Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities

Abstract

BACKGROUND: Long-term exposure to drugs of abuse causes an upregulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 (PDE4) is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse.

OBJECTIVE: Here, we review the current knowledge about central nervous system (CNS) distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction.

METHODS: A systematic literature search was performed using the Pubmed.

RESULTS: Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice.

CONCLUSIONS: Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.

Key words： PDE4; PDE4 inhibitors; VTA; nucleus accumbens; drug addiction

Acknowledgments

Work in the authors’ laboratories was supported by US NIH Grants DA035217 (QSL), MH101146 (QSL), DA039276 (CMO), and DA041212 (CMO). Research was also supported by the Medical College of Wisconsin Research and Education Initiative Fund, a component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin (CMO, QSL).

Compliance with ethics guidelines

Christopher M. Olsen and Qing-song Liu declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

References

1 Alberini C M (2009). Transcription factors in long-term memory and synaptic plasticity. Physiol Rev, 89(1): 121–145

PMID

2 Allain F, Minogianis E A, Roberts D C, Samaha A N (2015). How fast and how often: The pharmacokinetics of drug use are decisive in addiction. Neurosci Biobehav Rev, 56: 166–179

PMID

3 Anderson S M, Pierce R C (2005). Cocaine-induced alterations in dopamine receptor signaling: implications for reinforcement and reinstatement. Pharmacol Ther, 106(3): 389–403

PMID

4 Bardo M T, Bevins R A (2000). Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl), 153(1): 31–43

PMID

5 Beardsley P M, Hauser K F (2014). Glial modulators as potential treatments of psychostimulant abuse. Adv Pharmacol, 69: 1–69

PMID

6 Beardsley P M, Shelton K L, Hendrick E, Johnson K W (2010). The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse. Eur J Pharmacol, 637(1-3): 102–108

PMID

7 Bell R L, Lopez M F, Cui C, Egli M, Johnson K W, Franklin K M, Becker H C (2015). Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict Biol, 20(1): 38–42

PMID

8 Bertolino A, Crippa D, di Dio S, Fichte K, Musmeci G, Porro V, Rapisarda V, Sastre-y-Hernández M, Schratzer M (1988). Rolipram versus imipramine in inpatients with major, “minor” or atypical depressive disorder: a double-blind double-dummy study aimed at testing a novel therapeutic approach. Int Clin Psychopharmacol, 3(3): 245–253

PMID

9 Blednov Y A, Benavidez J M, Black M, Harris R A (2014). Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci, 8: 129

PMID

10 Britt J P, Benaliouad F, McDevitt R A, Stuber G D, Wise R A, Bonci A (2012). Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron, 76(4): 790–803

PMID

11 Carlezon W A Jr, Chartoff E H (2007). Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc, 2(11): 2987–2995

PMID

12 Cherry J A, Davis R L (1999). Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol, 407(2): 287–301

PMID

13 Conrad K L, Louderback K M, Milano E J, Winder D G (2013). Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement. Psychopharmacology (Berl), 227(1): 109–116

PMID

14 Conti M, Richter W, Mehats C, Livera G, Park J Y, Jin C (2003). Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem, 278(8): 5493–5496

PMID

15 Crabbe J C (2014). Rodent models of genetic contributions to motivation to abuse alcohol. Nebr Symp Motiv, 61: 5–29

PMID

16 Diamant Z, Spina D (2011). PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease. Pulm Pharmacol Ther, 24(4): 353–360

PMID

17 Fleischhacker W W H, Hinterhuber H, Bauer H, Pflug B, Berner P, Simhandl C, Wolf R, Gerlach W, Jaklitsch H, Sastre-y-Hernández M, Schmeding-Wiegel H, Sperner-Unterweger B, Voet B, Schubert H (1992). A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology, 26(1-2): 59–64

PMID

18 Franklin K M, Hauser S R, Lasek A W, McClintick J, Ding Z M, McBride W J, Bell R L (2015). Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). Psychopharmacology (Berl), 232(13): 2251–2262

