Skip to main content

Advertisement

SpringerLink
Log in

Effects of chronic voluntary alcohol consumption on PDE10A availability: a longitudinal behavioral and [18F]JNJ42259152 PET study in rats

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

A Correction to this article was published on 14 May 2022

This article has been updated

Abstract

Purpose

Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme highly enriched in dopamine-receptive striatal medium spiny neurons, which are involved in psychiatric disorders such as alcohol use disorders (AUD). Although preclinical studies suggest a correlation of PDE10A mRNA expression in neuronal and behavioral responses to alcohol intake, little is known about the effects of alcohol exposure on in vivo PDE10A activity in relation to apparent risk factors for AUD such as decision-making and anxiety.

Methods

We performed a longitudinal [18F]JNJ42259152 microPET study to evaluate PDE10A changes over a 9-week intermittent access to alcohol model, including 6 weeks of alcohol exposure, 2 weeks of abstinence followed by 1 week relapse. Parametric PDE10A-binding potential (BPND) images were generated using a Logan reference tissue model with cerebellum as reference region and were analyzed using both a volume-of-interest and voxel-based approach. Moreover, individual decision-making and anxiety levels were assessed with the rat Iowa Gambling Task and open-field test over the IAE model.

Results

We observed an increased alcohol preference especially in those animals that exhibited poor initial decision-making. The first 2 weeks of alcohol exposure resulted in an increased striatal PDE10A binding (> 10%). Comparing PDE10A-binding potential after 2 versus 4 weeks of exposure showed a significant decreased PDE10A in the caudate-putamen and nucleus accumbens (pFWE-corrected < 0.05). This striatal PDE10A decrease was related to alcohol consumption and preference. Normalization of striatal PDE10A to initial levels was observed after 1 week of relapse, apart from the globus pallidus.

Conclusion

This study shows that chronic voluntary alcohol consumption induces a reversible increased PDE10A enzymatic availability in the striatum, which is related to the amount of alcohol preference. Thus, PDE10A-mediated signaling plays an important role in modulating the reinforcing effects of alcohol, and the data suggest that PDE10A inhibition may have beneficial behavioral effects on alcohol intake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability of data and materials

Please contact the authors for data request.

Change history

Abbreviations

AUD:

Alcohol use disorders

BP:

Binding potential

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

D1:

Dopamine receptor type 1

D2:

Dopamine receptor type 2

IAE:

Intermittent access to ethanol

MSNs:

Medium spiny neurons

NuAc:

Nucleus accumbens

OFT:

Open-field test

PDE:

Phosphodiesterase

PDE10A:

Phosphodiesterase 10A

rIGT:

Rat Iowa Gambling Task

VOI:

Volumes of interest

References

  1. Leurquin-Sterk G, Ceccarini J, Crunelle CL, Weerasekera A, de Laat B, Himmelreich U, et al. Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study. Addict Biol. 2018;23:931–44.

    Article  CAS  PubMed  Google Scholar 

  2. de Laat B, Weerasekera A, Leurquin-Sterk G, Gsell W, Bormans G, Himmelreich U, et al. Effects of alcohol exposure on the glutamatergic system: a combined longitudinal 18 F-FPEB and 1 H-MRS study in rats. Addic Biol. 2019;24:696–706.

    Article  CAS  Google Scholar 

  3. Xiao C, Ye JH. Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: role of μ-opioid receptors. Neuroscience. 2008;153:240–8.

    Article  CAS  PubMed  Google Scholar 

  4. Logrip ML. Phosphodiesterase regulation of alcohol drinking in rodents. Alcohol. 2015;49:795–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sanderson TM, Sher E. The role of phosphodiesterases in hippocampal synaptic plasticity. Neuropharmacology. 2013;74:86–95.

    Article  CAS  PubMed  Google Scholar 

  6. García-Barroso C, Ugarte A, Martínez M, Rico AJ, Lanciego JL, Franco R, et al. Phosphodiesterase inhibition in cognitive decline. J Alzheimers Dis. 2014;42:S561–73.

    Article  PubMed  CAS  Google Scholar 

  7. Peng S, Sun H, Zhang X, Liu G, Wang G. Effects of selective phosphodiesterases-4 inhibitors on learning and memory: a review of recent research. Cell Biochem Biophys. 2014;70:83–5.

    Article  CAS  PubMed  Google Scholar 

  8. Kranz K, Warnecke A, Lenarz T, Durisin M, Scheper V. Phosphodiesterase type 4 Inhibitor rolipram improves survival of spiral ganglion neurons in vitro. Sokolowski B, editor. PLoS One. 2014;9:e92157.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wilson L, Brandon N. Emerging Biology of PDE10A. Curr Pharm Des. 2014;21:378–88.

    Article  CAS  Google Scholar 

  10. 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 

  11. Jäger R, Russwurm C, Schwede F, Genieser H-G, Koesling D, Russwurm M. Activation of PDE10 and PDE11 phosphodiesterases. The Journal of biological chemistry. J Biol Chem. 2012;287:1210–9.

