Cyclic nucleotide phosphodiesterases: potential therapeutic targets for alcohol use disorder



Alcohol use disorder (AUD), which combines the criteria of both alcohol abuse and dependence, contributes as an important causal factor to multiple health and social problems. Given the limitation of current treatments, novel medications for AUD are needed to better control alcohol consumption and maintain abstinence. It has been well established that the intracellular signal transduction mediated by the second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) crucially underlies the genetic predisposition, rewarding properties, relapsing features, and systemic toxicity of compulsive alcohol consumption. On this basis, the upstream modulators phosphodiesterases (PDEs), which critically control intracellular levels of cyclic nucleotides by catalyzing their degradation, are proposed to play a role in modulating alcohol abuse and dependent process. Here, we highlight existing evidence that correlates cAMP and cGMP signal cascades with the regulation of alcohol-drinking behavior and discuss the possibility that PDEs may become a novel class of therapeutic targets for AUD.


Alcohol use disorder (AUD) Central nervous system Alcohol dependence cAMP cGMP Phosphodiesterase (PDE) 



This work was supported by the research grants from NIH/NIAAA (AA020042, HHSN275201700001C; both to H.-T. Zhang), the Foundation of Overseas Distinguished Taishan Scholars of Shandong Province, China (to H.-T. Zhang), and National Nature Science Foundation of China (81773717, 81503050, to H.-T. Zhang and R.-T. Wen, respectively).


  1. Acquaah-Mensah GK, Misra V, Biswal S (2006) Ethanol sensitivity: a central role for CREB transcription regulation in the cerebellum. BMC Genomics 7:308PubMedPubMedCentralGoogle Scholar
  2. Ankur J, Mahesh R, Bhatt S (2013) Anxiolytic-like effect of etazolate, a type 4 phosphodiesterase inhibitor in experimental models of anxiety. Indian J Exp Biol 51:444–449PubMedGoogle Scholar
  3. Asher O, Cunningham TD, Yao L, Gordon AS, Diamond I (2002) Ethanol stimulates cAMP-responsive element (CRE)-mediated transcription via CRE-binding protein and cAMP-dependent protein kinase. J Pharmacol Exp Ther 301:66–70PubMedGoogle Scholar
  4. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5., 5th ed. edn. American Psychiatric Association, American Psychiatric AssociationGoogle Scholar
  5. Asyyed A, Storm D, Diamond I (2006) Ethanol activates cAMP response element-mediated gene expression in select regions of the mouse brain. Brain Res 1106:63–71PubMedGoogle Scholar
  6. Avila DV, Myers SA, Zhang J, Kharebava G, McClain CJ, Kim HY, Whittemore SR, Gobejishvili L, Barve S (2017) Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro-inflammation. Neuropharmacology 125:376–385PubMedGoogle Scholar
  7. Banerjee A, Patil S, Pawar MY, Gullapalli S, Gupta PK, Gandhi MN, Bhateja DK, Bajpai M, Sangana RR, Gudi GS, Khairatkar-Joshi N, Gharat LA (2012) Imidazopyridazinones as novel PDE7 inhibitors: SAR and in vivo studies in Parkinson's disease model. Bioorg Med Chem Lett 22:6286–6291PubMedGoogle Scholar
  8. Belknap JK, Crabbe JC, Young ER (1993) Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology 112:503–510PubMedGoogle Scholar
  9. Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, Becker HC (2015) Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict Biol 20:38–42PubMedGoogle Scholar
  10. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520PubMedGoogle Scholar
  11. Bison S, Crews F (2003) Alcohol withdrawal increases neuropeptide Y immunoreactivity in rat brain. Alcohol Clin Exp Res 27:1173–1183PubMedGoogle Scholar
  12. Blednov YA, Benavidez JM, Black M, Harris RA (2014) Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci 8:129PubMedPubMedCentralGoogle Scholar
  13. Blokland A, Schreiber R, Prickaerts J (2006) Improving memory: a role for phosphodiesterases. Curr Pharm Des 12:2511–2523PubMedGoogle Scholar
  14. Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, de Vente J, Prickaerts J, Blokland A, Koenig G (2004) Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47:1081–1092PubMedGoogle Scholar