PMID

19 Gisondi P, Girolomoni G (2016). Apremilast in the therapy of moderate-to-severe chronic plaque psoriasis. Drug Des Devel Ther, 10: 1763–1770

PMID

20 González-Cuello A, Sánchez L, Hernández J, Teresa Castells M, Victoria Milanés M, Laorden M L (2007). Phosphodiesterase 4 inhibitors, rolipram and diazepam block the adaptive changes observed during morphine withdrawal in the heart. Eur J Pharmacol, 570(1-3): 1–9

PMID

21 Graybiel A M (1990). Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci, 13(7): 244–254

PMID

22 Graybiel A M (2000). The basal ganglia. Curr Biol, 10(14): R509–R511

PMID

23 Grimm J W, Fyall A M, Osincup D P (2005). Incubation of sucrose craving: effects of reduced training and sucrose pre-loading. Physiol Behav, 84(1): 73–79

PMID

24 Grimm J W, Hope B T, Wise R A, Shaham Y (2001). Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature, 412(6843): 141–142

PMID

25 Hagen T J, Mo X, Burgin A B, Fox D 3rd, Zhang Z, Gurney M E (2014). Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorg Med Chem Lett, 24(16): 4031–4034

PMID

26 Hamdy M M, Mamiya T, Noda Y, Sayed M, Assi A A, 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(1): 85–93

PMID

27 Hansen R T 3rd, Zhang H T (2015). Phosphodiesterase-4 modulation as a potential therapeutic for cognitive loss in pathological and non-pathological aging: possibilities and pitfalls. Curr Pharm Des, 21(3): 291–302

PMID

28 Hiroi N, Nestler E J (1998). Nuclear memory: gene transcription and behavior. Adv Pharmacol, 42: 1037–1041

PMID

29 Horn C C, Kimball B A, Wang H, Kaus J, Dienel S, Nagy A, Gathright G R, Yates B J, Andrews P L (2013). Why can’t rodents vomit? A comparative behavioral, anatomical, and physiological study. PLoS ONE, 8(4): e60537

PMID

30 Howlett, A. C. (2005). “Cannabinoid receptor signaling.” Handb Exp Pharmacol(168): 53–79.

31 Hu W, Lu T, Chen A, Huang Y, Hansen R, Chandler L J, Zhang H T (2011). Inhibition of phosphodiesterase-4 decreases ethanol intake in mice. Psychopharmacology (Berl), 218(2): 331–339

PMID

32 Ikemoto S, Bonci A (2014). Neurocircuitry of drug reward. Neuropharmacology, 76 Pt B: 329–341

33 Itzhak Y, Anderson K L (2012). Changes in the magnitude of drug-unconditioned stimulus during conditioning modulate cocaine-induced place preference in mice. Addict Biol, 17(4): 706–716

PMID

34 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(2): 163–170

PMID

35 Janes A C, Kantak K M, Cherry J A (2009). The involvement of type IV phosphodiesterases in cocaine-induced sensitization and subsequent pERK expression in the mouse nucleus accumbens. Psychopharmacology (Berl), 206(2): 177–185

PMID

36 Johansson E M, Reyes-Irisarri E, Mengod G (2012). Comparison of cAMP-specific phosphodiesterase mRNAs distribution in mouse and rat brain. Neurosci Lett, 525(1): 1–6

PMID

37 Kauer J A (2004). Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu Rev Physiol, 66(1): 447–475

PMID

38 Kimura M, Tokumura M, Itoh T, Inoue O, Abe K (2006). Lack of cyclic AMP-specific phosphodiesterase 4 activation during naloxone-precipitated morphine withdrawal in rats. Neurosci Lett, 404(1-2): 107–111

PMID

39 Kimura S, Ohi Y, Haji A (2015). Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia. Life Sci, 127: 32–38

PMID

40 Knapp C M, Foye M M, Ciraulo D A, Kornetsky C (1999). The type IV phosphodiesterase inhibitors, Ro 20-1724 and rolipram, block the initiation of cocaine self-administration. Pharmacol Biochem Behav, 62(1): 151–158

