Phosphodiesterases:novel targets for treatment of alcoholism

OBJECTIVE Alcoholism is one of the most damaging psychiatric disorders and causes serious social and health problems in the world. However,there are no ideal treatments for this disease in clinic.Phosphodiesterases(PDEs) are a superfamily of enzymes consisting of 11 PDE families that hydrolyze cyclicAMP(cA MP) and/or cyclicGMP(cGMP). Among them,PDE4 is critical in the control of intracellular cAMP levels and has been shown to play an important role in the regulation of ethanol consumption.However,the functional role of PDE4 in mediating alcoholism remains unclear. METHODS Ethanol drinking and preference were examined using the two-bottle choice and/or drinking-in-dark(DID) test in high alcohol preferring(HAP) animals,including C57,HAP,and PDE4-subtype knockout mice,and Fawn-Hooded(FH/Wjd) rats,treated with or without the PDE4 inhibitor rolipram or roflumilast. Ethanol withdrawal-induced anxiety-and depressive-like behaviors were examined using the elevated plusmaze,holeboard,forced-swim,and tail-suspension tests in C57 mice or FH rats in the presence of PDE4 inhibition. Levels of cAMP,CREB were determined in brain regions. RESULTS Treatment with rolipram or roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in C57 and HAP mice as well as FH rats. Mice deficient in PDE4 B,but not PDE4 D,displayed similar effects to general PDE4 inhibition. In addition,rolipram reversed ethanol withdrawal-induced anxietyand depressive-like behaviors 1 d and 14 d,respectively,following withdrawal from ethanol drinking in the two-bottle choice in C57 mice or FH rats. Locomotor activity was not changed in either mice or rats treated with the PDE4 inhibitors. Levels of cAMP,p CREB in the brain were increased by rolipram.CONCLUSION The results provide solid evidence for the important role of PDE4 in ethanol consumptionand ethanol withdrawal-induced symptoms. Inhibitors of PDE4,in particular the PDE4 B isoform,can be a novel class of treatment for alcoholism.

Modeling perisaccadic time perception

There is an impressive scarcity of quantitative models of the clock patterns in the brain. We propose a mesoscopic approach, i.e. neither a description at single neuron level, nor at systemic level/too coarse granularity, of the time perception at the time of the saccade. This model uses functional pathway knowledge and is inspired by, and integrates, recent findings in both psychophysics and neurophysiology. Perceived time delays in the perisaccadic window are shown numerically consistent with recent experimental measures. Our model provides explanation for several experimental outcomes on saccades, estimates popu-lation variance of the error in time perception and represent a meaningful example for bridging psychophysics and neurophysiology. Finally we found that the insights into information processing during saccadic events lead to considerations on engineering exploitation of the underlying phenomena.

4-型磷酸二酯酶与局部cAMP信号调节（英文）

Of the eleven families of cyclic nucleotide phosphodiesterases(PDEs) present in the human body,PDE4s represent the most widely expressed family of PDEs. A large body of work has been published on the expression and function of these PDEs,which preferentially hydrolyze cAMP in all cells studied,including neurons and supporting cells of the CNS. Four distinct genes termed PDE4 A,PDE4B,PDE4C and PDE4D encode PDE4 proteins. However,the number of PDE4s identified in different tissues and cells is estimated to be more than 30. Differences in regulation and localization explain this extreme heterogeneity. PDE4 hydrolytic activity is regulated by phosphorylation,and protein kinase A(PKA) was the first kinase identified. This PKA-dependent regulation establishes a feedback loop where cAMP regulates its own degradation to control the intensity and localization of the hormone and neurotransmitter signal. In addition,numerous additional kinases phosphorylate PDE4s to modulate the PKA-dependent activation and fine tune cAMP levels by growth factors and other extracellular cues. Thus,PDE4 can be considered a coincidence detector that integrates multiple signaling pathways. Finally,different PDE4s are involved in numerous macromolecular complexes targeting the cAMP hydrolytic activity to different subcellular domains. Thus,PDE4s function in different subcellular compartments,and inhibition of different isoforms affects cAMP levels in different subdomains with consequently different functions. The dyad space and the control of excitation/contraction will be used as examples of these localized regulations.