  15. Bolger GB, Rodgers L, Riggs M (1994) Differential CNS expression of alternative mRNA isoforms of the mammalian genes encoding cAMP-specific phosphodiesterases. Gene 149:237–244PubMedGoogle Scholar
  16. Braun NN, Reutiman TJ, Lee S, Folsom TD, Fatemi SH (2007) Expression of phosphodiesterase 4 is altered in the brains of subjects with autism. Neuroreport 18:1841–1844PubMedGoogle Scholar
  17. Carlezon WJ, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445PubMedGoogle Scholar
  18. Carlezon WJ, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ (1998) Regulation of cocaine reward by CREB. Science 282:2272–2275PubMedGoogle Scholar
  19. Chao J, Nestler EJ (2004) Molecular neurobiology of drug addiction. Annu Rev Med 55:113–132PubMedGoogle Scholar
  20. Collins SP, Uhler MD (1999) Cyclic AMP- and cyclic GMP-dependent protein kinases differ in their regulation of cyclic AMP response element-dependent gene transcription. J Biol Chem 274:8391–8404PubMedGoogle Scholar
  21. Constantinescu A, Gordon AS, Diamond I (2002) cAMP-dependent protein kinase types I and II differentially regulate cAMP response element-mediated gene expression: implications for neuronal responses to ethanol. J Biol Chem 277:18810–18816PubMedGoogle Scholar
  22. Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511PubMedGoogle Scholar
  23. Conway KP, Compton W, Stinson FS, Grant BF (2006) Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 67:247–257PubMedGoogle Scholar
  24. Dar MS (1990) Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. J Pharmacol Exp Ther 255:1202–1209PubMedGoogle Scholar
  25. Dar MS (2001) Modulation of ethanol-induced motor incoordination by mouse striatal A (1) adenosinergic receptor. Brain Res Bull 55:513–520PubMedGoogle Scholar
  26. Deschatrettes E, Romieu P, Zwiller J (2013) Cocaine self-administration by rats is inhibited by cyclic GMP-elevating agents: involvement of epigenetic markers. Int J Neuropsychopharmacol 16:1587–1597PubMedGoogle Scholar
  27. Ding L, Zhang C, Masood A, Li J, Sun J, Nadeem A, Zhang HT, O' DJ, Xu Y (2014) Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: involvement of antioxidant and anti-apoptotic mechanisms. Behav Brain Res 268:150–158PubMedPubMedCentralGoogle Scholar
  28. Durcan MJ, Lister RG, Morgan PF, Linnoila M (1991) Interactions of intracerebroventricular pertussis toxin treatment with the ataxic and hypothermic effects of ethanol. Naunyn Schmiedeberg's Arch Pharmacol 344:252–258Google Scholar
  29. Filgueiras CC, Krahe TE, Medina AE (2010) Phosphodiesterase type 1 inhibition improves learning in rats exposed to alcohol during the third trimester equivalent of human gestation. Neurosci Lett 473(3):202–207PubMedPubMedCentralGoogle Scholar
  30. Franklin KM, Hauser SR, Lasek AW, McClintick J, Ding ZM, McBride WJ, Bell RL (2015) Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). Psychopharmacology 232:2251–2262PubMedPubMedCentralGoogle Scholar
  31. Froehlich JC, Wand GS (1997) Adenylyl cyclase signal transduction and alcohol-induced sedation. Pharmacol Biochem Behav 58:1021–1030PubMedGoogle Scholar
  32. Garcia AM, Redondo M, Martinez A, Gil C (2014) Phosphodiesterase 10 inhibitors: new disease modifying drugs for Parkinson's disease? Curr Med Chem 21:1171–1187PubMedGoogle Scholar
  33. Garcia-Osta A, Cuadrado-Tejedor M, Garcia-Barroso C, Oyarzabal J, Franco R (2012) Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem Neurosci 3:832–844PubMedPubMedCentralGoogle Scholar
  34. Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ (2006) The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur J Pharmacol 538:39–42PubMedGoogle Scholar
  35. Gobejishvili L, Barve S, Joshi-Barve S, McClain C (2008) Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 295:G718–G724PubMedPubMedCentralGoogle Scholar
  36. Gobejishvili L, Barve S, Joshi-Barve S, Uriarte S, Song Z, McClain C (2006) Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 291:G681–G688PubMedGoogle Scholar
