Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

PDE4 inhibitor rolipram dynamically regulates the balance between D1-MSNs and D2-MSNs in the DMS to modulate abnormal “Go” behavior associated with alcohol addiction

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Addiction is a chronic relapsing disorder characterized by compulsive seeking and consumption of drugs, with this abnormal “Go” behavior resulting in significant negative consequences. Research has shown that the dorsal medial striatum (DMS) is associated with the pathophysiological mechanisms of addiction; however, drugs targeting the DMS to achieve therapeutic effects for addiction remain unavailable. Intracellular cAMP signaling, regulated by G protein–coupled receptors (GPCRs), critically modulates the excitability, plasticity and neurotransmission of GABAergic medium spiny neurons (MSNs). In this study we investigated how inhibition of PDE4 modulated cAMP levels with a specific focus on how these changes influenced the dopamine D1 receptor MSNs (D1-MSNs) and D2 receptor MSNs (D2-MSNs) in the DMS, thereby influencing abnormal “Go” behavior. We established alcohol-induced conditioned place preference (CPP) model and two-bottle choice drinking model in mice. PDE4 inhibitor rolipram (0.5 μg) were bilaterally microinjected into the DMS of mice 2 h prior to the combination of alcohol. The activation of D1-MSNs and D2-MSNs in the DMS was assayed using c-Fos immunofluorescence staining. We showed that rolipram microinjection significantly increased cAMP levels in MSNs of the DMS and restored the activation balance between D1-MSNs and D2-MSNs. This rebalancing of MSN activity attenuated abnormal “Go” behaviors including high-drinking behavior. We further identified the ERK signaling downstream of cAMP in D2-MSNs of the DMS, together with the PDE4 subtype PDE4B, as key mediators of the inhibitory effects of PDE4 inhibitors on high-drinking behavior. These results highlight a new strategy emphasizing the pivotal role of PDE4 as a key regulator of cAMP signaling in MSNs, maintaining the dynamic balance between D1-MSNs and D2-MSNs, and further identify D2-MSNs specific PDE4B/cAMP/ERK modulation as a promising target for addiction treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Inhibition of PDE4 activates cAMP signaling of D1-MSNs and D2-MSNs in the DMS.
Fig. 2: Inhibition of PDE4 reverses abnormal “Go” behavior by balancing the activation of D1-MSNs and D2-MSNs in the DMS.
Fig. 3: Inhibition of PDE4 enhances cAMP signaling of MSNs in the DMS to prevent abnormal “Go” behavior.
Fig. 4: Inhibition of PDE4 inhibits high-drinking behavior by balancing the activation of D1-MSNs and D2-MSNs in the DMS.
Fig. 5: Inhibition of PDE4 enhances cAMP signaling of MSNs in the DMS to inhibit high-drinking behavior.
Fig. 6: ERK in D2-MSNs is a key factor to inhibit high-drinking behavior by PDE4 inhibitor in the DMS.
Fig. 7: PDE4 subtype PDE4B in D2-MSNs is involved in the regulation of high-drinking behavior.

Similar content being viewed by others

References

  1. Chamberlain SR, Lochner C, Stein DJ, Goudriaan AE, van Holst RJ, Zohar J, et al. Behavioural addiction-A rising tide. Eur Neuropsychopharmacol. 2016;26:841–55.

    Article  CAS  PubMed  Google Scholar 

  2. Christian DT, Alexander NJ, Diaz MR, Robinson S, McCool BA. Chronic intermittent ethanol and withdrawal differentially modulate basolateral amygdala AMPA-type glutamate receptor function and trafficking. Neuropharmacology. 2012;62:2430–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nimitvilai S, Lopez MF, Mulholland PJ, Woodward JJ. Chronic intermittent ethanol exposure enhances the excitability and synaptic plasticity of lateral orbitofrontal cortex neurons and induces a tolerance to the acute inhibitory actions of ethanol. Neuropsychopharmacology. 2016;41:1112–27.

    Article  CAS  PubMed  Google Scholar 

  4. Jeanes ZM, Buske TR, Morrisett RA. Cell type-specific synaptic encoding of ethanol exposure in the nucleus accumbens shell. Neuroscience. 2014;277:184–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zorumski CF, Mennerick S, Izumi Y. Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol. 2014;48:1–17.