    Article  PubMed  CAS  Google Scholar 

  12. Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE. cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11. The Journal of biological chemistry. J Biol Chem. 2006;281:2841–6.

    Article  CAS  PubMed  Google Scholar 

  13. Nishi A, Kuroiwa M, Miller DB, O’Callaghan JP, Bateup HS, Shuto T, et al. Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci. 2008;28:10460–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dlaboga D, Hajjhussein H, O’Donnell JM. Chronic haloperidol and clozapine produce different patterns of effects on phosphodiesterase-1B, -4B, and -10A expression in rat striatum. Neuropharmacol. 2008;54:745–54.

    Article  CAS  Google Scholar 

  15. Giorgi M, Melchiorri G, Nuccetelli V, D’Angelo V, Martorana A, Sorge R, et al. PDE10A and PDE10A-dependent cAMP catabolism are dysregulated oppositely in striatum and nucleus accumbens after lesion of midbrain dopamine neurons in rat: a key step in parkinsonism physiopathology. Neurobiol Dis. 2011;43:293–303.

    Article  CAS  PubMed  Google Scholar 

  16. Ooms M, Celen S, De Hoogt R, Lenaerts I, Liebregts J, Vanhoof G, et al. Striatal phosphodiesterase 10A availability is altered secondary to chronic changes in dopamine neurotransmission. EJNMMI Radiopharm Chem. 2017;1:3.

    Article  PubMed  Google Scholar 

  17. Niccolini F, Foltynie T, Reis Marques T, Muhlert N, Tziortzi AC, Searle GE, et al. Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson’s disease. Brain. 2015;138:3003–15.

    Article  PubMed  Google Scholar 

  18. Pagano G, Niccolini F, Wilson H, Yousaf T, Khan NL, Martino D, et al. Comparison of phosphodiesterase 10A and dopamine transporter levels as markers of disease burden in early Parkinson’s disease. Movement Disord. 2019;34:1505–15.

    Article  CAS  PubMed  Google Scholar 

  19. Beaumont V, Zhong S, Lin H, Xu W, Bradaia A, Steidl E, et al. Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models. Neuron. 2016;92:1220–37.

    Article  CAS  PubMed  Google Scholar 

  20. Wilson H, Niccolini F, Haider S, Marques TR, Pagano G, Coello C, et al. Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington’s disease gene carriers. J Neurol Sci. 2016;368:243–8.

    Article  CAS  PubMed  Google Scholar 

  21. Koole M, Van Laere K, Ahmad R, Ceccarini J, Bormans G, Vandenberghe W. Brain PET imaging of phosphodiesterase 10A in progressive supranuclear palsy and Parkinson’s disease. Movement Disord. 2017;32:943–5.

    Article  PubMed  Google Scholar 

  22. Ahmad R, Bourgeois S, Postnov A, Schmidt ME, Bormans G, Van Laere K, et al. PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology. 2014;82:279–81.

    Article  PubMed  Google Scholar 

  23. Persson J, Szalisznyó K, Antoni G, Wall A, Fällmar D, Zora H, et al. Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study. Eur Arch Psychiatry Clin Neurosci. 2020;270:451–9.

    Article  PubMed  Google Scholar 

  24. Bodén R, Persson J, Wall A, Lubberink M, Ekselius L, Larsson E-M, et al. Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study. Transl Psychiatry. 2017;7:e1050.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Chappie T, Humphrey J, Menniti F, Schmidt C. PDE10A inhibitors: an assessment of the current CNS drug discovery landscape. Curr Opin Drug Discov Devel. 2009;12:458–67.

    CAS  PubMed  Google Scholar 

  26. Mu Y, Ren Z, Jia J, Gao B, Zheng L, Wang G, et al. Inhibition of phosphodiesterase10A attenuates morphine-induced conditioned place preference. Mol Brain. 2014;7:70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Liddie S, Anderson KL, Paz A, Itzhak Y. The effect of phosphodiesterase inhibitors on the extinction of cocaine-induced conditioned place preference in mice. J Psychopharmacol. 2012;26:1375–82.

    Article  CAS  PubMed  Google Scholar 

  28. Logrip ML, Zorrilla EP. Stress history increases alcohol intake in relapse: relation to phosphodiesterase 10A. Addict Biol. 2012;17:920–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Logrip ML, Zorrilla EP. Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal. Front Integr Neurosci. 2014;8:30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Celen S, Koole M, Ooms M, De Angelis M, Sannen I, Cornelis J, et al. Preclinical evaluation of [18F]JNJ42259152 as a PET tracer for PDE10A. Neuroimage. 2013;82:13–22.

    Article  CAS  PubMed  Google Scholar 

  32. Logrip ML, Gainey SC. Sex differences in the long-term effects of past stress on alcohol self-administration, glucocorticoid sensitivity and phosphodiesterase 10A expression. Neuropharmacology. 2020;164:107857. https://doi.org/10.1016/j.neuropharm.2019.107857.

    Article  CAS  PubMed  Google Scholar 

  33. Hsu YT, Liao G, Bi X, Oka T, Tamura S, Baudry M. The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices. Neuropharmacology. 2011;61:1275–81.