  37. Gong MF, Wen RT, Xu Y, Pan JC, Fei N, Zhou YM, Xu JP, Liang JH, Zhang HT (2017) Attenuation of ethanol abstinence-induced anxiety- and depressive-like behavior by the phosphodiesterase-4 inhibitor rolipram in rodents. Psychopharmacology 234:3143–3151PubMedGoogle Scholar
  38. Gonzales RA, Job MO, Doyon WM (2004) The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement. Pharmacol Ther 103:121–146PubMedGoogle Scholar
  39. Gonzalez-Cuello A, Sanchez L, Hernandez J, Teresa CM, Victoria MM, Laorden ML (2007) Phosphodiesterase 4 inhibitors, rolipram and diazepam block the adaptive changes observed during morphine withdrawal in the heart. Eur J Pharmacol 570:1–9PubMedGoogle Scholar
  40. Gordon AS, Collier K, Diamond I (1986) Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol. Proc Natl Acad Sci U S A 83:2105–2108PubMedPubMedCentralGoogle Scholar
  41. Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, Langen B, Logue S, Brennan J, Jiang L, Charych E, Egerland U, Liu F, Marquis KL, Malamas M, Hage T, Comery TA, Brandon NJ (2009) Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther 331:574–590PubMedGoogle Scholar
  42. Guevara-Guzman R, Emson PC, Kendrick KM (1994) Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J Neurochem 62:807–810PubMedGoogle Scholar
  43. Hamdy MM, Mamiya T, Noda Y, Sayed M, Assi AA, Gomaa A, Yamada K, Nabeshima T (2001) A selective phosphodiesterase IV inhibitor, rolipram blocks both withdrawal behavioral manifestations, and c-Fos protein expression in morphine dependent mice. Behav Brain Res 118:85–93PubMedGoogle Scholar
  44. Hashimoto E, Frolich L, Ozawa H, Saito T, Maurer K, Boning J, Takahata N, Riederer P (1998) Reduced immunoreactivity of type I adenylyl cyclase in the postmortem brains of alcoholics. Alcohol Clin Exp Res 22:88S–92SPubMedGoogle Scholar
  45. Heckman PR, Wouters C, Prickaerts J (2015) Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer's disease: a translational overview. Curr Pharm Des 21:317–331PubMedGoogle Scholar
  46. Hu W, Lu T, Chen A, Huang Y, Hansen R, Chandler LJ, Zhang HT (2011) Inhibition of phosphodiesterase-4 decreases ethanol intake in mice. Psychopharmacology 218:331–339PubMedPubMedCentralGoogle Scholar
  47. Hyman SE, Malenka RC (2001) Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2:695–703PubMedGoogle Scholar
  48. Imperato A, Di Chiara G (1986) Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. J Pharmacol Exp Ther 239:219–228PubMedGoogle Scholar
  49. Iyo M, Bi Y, Hashimoto K, Inada T, Fukui S (1996) Prevention of methamphetamine-induced behavioral sensitization in rats by a cyclic AMP phosphodiesterase inhibitor, rolipram. Eur J Pharmacol 312:163–170PubMedGoogle Scholar
  50. Janes AC, Kantak KM, Cherry JA (2009) The involvement of type IV phosphodiesterases in cocaine-induced sensitization and subsequent pERK expression in the mouse nucleus accumbens. Psychopharmacology 206:177–185PubMedGoogle Scholar
  51. Jiao S, Liu Z, Ren WH, Ding Y, Zhang YQ, Zhang ZH, Mei YA (2007) cAMP/protein kinase A signalling pathway protects against neuronal apoptosis and is associated with modulation of Kv2.1 in cerebellar granule cells. J Neurochem 100:979–991PubMedGoogle Scholar
  52. Johnson BA (2003) The role of serotonergic agents as treatments for alcoholism. Drugs Today (Barc) 39:665–672Google Scholar
  53. Karacay B, Li G, Pantazis NJ, Bonthius DJ (2007) Stimulation of the cAMP pathway protects cultured cerebellar granule neurons against alcohol-induced cell death by activating the neuronal nitric oxide synthase (nNOS) gene. Brain Res 1143:34–45PubMedPubMedCentralGoogle Scholar
  54. Kelly MP, Isiegas C, Cheung YF, Tokarczyk J, Yang X, Esposito MF, Rapoport DA, Fabian SA, Siegel SJ, Wand G, Houslay MD, Kanes SJ, Abel T (2007) Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology 32:577–588PubMedGoogle Scholar
  55. Kim KS, Kim H, Baek IS, Lee KW, Han PL (2011) Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity. Psychopharmacology 215:391–398PubMedGoogle Scholar
  56. Kim KS, Lee KW, Baek IS, Lim CM, Krishnan V, Lee JK, Nestler EJ, Han PL (2008) Adenylyl cyclase-5 activity in the nucleus accumbens regulates anxiety-related behavior. J Neurochem 107:105–115PubMedPubMedCentralGoogle Scholar