    Article  CAS  PubMed  Google Scholar 

  6. Egli M. Advancing pharmacotherapy development from preclinical animal studies. Handb Exp Pharmacol. 2018;248:537–78.

    Article  PubMed  Google Scholar 

  7. Akbar M, Egli M, Cho YE, Song BJ, Noronha A. Medications for alcohol use disorders: An overview. Pharmacol Ther. 2018;185:64–85.

    Article  CAS  PubMed  Google Scholar 

  8. da Silva D, Matsui A, Murray EM, Mamais A, Authement ME, Shin JH, et al. Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking. Neuropsychopharmacology. 2024;49:824–36.

    Article  PubMed  Google Scholar 

  9. Peak J, Hart G, Balleine BW. From learning to action: the integration of dorsal striatal input and output pathways in instrumental conditioning. Eur J Neurosci. 2019;49:658–71.

    Article  PubMed  Google Scholar 

  10. Zillich L, Poisel E, Frank J, Foo JC, Friske MM, Streit F, et al. Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum. Transl Psychiatry. 2022;12:190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Balleine BW, O’Doherty JP. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology. 2010;35:48–69.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ehinger Y, Morisot N, Phamluong K, Sakhai SA, Soneja D, Adrover MF, et al. cAMP-Fyn signaling in the dorsomedial striatum direct pathway drives excessive alcohol use. Neuropsychopharmacology. 2021;46:334–42.

    Article  CAS  PubMed  Google Scholar 

  13. Shaw JK, Pamela Alonso I, Lewandowski SI, Scott MO, O’Connor BM, Aggarwal S, et al. Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats. Neuropsychopharmacology. 2021;46:1757–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang J, Ben Hamida S, Darcq E, Zhu W, Gibb SL, Lanfranco MF, et al. Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior. J Neurosci. 2012;32:15124–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Maia TV, Frank MJ. From reinforcement learning models to psychiatric and neurological disorders. Nat Neurosci. 2011;14:154–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 2011;34:441–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lobo MK, Covington HE, Chaudhury D, Friedman AK, Sun H, Damez-Werno D, et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science. 2010;330:385–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chandra R, Lenz JD, Gancarz AM, Chaudhury D, Schroeder GL, Han M-H, et al. Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1. Front Mol Neurosci. 2013;6:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Durieux PF, Bearzatto B, Guiducci S, Buch T, Waisman A, Zoli M, et al. D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci. 2009;12:393–5.

    Article  CAS  PubMed  Google Scholar 

  20. Ferguson SM, Eskenazi D, Ishikawa M, Wanat MJ, Phillips PEM, Dong Y, et al. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci. 2011;14:22–4.

    Article  CAS  PubMed  Google Scholar 

  21. Cheng Y, Huang CCY, Ma T, Wei X, Wang X, Lu J, et al. Distinct synaptic strengthening of the striatal direct and indirect pathways drives alcohol consumption. Biol Psychiatry. 2017;81:918–29.

    Article  CAS  PubMed  Google Scholar 

  22. Dai KZ, Choi IB, Levitt R, Blegen MB, Kaplan AR, Matsui A, et al. Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward. Cell Rep. 2022;40:111440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang J, Lanfranco MF, Gibb SL, Yowell QV, Carnicella S, Ron D. Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse. J Neurosci. 2010;30:10187–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nagai T, Yoshimoto J, Kannon T, Kuroda K, Kaibuchi K. Phosphorylation signals in striatal medium spiny neurons. Trends Pharmacol Sci. 2016;37:858–71.

    Article  CAS  PubMed  Google Scholar 

  25. Muntean BS, Dao MT, Martemyanov KA. Allostatic changes in the cAMP system drive opioid-induced adaptation in striatal dopamine signaling. Cell Rep. 2019;29:946–960.e2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Morales-Figueroa G-E, Rivera-Ramírez N, González-Pantoja R, Escamilla-Sánchez J, García-Hernández U, Galván EJ, et al. Adenosine A2A and histamine H3 receptors interact at the cAMP/PKA pathway to modulate depolarization-evoked [3H]-GABA release from rat striato-pallidal terminals. Purinergic Signal. 2019;15:85–93.