PMID

41 Knapp C M, Lee K, Foye M, Ciraulo D A, 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(14): 1673–1682

PMID

42 Kuroiwa M, Snyder G L, Shuto T, Fukuda A, Yanagawa Y, Benavides D R, Nairn A C, Bibb J A, Greengard P, Nishi A (2012). Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology (Berl), 219(4): 1065–1079

PMID

43 Lai M, Zhu H, Sun A, Zhuang D, Fu D, Chen W, Zhang H T, Zhou W (2014). The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats. Int J Neuropsychopharmacol, 17(9): 1397–1407

PMID

44 Lakics V, Karran E H, Boess F G (2010). Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology, 59(6): 367–374

PMID

45 Lamontagne S, Meadows E, Luk P, Normandin D, Muise E, Boulet L, Pon D J, Robichaud A, Robertson G S, Metters K M, Nantel F (2001). Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey. Brain Res, 920(1-2): 84–96

PMID

46 Liddie S, Anderson K L, Paz A, Itzhak Y (2012). The effect of phosphodiesterase inhibitors on the extinction of cocaine-induced conditioned place preference in mice. J Psychopharmacol, 26(10): 1375–1382

PMID

47 Lim Y W, Meyer N P, Shah A S, Budde M D, Stemper B D, Olsen C M (2015). Voluntary Alcohol Intake following Blast Exposure in a Rat Model of Mild Traumatic Brain Injury. PLoS ONE, 10(4): e0125130

PMID

48 Liu X, Liu Y, Zhong P, Wilkinson B, Qi J, Olsen C M, Bayer K U, Liu Q S (2014). CaMKII activity in the ventral tegmental area gates cocaine-induced synaptic plasticity in the nucleus accumbens. Neuropsychopharmacology, 39(4): 989–999

PMID

49 Logrip M L (2015). Phosphodiesterase regulation of alcohol drinking in rodents. Alcohol, 49(8): 795–802

PMID

50 Logrip M L, Vendruscolo L F, Schlosburg J E, Koob G F, Zorrilla E P (2014). Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats. Neuropsychopharmacology, 39(7): 1722–1731

PMID

51 Lu L, Grimm J W, Hope B T, Shaham Y (2004). Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology, 47(Suppl 1): 214–226

PMID

52 Lugnier C (2006). Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther, 109(3): 366–398

PMID

53 MacKenzie S J, Houslay M D (2000). Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells. Biochem J, 347(Pt 2): 571–578

PMID

54 Mamiya T, Noda Y, Ren X, Hamdy M, Furukawa S, Kameyama T, Yamada K, Nabeshima T (2001). Involvement of cyclic AMP systems in morphine physical dependence in mice: prevention of development of morphine dependence by rolipram, a phosphodiesterase 4 inhibitor. Br J Pharmacol, 132(5): 1111–1117

PMID

55 Mantsch J R, Baker D A, Funk D, Lê A D, Shaham Y (2016). Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress. Neuropsychopharmacology, 41(1): 335–356

PMID

56 McGirr A, Lipina T V, Mun H S, Georgiou J, Al-Amri A H, Ng E, Zhai D, Elliott C, Cameron R T, Mullins J G, Liu F, Baillie G S, Clapcote S J, Roder J C (2016). Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition. Neuropsychopharmacology, 41(4): 1080–1092

PMID

57 Mori F, Pérez-Torres S, De Caro R, Porzionato A, Macchi V, Beleta J, Gavaldà A, Palacios J M, 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(1): 36–42

PMID

58 Mori T, Baba J, Ichimaru Y, Suzuki T (2000). Effects of rolipram, a selective inhibitor of phosphodiesterase 4, on hyperlocomotion induced by several abused drugs in mice. Jpn J Pharmacol, 83(2): 113–118

PMID

59 Muelbl M J,Nawarawong N N, Clancy P T, Nettesheim C E, Lim Y W,Olsen C M (2016). Responses to drugs of abuse and non-drug rewards in leptin deficient ob/ob mice. Psychopharmacology (Berl),233(14):2799–2811