  57. Kleppisch T, Feil R (2009) cGMP signalling in the mammalian brain: role in synaptic plasticity and behaviour. Handb Exp Pharmacol 191:549–579Google Scholar
  58. Knapp CM, Foye MM, Ciraulo DA, Kornetsky C (1999) The type IV phosphodiesterase inhibitors, Ro 20-1724 and rolipram, block the initiation of cocaine self-administration. Pharmacol Biochem Behav 62:151–158PubMedGoogle Scholar
  59. Knapp CM, Lee K, Foye M, Ciraulo DA, Kornetsky C (2001) Additive effects of intra-accumbens infusion of the cAMP-specific phosphodiesterase inhibitor, rolipram and cocaine on brain stimulation reward. Life Sci 69:1673–1682PubMedGoogle Scholar
  60. Koob GF (2003) Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232–243PubMedGoogle Scholar
  61. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58PubMedGoogle Scholar
  62. Lai M, Zhu H, Sun A, Zhuang D, Fu D, Chen W, Zhang HT, Zhou W (2014) The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats. Int J Neuropsychopharmacol 17:1397–1407PubMedGoogle Scholar
  63. Lakics V, Karran EH, Boess FG (2010) Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 59:367–374PubMedGoogle Scholar
  64. Lantz CL, Wang W, Medina AE (2012) Early alcohol exposure disrupts visual cortex plasticity in mice. Int J Dev Neurosci 30:351–357PubMedPubMedCentralGoogle Scholar
  65. Li S, Doss JC, Hardee EJ, Quock RM (2005) Involvement of cyclic GMP-dependent protein kinase in nitrous oxide-induced anxiolytic-like behavior in the mouse light/dark exploration test. Brain Res 1038:113–117PubMedGoogle Scholar
  66. Li YF, Huang Y, Amsdell SL, Xiao L, O'Donnell JM, Zhang HT (2009) Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus. Neuropsychopharmacology 34:2404–2419PubMedPubMedCentralGoogle Scholar
  67. Liebenberg N, Harvey BH, Brand L, Brink CB (2010) Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression. Behav Pharmacol 21:540–547PubMedGoogle Scholar
  68. Lingford-Hughes A, Watson B, Kalk N, Reid A (2010) Neuropharmacology of addiction and how it informs treatment. Br Med Bull 96:93–110PubMedGoogle Scholar
  69. Liu X, Hao PD, Yang MF, Sun JY, Mao LL, Fan CD, Zhang ZY, Li DW, Yang XY, Sun BL, Zhang HT (2017a) The phosphodiesterase-4 inhibitor roflumilast decreases ethanol consumption in C57BL/6J mice. Psychopharmacology 234:2409–2419PubMedGoogle Scholar
  70. Liu X, Zhong P, Vickstrom C, Li Y, Liu QS (2017b) PDE4 inhibition restores the balance between excitation and inhibition in VTA dopamine neurons disrupted by repeated in vivo cocaine exposure. Neuropsychopharmacology 42:1991–1999PubMedGoogle Scholar
  71. Logrip ML (2015) Phosphodiesterase regulation of alcohol drinking in rodents. Alcohol 49:795–802PubMedPubMedCentralGoogle Scholar
  72. Logrip ML, Vendruscolo LF, Schlosburg JE, Koob GF, Zorrilla EP (2014) Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats. Neuropsychopharmacology 39:1722–1731PubMedPubMedCentralGoogle Scholar
  73. Logrip ML, Zorrilla EP (2012) Stress history increases alcohol intake in relapse: relation to phosphodiesterase 10A. Addict Biol 17:920–933PubMedPubMedCentralGoogle Scholar
  74. Logrip ML, Zorrilla EP (2014) Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal. Front Integr Neurosci 8:30PubMedPubMedCentralGoogle Scholar
  75. Loughney K, Taylor J, Florio VA (2005) 3′,5′-cyclic nucleotide phosphodiesterase 11A: localization in human tissues. Int J Impot Res 17:320–325PubMedGoogle Scholar
  76. Lugnier C (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109:366–398PubMedGoogle Scholar
  77. Maas JJ, Vogt SK, Chan GC, Pineda VV, Storm DR, Muglia LJ (2005) Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity. J Neurosci 25:4118–4126PubMedGoogle Scholar
  78. McClung CA, Nestler EJ (2003) Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat Neurosci 6:1208–1215PubMedGoogle Scholar
  79. McLachlan CS, Chen ML, Lynex CN, Goh DL, Brenner S, Tay SK (2007) Changes in PDE4D isoforms in the hippocampus of a patient with advanced Alzheimer disease. Arch Neurol 64:456–457PubMedGoogle Scholar