    Article  CAS  PubMed  Google Scholar 

  27. Jijón-Lorenzo R, Caballero-Florán IH, Recillas-Morales S, Cortés H, Avalos-Fuentes JA, Paz-Bermúdez FJ, et al. Presynaptic dopamine D2 receptors modulate [3H]GABA release at StriatoPallidal terminals via activation of PLC→IP3→calcineurin and inhibition of AC→cAMP→PKA signaling cascades. Neuroscience. 2018;372:74–86.

    Article  PubMed  Google Scholar 

  28. Wallace DL, Han M-H, Graham DL, Green TA, Vialou V, Iñiguez SD, et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci. 2009;12:200–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lobo MK. Molecular profiling of striatonigral and striatopallidal medium spiny neurons past, present, and future. Int Rev Neurobiol. 2009;89:1–35.

    Article  CAS  PubMed  Google Scholar 

  30. Dinieri JA, Nemeth CL, Parsegian A, Carle T, Gurevich VV, Gurevich E, et al. Altered sensitivity to rewarding and aversive drugs in mice with inducible disruption of cAMP response element-binding protein function within the nucleus accumbens. J Neurosci. 2009;29:1855–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hutton SR, Otis JM, Kim EM, Lamsal Y, Stuber GD, Snider WD. ERK/MAPK signaling is required for pathway-specific striatal motor functions. J Neurosci. 2017;37:8102–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Urs NM, Snyder JC, Jacobsen JPR, Peterson SM, Caron MG. Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci USA. 2012;109:20732–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dong Y, Green T, Saal D, Marie H, Neve R, Nestler EJ, et al. CREB modulates excitability of nucleus accumbens neurons. Nat Neurosci. 2006;9:475–7.

    Article  CAS  PubMed  Google Scholar 

  34. Soderling SH, Beavo JA. Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol. 2000;12:174–9.

    Article  CAS  PubMed  Google Scholar 

  35. Cherry JA, Davis RL. Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol. 1999;407:287–301.

    Article  CAS  PubMed  Google Scholar 

  36. O’Donnell JM, Zhang HT. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci. 2004;25:158–63.

    Article  PubMed  Google Scholar 

  37. Blednov YA, Benavidez JM, Black M, Harris RA. Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci. 2014;8:129.

  38. Hu W, Lu T, Chen A, Huang Y, Hansen R, Chandler LJ, et al. Inhibition of phosphodiesterase-4 decreases ethanol intake in mice. Psychopharmacology (Berl). 2011;218:331–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu X, Zhong P, Vickstrom C, Li Y, Liu QS. PDE4 inhibition restores the balance between excitation and inhibition in VTA dopamine neurons disrupted by repeated in vivo cocaine exposure. Neuropsychopharmacology. 2017;42:1991–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thompson BE, Sachs BD, Kantak KM, Cherry JA. The Type IV phosphodiesterase inhibitor rolipram interferes with drug-induced conditioned place preference but not immediate early gene induction in mice. Eur J Neurosci. 2004;19:2561–8.

    Article  PubMed  Google Scholar 

  41. Wen RT, Zhang M, Qin WJ, Liu Q, Wang WP, Lawrence AJ, et al. The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring Fawn-Hooded rats. Alcohol Clin Exp Res. 2012;36:2157–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Franklin KM, Hauser SR, Lasek AW, McClintick J, Ding Z-M, McBride WJ, et al. Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). Psychopharmacology (Berl). 2015;232:2251–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jimenez Chavez CL, Bryant CD, Munn-Chernoff MA, Szumlinski KK. Selective inhibition of PDE4B reduces binge drinking in two C57BL/6 substrains. Int J Mol Sci. 2021;22:5443.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ferraro L, Frankowska M, Marcellino D, Zaniewska M, Beggiato S, Filip M, et al. A novel mechanism of cocaine to enhance dopamine d2-like receptor mediated neurochemical and behavioral effects. An in vivo and in vitro study. Neuropsychopharmacology. 2012;37:1856–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dobbs LK, Kaplan AR, Bock R, Phamluong K, Shin JH, Bocarsly ME, et al. D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors. Neuropsychopharmacology. 2019;44:805–16.