60 Mulhall A M, Droege C A, Ernst N E, Panos R J, Zafar M A (2015). Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs. Expert Opin Investig Drugs, 24(12): 1597–1611

PMID

61 Muschamp J W, Carlezon W A Jr (2013). Roles of nucleus accumbens CREB and dynorphin in dysregulation of motivation. Cold Spring Harb Perspect Med, 3(2): a012005

PMID

62 Naganuma K, Omura A, Maekawara N, Saitoh M, Ohkawa N, Kubota T, Nagumo H, Kodama T, Takemura M, Ohtsuka Y, Nakamura J, Tsujita R, Kawasaki K, Yokoi H, Kawanishi M (2009). Discovery of selective PDE4B inhibitors. Bioorg Med Chem Lett, 19(12): 3174–3176

PMID

63 Negus S S, Miller L L (2014). Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev, 66(3): 869–917

PMID

64 Nestler E J (2015). Reflections on: “A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res

PMID

65 Nishi A, Kuroiwa M, Miller D B, O’Callaghan J P, Bateup H S, Shuto T, Sotogaku N, Fukuda T, Heintz N, Greengard P, Snyder G L (2008). Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci, 28(42): 10460–10471

PMID

66 Núñez C, González-Cuello A, Sánchez L, Vargas M L, Milanés M V, Laorden M L (2009). Effects of rolipram and diazepam on the adaptive changes induced by morphine withdrawal in the hypothalamic paraventricular nucleus. Eur J Pharmacol, 620(1-3): 1–8

PMID

67 O’Donnell J M, Zhang H T (2004). Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci, 25(3): 158–163

PMID

68 Olsen C M, Childs D S, Stanwood G D, Winder D G (2010). Operant sensation seeking requires metabotropic glutamate receptor 5 (mGluR5). PLoS ONE, 5(11): e15085

PMID

69 Olsen C M, Winder D G (2006). A method for single-session cocaine self-administration in the mouse. Psychopharmacology (Berl), 187(1): 13–21

PMID

70 Page C P, Spina D (2012). Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol, 12(3): 275–286

PMID

71 Pan B, Hillard C J, Liu Q S (2008). D2 dopamine receptor activation facilitates endocannabinoid-mediated long-term synaptic depression of GABAergic synaptic transmission in midbrain dopamine neurons via cAMP-protein kinase A signaling. J Neurosci, 28(52): 14018–14030

PMID

72 Pan B, Hillard C J, Liu Q S (2008). Endocannabinoid signaling mediates cocaine-induced inhibitory synaptic plasticity in midbrain dopamine neurons. J Neurosci, 28(6): 1385–1397

PMID

73 Pan B, Zhong P, Sun D, Liu Q S (2011). Extracellular signal-regulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects. J Neurosci, 31(31): 11244–11255

PMID

74 Pérez-Cadahía B, Drobic B, Davie J R (2011). Activation and function of immediate-early genes in the nervous system. Biochem Cell Biol, 89(1): 61–73

PMID

75 Pérez-Torres S, Miró X, Palacios J M, Cortés R, Puigdoménech 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(3-4): 349–374

PMID

76 Pierce R C, Kalivas P W (1997). A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev, 25(2): 192–216

PMID

77 Richter W, Menniti F S, Zhang H T, Conti M (2013). PDE4 as a target for cognition enhancement. Expert Opin Ther Targets, 17(9): 1011–1027

PMID

78 Robichaud A, Stamatiou P B, Jin S L, Lachance N, MacDonald D, Laliberté F, Liu S, Huang Z, Conti M, Chan C C (2002). Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest, 110(7): 1045–1052

PMID

79 Robinson T E, Berridge K C (1993). The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev, 18(3): 247–291

PMID

80 Robinson T E, Berridge K C (2008). Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond B Biol Sci, 363(1507): 3137–3146