  80. Medina AE, Krahe TE, Ramoa AS (2006) Restoration of neuronal plasticity by a phosphodiesterase type 1 inhibitor in a model of fetal alcohol exposure. J Neurosci 26:1057–1060PubMedGoogle Scholar
  81. Megens AA, Hendrickx HM, Hens KA, Fonteyn I, Langlois X, Lenaerts I, Somers MV, de Boer P, Vanhoof G (2014) Pharmacology of JNJ-42314415, a centrally active phosphodiesterase 10A (PDE10A) inhibitor: a comparison of PDE10A inhibitors with D2 receptor blockers as potential antipsychotic drugs. J Pharmacol Exp Ther 349:138–154PubMedGoogle Scholar
  82. Menniti FS, Faraci WS, Schmidt CJ (2006) Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5:660–670PubMedGoogle Scholar
  83. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310:1187–1191PubMedGoogle Scholar
  84. Milton AL, Everitt BJ (2012) The persistence of maladaptive memory: addiction, drug memories and anti-relapse treatments. Neurosci Biobehav Rev 36:1119–1139PubMedGoogle Scholar
  85. Misra K, Pandey SC (2003) Differences in basal levels of CREB and NPY in nucleus accumbens regions between C57BL/6 and DBA/2 mice differing in inborn alcohol drinking behavior. J Neurosci Res 74:967–975PubMedGoogle Scholar
  86. Montesinos J, Alfonso-Loeches S, Guerri C (2016) Impact of the innate immune response in the actions of ethanol on the central nervous system. Alcohol Clin Exp Res 40:2260–2270PubMedGoogle Scholar
  87. Monti B, Marri L, Contestabile A (2002) NMDA receptor-dependent CREB activation in survival of cerebellar granule cells during in vivo and in vitro development. Eur J Neurosci 16:1490–1498PubMedGoogle Scholar
  88. Mori F, Perez-Torres S, De Caro R, Porzionato A, Macchi V, Beleta J, Gavalda A, Palacios JM, Mengod G (2010) The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. J Chem Neuroanat 40:36–42PubMedGoogle Scholar
  89. Muglia LM, Schaefer ML, Vogt SK, Gurtner G, Imamura A, Muglia LJ (1999) The 5′-flanking region of the mouse adenylyl cyclase type VIII gene imparts tissue-specific expression in transgenic mice. J Neurosci 19:2051–2058PubMedGoogle Scholar
  90. Nakayama T, Asai S, Sato N, Soma M (2007) PDE4D gene in the STRK1 region on 5q12: susceptibility gene for ischemic stroke. Curr Med Chem 14:3171–3178PubMedGoogle Scholar
  91. Nelson EJ, Hellevuo K, Yoshimura M, Tabakoff B (2003) Ethanol-induced phosphorylation and potentiation of the activity of type 7 adenylyl cyclase. Involvement of protein kinase C delta. J Biol Chem 278:4552–4560PubMedGoogle Scholar
  92. Nikolaev VO, Gambaryan S, Engelhardt S, Walter U, Lohse MJ (2005) Real-time monitoring of the PDE2 activity of live cells: hormone-stimulated cAMP hydrolysis is faster than hormone-stimulated cAMP synthesis. J Biol Chem 280:1716–1719PubMedGoogle Scholar
  93. Nugent FS, Penick EC, Kauer JA (2007) Opioids block long-term potentiation of inhibitory synapses. Nature 446:1086–1090PubMedGoogle Scholar
  94. Nunes F, Ferreira-Rosa K, Pereira MS, Kubrusly RC, Manhaes AC, Abreu-Villaca Y, Filgueiras CC (2011) Acute administration of vinpocetine, a phosphodiesterase type 1 inhibitor, ameliorates hyperactivity in a mice model of fetal alcohol spectrum disorder. Drug Alcohol Depend 119:81–87PubMedGoogle Scholar
  95. Nunez C, Gonzalez-Cuello A, Sanchez L, Vargas ML, Milanes MV, Laorden ML (2009) Effects of rolipram and diazepam on the adaptive changes induced by morphine withdrawal in the hypothalamic paraventricular nucleus. Eur J Pharmacol 620:1–8PubMedGoogle Scholar
  96. Pandey SC (2003) Anxiety and alcohol abuse disorders: a common role for CREB and its target, the neuropeptide Y gene. Trends Pharmacol Sci 24:456–460PubMedGoogle Scholar
  97. Pandey SC (2004) The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction. Pharmacol Ther 104:47–58PubMedGoogle Scholar
  98. Pandey SC, Mittal N, Lumeng L, Li TK (1999a) Involvement of the cyclic AMP-responsive element binding protein gene transcription factor in genetic preference for alcohol drinking behavior. Alcohol Clin Exp Res 23:1425–1434PubMedGoogle Scholar
