiesterase (PDE4) is critical for hydrolysis of cAMP formed by stimulation of beta adrenergic receptors. However, it is not known if PDE4 is associated with beta adrenergic receptors in the mediation of antidepressant-like effects.
The aim of the study is to determine the relationship between PDE4 and beta adrenergic receptor-mediated cAMP signaling in mediating antidepressant-like effects.
The effects of the PDE4 inhibitor rolipram, alone or combined with dobutamine or clenbuterol, selective beta-1 and beta-2 adrenergic agonists, respectively, on behavior were examined in rats under a differential reinforcement of low rate (DRL) schedule and rats trained to discriminate rolipram from vehicle. Their effects on cAMP in primary cultures of rat cerebral cortical neurons also were determined.
Rolipram (0.01-0.3 mg/kg), dobutamine (1-30 mg/kg), and clenbuterol (0.03-0.3 mg/kg) dose-dependently produced antidepressant-like effects on DRL behavior, decreasing response rate and increasing reinforcement rate. The effects of beta adrenergic agonists were potentiated by rolipram. Isobolographic analysis revealed that rolipram enhanced the antidepressant-like effect of dobutamine additively and that of clenbuterol synergistically. Consistently, a combination of ineffective doses of rolipram (0.03 mg/kg) and dobutamine (3 mg/kg) or clenbuterol (0.03 mg/kg) completely substituted for the rolipram discrimination stimulus. Further, incubation with an ineffective concentration of clenbuterol, but not dobutamine, in the presence of a subeffective concentration of rolipram, significantly increased cAMP in cultured cortical neurons.
PDE4 plays an important role in regulating cAMP signaling by either beta-1 or beta-2 adrenergic receptors that mediate antidepressant-like actions; beta-2 adrenergic receptor-mediated cAMP signaling appears more responsive than beta-1 cAMP signaling to PDE4 inhibition.
4型磷酸二酯酶（PDE4）对于由β肾上腺素能受体刺激所形成的环磷酸腺苷（cAMP）的水解至关重要。然而，在介导类抗抑郁作用中，PDE4是否与β肾上腺素能受体相关尚不清楚。
本研究旨在确定PDE4与β肾上腺素能受体介导的cAMP信号传导在介导类抗抑郁作用中的关系。
分别在低比率差异强化（DRL）程序下的大鼠以及训练用于区分咯利普兰与赋形剂的大鼠中，检测PDE4抑制剂咯利普兰单独使用或与多巴酚丁胺或克仑特罗联合使用（分别为选择性β-1和β-2肾上腺素能激动剂）对行为的影响。还测定了它们对大鼠大脑皮质神经元原代培养物中cAMP的影响。
咯利普兰（0.01 - 0.3毫克/千克）、多巴酚丁胺（1 - 30毫克/千克）和克仑特罗（0.03 - 0.3毫克/千克）对DRL行为产生剂量依赖性的类抗抑郁作用，降低反应率并提高强化率。咯利普兰增强了β肾上腺素能激动剂的作用。等效应线分析显示，咯利普兰增强多巴酚丁胺的类抗抑郁作用为相加作用，增强克仑特罗的类抗抑郁作用为协同作用。一致地，无效剂量的咯利普兰（0.03毫克/千克）与多巴酚丁胺（3毫克/千克）或克仑特罗（0.03毫克/千克）的组合完全替代了咯利普兰辨别刺激。此外，在亚有效浓度的咯利普兰存在下，用无效浓度的克仑特罗而非多巴酚丁胺孵育，可显著增加培养的皮质神经元中的cAMP。
PDE4在通过介导类抗抑郁作用的β-1或β-2肾上腺素能受体调节cAMP信号传导中起重要作用；β-2肾上腺素能受体介导的cAMP信号传导似乎比β-1 cAMP信号传导对PDE4抑制更敏感。