    Article  CAS  PubMed  Google Scholar 

  46. Bocarsly ME, da Silva E Silva D, Kolb V, Luderman KD, Shashikiran S, Rubinstein M, et al. A mechanism linking two known vulnerability factors for alcohol abuse: heightened alcohol stimulation and low striatal dopamine D2 receptors. Cell Rep. 2019;29:1147–1163.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Agoglia AE, Sharko AC, Psilos KE, Holstein SE, Reid GT, Hodge CW. Alcohol alters the activation of ERK1/2, a functional regulator of binge alcohol drinking in adult C57BL/6J mice. Alcohol Clin Exp Res. 2015;39:463–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhong P, Wang W, Yu F, Nazari M, Liu X, Liu QS. Phosphodiesterase 4 inhibition impairs cocaine-induced inhibitory synaptic plasticity and conditioned place preference. Neuropsychopharmacology. 2012;37:2377–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Juarez B, Morel C, Ku SM, Liu Y, Zhang H, Montgomery S, et al. Midbrain circuit regulation of individual alcohol drinking behaviors in mice. Nat Commun. 2017;8:2220.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Lei J, Zhang P, Li T, Cui C, Li M, Yang X, et al. Alternating bilateral sensory stimulation alleviates alcohol-induced conditioned place preference via a superior colliculus-VTA circuit. Cell Rep. 2024;43:114383.

    Article  CAS  PubMed  Google Scholar 

  51. Wang J, Liang M, Shang Q, Qian H, An R, Liu H, et al. Psilocin suppresses methamphetamine-induced hyperlocomotion and acquisition of conditioned place preference via D2R-mediated ERK signaling. CNS Neurosci Ther. 2023;29:831–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu MY, Yin CY, Zhu LJ, Zhu XH, Xu C, Luo CX, et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat Protoc. 2018;13:1686–98.

    Article  CAS  PubMed  Google Scholar 

  53. Barrio-Alonso E, Lituma PJ, Notaras MJ, Albero R, Bouchekioua Y, Wayland N, et al. Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling. Cell Rep. 2023;42:112375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fasano S, Pittenger C, Brambilla R. Inhibition of CREB activity in the dorsal portion of the striatum potentiates behavioral responses to drugs of abuse. Front Behav Neurosci. 2009;3:29.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Shiflett MW, Balleine BW. Contributions of ERK signaling in the striatum to instrumental learning and performance. Behav Brain Res. 2011;218:240–7.

    Article  CAS  PubMed  Google Scholar 

  56. Kranzler HR. Overview of alcohol use disorder. Am J Psychiatry. 2023;180:565–72.

    Article  PubMed  Google Scholar 

  57. Faccidomo S, Besheer J, Stanford PC, Hodge CW. Increased operant responding for ethanol in male C57BL/6J mice: specific regulation by the ERK1/2, but not JNK, MAP kinase pathway. Psychopharmacology (Berl). 2009;204:135–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hagen TJ, Mo X, Burgin AB, Fox D, Zhang Z, Gurney ME. Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorg Med Chem Lett. 2014;24:4031–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fox D, Burgin AB, Gurney ME. Structural basis for the design of selective phosphodiesterase 4B inhibitors. Cell Signal. 2014;26:657–63.

    Article  CAS  PubMed  Google Scholar 

  60. Zhao Z-D, Han X, Chen R, Liu Y, Bhattacherjee A, Chen W, et al. A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction. Sci Adv. 2022;8:eabn3552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lobo MK, Nestler EJ. The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons. Front Neuroanat. 2011;5:41.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Li Z, Li J, Wei Y, Zou W, Vidjro OE, Wang J, et al. Anterior and posterior basolateral amygdala projections of cell type-specific D1-expressing neurons from the medial prefrontal cortex differentially control alcohol-seeking behavior. Biol Psychiatry. 2023;S0006-3223:01698–0.

    Google Scholar 

  63. Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology. 2009;56:3–8.