  99. Pandey SC, Roy A, Mittal N (2001a) Effects of chronic ethanol intake and its withdrawal on the expression and phosphorylation of the creb gene transcription factor in rat cortex. J Pharmacol Exp Ther 296:857–868PubMedGoogle Scholar
  100. Pandey SC, Roy A, Zhang H (2003) The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats. Alcohol Clin Exp Res 27:396–409PubMedGoogle Scholar
  101. Pandey SC, Roy A, Zhang H, Xu T (2004) Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors. J Neurosci 24:5022–5030PubMedGoogle Scholar
  102. Pandey SC, Saito T, Yoshimura M, Sohma H, Gotz ME (2001b) cAmp signaling cascade: a promising role in ethanol tolerance and dependence. Alcohol Clin Exp Res 25:46S–48SPubMedGoogle Scholar
  103. Pandey SC, Zhang D, Mittal N, Nayyar D (1999b) Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal-related anxiety. J Pharmacol Exp Ther 288:866–878PubMedGoogle Scholar
  104. Pandey SC, Zhang H, Roy A, Xu T (2005) Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest 115:2762–2773PubMedPubMedCentralGoogle Scholar
  105. Perez-Torres S, Miro X, Palacios JM, Cortes R, Puigdomenech P, Mengod G (2000) Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and[3H]rolipram binding autoradiography. Comparison with monkey and rat brain. J Chem Neuroanat 20:349–374PubMedGoogle Scholar
  106. Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD (2005) Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 366:563–571PubMedGoogle Scholar
  107. Ramirez AD, Smith SM (2014) Regulation of dopamine signaling in the striatum by phosphodiesterase inhibitors: novel therapeutics to treat neurological and psychiatric disorders. Cent Nerv Syst Agents Med Chem 14:72–82PubMedGoogle Scholar
  108. Ray LA, Bujarski S, Shoptaw S, Roche DJ, Heinzerling K, Miotto K (2017) Development of the neuroimmune modulator ibudilast for the treatment of alcoholism: a randomized, placebo-controlled, human laboratory trial. Neuropsychopharmacology 42:1776–1788PubMedGoogle Scholar
  109. Reyes-Irisarri E, Perez-Torres S, Mengod G (2005) Neuronal expression of cAMP-specific phosphodiesterase 7B mRNA in the rat brain. Neuroscience 132:1173–1185PubMedGoogle Scholar
  110. Romieu P, Gobaille S, Aunis D, Zwiller J (2008) Injection of the neuropeptide CNP into dopaminergic rat brain areas decreases alcohol intake. Ann N Y Acad Sci 1139:27–33PubMedGoogle Scholar
  111. Rutter AR, Poffe A, Cavallini P, Davis TG, Schneck J, Negri M, Vicentini E, Montanari D, Arban R, Gray FA, Davies CH, Wren PB (2014) GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. J Pharmacol Exp Ther 350:153–163PubMedGoogle Scholar
  112. Saito T, Lee JM, Hoffman PL, Tabakoff B (1987) Effects of chronic ethanol treatment on the beta-adrenergic receptor-coupled adenylate cyclase system of mouse cerebral cortex. J Neurochem 48:1817–1822PubMedGoogle Scholar
  113. Samson WK, Bianchi R, Mogg R (1988) Evidence for a dopaminergic mechanism for the prolactin inhibitory effect of atrial natriuretic factor. Neuroendocrinology 47:268–271PubMedGoogle Scholar
  114. Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, Hoffman WE, Lebel LA, McCarthy SA, Nelson FR, Proulx-LaFrance C, Majchrzak MJ, Ramirez AD, Schmidt K, Seymour PA, Siuciak JA, Tingley FR, Williams RD, Verhoest PR, Menniti FS (2008) Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 325:681–690PubMedGoogle Scholar
  115. Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, Schmidt CJ (2006) Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 51:386–396PubMedGoogle Scholar
  116. Siuciak JA, Chapin DS, McCarthy SA, Martin AN (2007) Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology 192:415–424PubMedGoogle Scholar
  117. Smith SM, Uslaner JM, Cox CD, Huszar SL, Cannon CE, Vardigan JD, Eddins D, Toolan DM, Kandebo M, Yao L, Raheem IT, Schreier JD, Breslin MJ, Coleman PJ, Renger JJ (2013) The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Neuropharmacology 64:215–223PubMedGoogle Scholar
  118. Snyder GL, Vanover KE (2017) PDE inhibitors for the treatment of schizophrenia. Adv Neurobiol 17:385–409PubMedGoogle Scholar