PMID

81 Rodd Z A, Bell R L, Sable H J, Murphy J M, McBride W J (2004). Recent advances in animal models of alcohol craving and relapse. Pharmacol Biochem Behav, 79(3): 439–450

PMID

82 Schroeder J A, Ruta J D, Gordon J S, Rodrigues A S, Foote C C (2012). The phosphodiesterase inhibitor isobutylmethylxanthine attenuates behavioral sensitization to cocaine. Behav Pharmacol, 23(3): 310–314

PMID

83 Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003). The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl), 168(1-2): 3–20

PMID

84 Siuciak J A, McCarthy S A, Chapin D S, Martin A N (2008). Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl), 197(1): 115–126

PMID

85 Snider S E, Hendrick E S, Beardsley P M (2013). Glial cell modulators attenuate methamphetamine self-administration in the rat. Eur J Pharmacol, 701(1-3): 124–130

PMID

86 Snider S E, Vunck S A, van den Oord E J, Adkins D E, McClay J L, Beardsley P M (2012). The glial cell modulators, ibudilast and its amino analog, AV1013, attenuate methamphetamine locomotor activity and its sensitization in mice. Eur J Pharmacol, 679(1-3): 75–80

PMID

87 Stolerman I P, Childs E, Ford M M, Grant K A (2011). Role of training dose in drug discrimination: a review. Behav Pharmacol, 22(5-6): 415–429

PMID

88 Sun A, Zhuang D, Zhu H, Lai M, Chen W, Liu H, Zhang F, Zhou W (2015). Decrease of phosphorylated CREB and ERK in nucleus accumbens is associated with the incubation of heroin seeking induced by cues after withdrawal. Neurosci Lett, 591: 166–170

PMID

89 Thompson B E, Sachs B D, Kantak K M, Cherry J A (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(9): 2561–2568

PMID

90 Thomsen M, Caine S B (2005). Chronic intravenous drug self-administration in rats and mice. Curr Protoc Neurosci, 32:9.20:9.20.1–9.20.40

91 Todd T P, Vurbic D, Bouton M E (2014). Behavioral and neurobiological mechanisms of extinction in Pavlovian and instrumental learning. Neurobiol Learn Mem, 108: 52–64

PMID

92 Tzschentke T M (2007). Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol, 12(3-4): 227–462

PMID

93 Wang Z Z, Zhang Y, Zhang H T, Li Y F (2015). Phosphodiesterase: an interface connecting cognitive deficits to neuropsychiatric and neurodegenerative diseases. Curr Pharm Des, 21(3): 303–316

PMID

94 Wen R T, Feng W Y, Liang J H, Zhang H T (2015). Role of phosphodiesterase 4-mediated cyclic AMP signaling in pharmacotherapy for substance dependence. Curr Pharm Des, 21(3): 355–364

PMID

95 Wen R T, Zhang M, Qin W J, Liu Q, Wang W P, Lawrence A J, Zhang H T, Liang J H (2012). The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring Fawn-Hooded rats. Alcohol Clin Exp Res, 36(12): 2157–2167

PMID

96 Yan Y, Nitta A, Mizuno T, Nakajima A, Yamada K, Nabeshima T (2006). Discriminative-stimulus effects of methamphetamine and morphine in rats are attenuated by cAMP-related compounds. Behav Brain Res, 173(1): 39–46

PMID

97 Young R (2009). Drug Discrimination. In: Buccafusco J J, editor. Source Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis

98 Zhang H T (2009). Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des, 15(14): 1688–1698

PMID

99 Zhang H T, Huang Y, Masood A, Stolinski L R, Li Y, Zhang L, Dlaboga D, Jin S L, Conti M, O’Donnell J M (2008). Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology, 33(7): 1611–1623

PMID

100 Zhong P, Wang W, Yu F, Nazari M, Liu X, Liu Q S (2012). Phosphodiesterase 4 inhibition impairs cocaine-induced inhibitory synaptic plasticity and conditioned place preference. Neuropsychopharmacology, 37(11): 2377–2387