    Article  CAS  PubMed  Google Scholar 

  64. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85:5274–8.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Volkow ND, Morales M. The brain on drugs: from reward to addiction. Cell. 2015;162:712–25.

    Article  CAS  PubMed  Google Scholar 

  66. Cui S, Wang S, Li J, Xie G, Zhou R, Chen L, et al. Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway. Acta Pharmacol Sin. 2011;32:175–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhu Y, Wang Y, Zhao B, Wei S, Xu M, Liu E, et al. Differential phosphorylation of GluN1-MAPKs in rat brain reward circuits following long-term alcohol exposure. PLoS One. 2013;8:e54930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tecuapetla F, Koós T, Tepper JM, Kabbani N, Yeckel MF. Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals. J Neurosci. 2009;29:8977–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Giembycz MA. 4D or not 4D - the emetogenic basis of PDE4 inhibitors uncovered?. Trends Pharmacol Sci. 2002;23:548.

    Article  CAS  PubMed  Google Scholar 

  70. Fatemi SH, King DP, Reutiman TJ, Folsom TD, Laurence JA, Lee S, et al. PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res. 2008;101:36–49.

    Article  PubMed  Google Scholar 

  71. Rutten K, Wallace TL, Works M, Prickaerts J, Blokland A, Novak TJ, et al. Enhanced long-term depression and impaired reversal learning in phosphodiesterase 4B-knockout (PDE4B-/-) mice. Neuropharmacology. 2011;61:138–47.

    Article  CAS  PubMed  Google Scholar 

  72. Logrip ML, Vendruscolo LF, Schlosburg JE, Koob GF, Zorrilla EP. Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats. Neuropsychopharmacology. 2014;39:1722–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, et al. Immunohistochemical localization of PDE10A in the rat brain. Brain Res. 2003;985:113–26.

    Article  CAS  PubMed  Google Scholar 

  74. Nawrocki AR, Rodriguez CG, Toolan DM, Price O, Henry M, Forrest G, et al. Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance. Diabetes. 2014;63:300–11.

    Article  CAS  PubMed  Google Scholar 

  75. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012;148:421–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li J, Zhou Y, Yin F, Du Y, Xu J, Fan S, et al. The orbitofrontal cortex to striatal cholinergic interneuron circuit controls cognitive flexibility shaping alcohol-seeking behavior. Biol Psychiatry. 2025;97:614–26.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by National Natural Science Foundation of China (82301679), Key Program of Brain Science and Brain-Like Intelligence Technology of the China Ministry of Science and Technology (STI2030-Major Projects 2021ZD0202900), Taishan Scholar Young Talent Program (tsqn202312172), China Postdoctoral Science Foundation (2024T170449), Natural Science Foundation of Shandong Province (ZR2023QH444), Key Project by Qingdao Bureau of Sciences and Technology (22-3-3-hygg-25-hy), and Qingdao Postdoctoral Applied Research Project (QDBSH20230102104).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266071, China

    Wei Zhao, Shuang Zhao, Zi-qi Wang, Xiao-fei Chen, Fang-jiao Zong & Han-ting Zhang

  2. School of Pharmacy, Nanchang University, Nanchang, 330006, China

    Han-ting Zhang

Authors
  1. Wei Zhao
    View author publications

    Search author on:PubMed Google Scholar

  2. Shuang Zhao
    View author publications

    Search author on:PubMed Google Scholar

  3. Zi-qi Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Xiao-fei Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. Fang-jiao Zong
    View author publications

    Search author on:PubMed Google Scholar

  6. Han-ting Zhang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

WZ, FJZ, and HTZ designed research; WZ and SZ performed research; WZ, ZQW, and XFZ analyzed data; WZ wrote the original manuscript; FJZ and HTZ reviewed and edited the manuscript; FJZ and HTZ provide funding.

Corresponding authors

Correspondence to Fang-jiao Zong or Han-ting Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, W., Zhao, S., Wang, Zq. et al. PDE4 inhibitor rolipram dynamically regulates the balance between D1-MSNs and D2-MSNs in the DMS to modulate abnormal “Go” behavior associated with alcohol addiction. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01738-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41401-025-01738-w

Keywords

Search

Advanced search

Quick links