  119. Sohma H, Hashimoto E, Shirasaka T, Tsunematsu R, Ozawa H, Boissl KW, Boning J, Riederer P, Saito T (1999) Quantitative reduction of type I adenylyl cyclase in human alcoholics. Biochim Biophys Acta 1454:11–18PubMedGoogle Scholar
  120. Sotty F, Montezinho LP, Steiniger-Brach B, Nielsen J (2009) Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to D-amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons. J Neurochem 109:766–775PubMedGoogle Scholar
  121. Stoltenberg SF (2003) Serotonergic agents and alcoholism treatment: a simulation. Alcohol Clin Exp Res 27:1853–1859PubMedGoogle Scholar
  122. Suzuki K, Harada A, Shiraishi E, Kimura H (2015) In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents. J Pharmacol Exp Ther 352:471–479PubMedGoogle Scholar
  123. Swart PC, Currin CB, Russell VA, Dimatelis JJ (2017) Early ethanol exposure and vinpocetine treatment alter learning- and memory-related proteins in the rat hippocampus and prefrontal cortex. J Neurosci Res 95:1204–1215PubMedGoogle Scholar
  124. Thiriet N, Jouvert P, Gobaille S, Solov'Eva O, Gough B, Aunis D, Ali S, Zwiller J (2001) C-type natriuretic peptide (CNP) regulates cocaine-induced dopamine increase and immediate early gene expression in rat brain. Eur J Neurosci 14:1702–1708PubMedGoogle Scholar
  125. Thompson BE, Sachs BD, Kantak KM, Cherry JA (2004) The type IV phosphodiesterase inhibitor rolipram interferes with drug-induced conditioned place preference but not immediate early gene induction in mice. Eur J Neurosci 19:2561–2568PubMedGoogle Scholar
  126. Torregrossa MM, Corlett PR, Taylor JR (2011) Aberrant learning and memory in addiction. Neurobiol Learn Mem 96:609–623PubMedPubMedCentralGoogle Scholar
  127. Uzbay IT, Celik T, Aydin A, Kayir H, Tokgoz S, Bilgi C (2004) Effects of chronic ethanol administration and ethanol withdrawal on cyclic guanosine 3′,5′-monophosphate (cGMP) levels in the rat brain. Drug Alcohol Depend 74:55–59PubMedGoogle Scholar
  128. Valverius P, Hoffman PL, Tabakoff B (1989) Hippocampal and cerebellar beta-adrenergic receptors and adenylate cyclase are differentially altered by chronic ethanol ingestion. J Neurochem 52:492–497PubMedGoogle Scholar
  129. van der Staay FJ, Rutten K, Barfacker L, Devry J, Erb C, Heckroth H, Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J, Reymann KG, Schroder UH, Hendrix M (2008) The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology 55:908–918PubMedGoogle Scholar
  130. Volke V, Wegener G, Vasar E (2003) Augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice. J Physiol Pharmacol 54:653–660PubMedGoogle Scholar
  131. Walters CL, Blendy JA (2001) Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J Neurosci 21:9438–9444PubMedGoogle Scholar
  132. Walton M, Woodgate AM, Muravlev A, Xu R, During MJ, Dragunow M (1999) CREB phosphorylation promotes nerve cell survival. J Neurochem 73:1836–1842PubMedGoogle Scholar
  133. Wang C, Yang XM, Zhuo YY, Zhou H, Lin HB, Cheng YF, Xu JP, Zhang HT (2012) The phosphodiesterase-4 inhibitor rolipram reverses Abeta-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats. Int J Neuropsychopharmacol 15:749–766PubMedGoogle Scholar
  134. Wen RT, Feng WY, Liang JH, Zhang HT (2015) Role of phosphodiesterase 4-mediated cyclic AMP signaling in pharmacotherapy for substance dependence. Curr Pharm Des 21:355–364PubMedGoogle Scholar
  135. Wen RT, Liang JH, Zhang HT (2017) Targeting phosphodiesterases in pharmacotherapy for substance dependence. Adv Neurobiol 17:413–444PubMedGoogle Scholar
  136. Wen RT, Zhang M, Qin WJ, Liu Q, Wang WP, Lawrence AJ, Zhang HT, Liang JH (2012) The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring fawn-hooded rats. Alcohol Clin Exp Res 36:2157–2167PubMedPubMedCentralGoogle Scholar
  137. Wennogle LP, Hoxie H, Peng Y, Hendrick JP (2017) Phosphodiesterase 1: a unique drug target for degenerative diseases and cognitive dysfunction. Adv Neurobiol 17:349–384PubMedGoogle Scholar
  138. Werner C, Raivich G, Cowen M, Strekalova T, Sillaber I, Buters JT, Spanagel R, Hofmann F (2004) Importance of NO/cGMP signalling via cGMP-dependent protein kinase II for controlling emotionality and neurobehavioural effects of alcohol. Eur J Neurosci 20:3498–3506PubMedGoogle Scholar
  139. Xia ZG, Refsdal CD, Merchant KM, Dorsa DM, Storm DR (1991) Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: expression in areas associated with learning and memory. Neuron 6:431–443PubMedGoogle Scholar
  140. Xu Y, Pan J, Sun J, Ding L, Ruan L, Reed M, Yu X, Klabnik J, Lin D, Li J, Chen L, Zhang C, Zhang H, O'Donnell JM (2015) Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress. Neurobiol Aging 36:955–970PubMedGoogle Scholar
  141. Xu Y, Zhang HT, O’Donnell JM (2011) Phosphodiesterases in the central nervous system: implications in mood and cognitive disorders. Handb Exp Pharmacol 204:447–485Google Scholar
  142. Yang X, Diehl AM, Wand GS (1996) Ethanol exposure alters the phosphorylation of cyclic AMP responsive element binding protein and cyclic AMP responsive element binding activity in rat cerebellum. J Pharmacol Exp Ther 278:338–346PubMedGoogle Scholar
  143. Yang X, Horn K, Baraban JM, Wand GS (1998a) Chronic ethanol administration decreases phosphorylation of cyclic AMP response element-binding protein in granule cells of rat cerebellum. J Neurochem 70:224–232PubMedGoogle Scholar
  144. Yang X, Horn K, Wand GS (1998b) Chronic ethanol exposure impairs phosphorylation of CREB and CRE-binding activity in rat striatum. Alcohol Clin Exp Res 22:382–390PubMedGoogle Scholar
  145. Yoshimura M, Tabakoff B (1995) Selective effects of ethanol on the generation of cAMP by particular members of the adenylyl cyclase family. Alcohol Clin Exp Res 19:1435–1440PubMedGoogle Scholar
  146. Zalewska-Kaszubska J, Gorska D, Dyr W, Czarnecka E (2008) Lack of changes in beta-endorphin plasma levels after repeated treatment with fluoxetine: possible implications for the treatment of alcoholism--a pilot study. Pharmazie 63:308–311PubMedGoogle Scholar
  147. Zee RY, Brophy VH, Cheng S, Hegener HH, Erlich HA, Ridker PM (2006) Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation. Stroke 37:2012–2017PubMedGoogle Scholar
  148. Zhang HT (2009) Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 15:1688–1698PubMedGoogle Scholar
  149. Zhang HT, Crissman AM, Dorairaj NR, Chandler LJ, O'Donnell JM (2000) Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 23:198–204PubMedGoogle Scholar
  150. Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M, O'Donnell JM (2002) Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27:587–595PubMedGoogle Scholar
  151. Zhang HT, Huang Y, Masood A, Stolinski LR, Li Y, Zhang L, Dlaboga D, Jin SL, Conti M, O'Donnell JM (2008) Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 33:1611–1623PubMedGoogle Scholar
  152. Zhang HT, Huang Y, Suvarna NU, Deng C, Crissman AM, Hopper AT, De Vivo M, Rose GM, O'Donnell JM (2005) Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology 179:613–619PubMedGoogle Scholar
  153. Zhang HT, Zhao Y, Huang Y, Deng C, Hopper AT, De Vivo M, Rose GM, O'Donnell JM (2006) Antidepressant-like effects of PDE4 inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats. Psychopharmacology 186:209–217PubMedGoogle Scholar
  154. Zhong P, Wang W, Yu F, Nazari M, Liu X, Liu QS (2012) Phosphodiesterase 4 inhibition impairs cocaine-induced inhibitory synaptic plasticity and conditioned place preference. Neuropsychopharmacology 37:2377–2387PubMedPubMedCentralGoogle Scholar
  155. Zocchi A, Girlanda E, Varnier G, Sartori I, Zanetti L, Wildish GA, Lennon M, Mugnaini M, Heidbreder CA (2003) Dopamine responsiveness to drugs of abuse: a shell-core investigation in the nucleus accumbens of the mouse. Synapse 50:293–302PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Rui-Ting Wen
    • 1
  • Fang-Fang Zhang
    • 2
  • Han-Ting Zhang
    • 2
    • 3
  1. 1.Department of PharmacyPeking University People’s HospitalBeijingChina
  2. 2.Institute of PharmacologyQilu Medical UniversityTaianChina
  3. 3.Departments of Behavioral Medicine and Psychiatry and Physiology, Pharmacology and Neuroscience, Rockefeller Neurosciences InstituteWest Virginia University Health Sciences CenterMorgantownUSA

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