    Article  CAS  PubMed  Google Scholar 

  34. Fazio P, Schain M, Mrzljak L, Amini N, Nag S, Al-Tawil N, et al. Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3 receptors and sub-cortical volumes in the human basal ganglia: A PET study with 18F-MNI-659 and 11C-raclopride with correction for partial volume effect. Neuroimage. 2017;152:330–9.

    Article  CAS  PubMed  Google Scholar 

  35. Simms JA, Steensland P, Medina B, Abernathy KE, Chandler LJ, Wise R, et al. Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol Clin Exp Res. 2008;32:1816–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Laat B, Weerasekera A, Leurquin-Sterk G, Gsell W, Bormans G, Himmelreich U, et al. Effects of alcohol exposure on the glutamatergic system: a combined longitudinal 18F-FPEB and 1H-MRS study in rats. Addict Biol. 2019;24:696–706.

    Article  PubMed  CAS  Google Scholar 

  37. Kimbrough A, Kim S, Cole M, Brennan M, George O. Intermittent access to ethanol drinking facilitates the transition to excessive drinking after chronic intermittent ethanol vapor exposure. Alcohol Clin Exp Res. 2017;41:1502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zeeb FD, Robbins TW, Winstanley CA. Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task. Neuropsychopharmacol. 2009;34:2329–43.

    Article  CAS  Google Scholar 

  39. Van Laere K, Ahmad RU, Hudyana H, Dubois K, Schmidt ME, Celen S, et al. Quantification of 18F-JNJ-42259152, a novel phosphodiesterase 10A PET tracer: Kinetic modeling and test-retest study in human brain. J Nucl Med. 2013;54:1285–93.

    Article  PubMed  CAS  Google Scholar 

  40. Ooms M, Attili B, Celen S, Koole M, Verbruggen A, Van Laere K, et al. [18F]JNJ42259152 binding to phosphodiesterase 10A, a key regulator of medium spiny neuron excitability, is altered in the presence of cyclic AMP. J Neurochem. 2016;139:897–906.

    Article  CAS  PubMed  Google Scholar 

  41. Celen S, Koole M, De Angelis M, Sannen I, Chitneni SK, Alcazar J, et al. Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain. J Nucl Med. 2010;51:1584–91.

    Article  CAS  PubMed  Google Scholar 

  42. Casteels C, Vermaelen P, Nuyts J, Van Der Linden A, Baekelandt V, Mortelmans L, et al. Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. J Nucl Med. 2006;47:1858–66.

    PubMed  Google Scholar 

  43. Carnicella S, Ron D, Barak S. Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol. 2014;48:243–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Poulos CX, Le AD, Parker JL. Impulsivity predicts individual susceptibility to high levels of alcohol self-administration. Behav Pharmacol. 1995;6:810–4.

    Article  PubMed  Google Scholar 

  45. Tollefson S, Gertler J, Himes ML, Paris J, Kendro S, Lopresti B, et al. Imaging phosphodiesterase-10a availability in cocaine use disorder with [11 C]IMA107 and PET. Synapse. 2019;73:e22070.

    Article  PubMed  CAS  Google Scholar 

  46. Wen R-T, Zhang F-F, Zhang H-T. Cyclic nucleotide phosphodiesterases: potential therapeutic targets for alcohol use disorder. Psychopharmacology. 2018;235(6):1793–805. https://doi.org/10.1007/s00213-018-4895-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Piccart E, De Backer J-F, Gall D, Lambot L, Raes A, Vanhoof G, et al. Genetic deletion of PDE10A selectively impairs incentive salience attribution and decreases medium spiny neuron excitability. Behav Brain Res. 2014;268:48–54.

    Article  CAS  PubMed  Google Scholar 

  48. Narendran R, Mason NS, Paris J, Himes ML, Douaihy AB, Frankle WG. Decreased prefrontal cortical dopamine transmission in alcoholism. Am J Psychiatry. 2014;171:881–8.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Volkow ND, Wang G-J, Telang F, Fowler JS, Logan J, Jayne M, et al. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci. 2007;27:12700–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Martinez D, Gil R, Slifstein M, Hwang D-R, Huang Y, Perez A, et al. Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiat. 2005;58:779–86.

    Article  CAS  PubMed  Google Scholar 

  51. Heinz A, Siessmeier T, Wrase J, Buchholz HG, Gründer G, Kumakura Y, et al. Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined [18F]DOPA and [18F]DMFP PET study in detoxified alcoholic patients. Am J Psychiatry. 2005;162:1515–20.

    Article  PubMed  Google Scholar 

  52. Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, et al. Preclinical characterization of selective phosphodiesterase 10a inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther. 2008;325:681–90.

    Article  CAS  PubMed  Google Scholar 

  53. 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 

  54. Zhao Y, Weiss F, Zorrilla EP. Remission and resurgence of anxiety-like behavior across protracted withdrawal stages in ethanol-dependent rats. Alcoholism: Clin Exp Res. 2007;31:1505–15.

    Article  Google Scholar 

  55. Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, et al. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther. 2009;331:574–90.

    Article  CAS  PubMed  Google Scholar 

  56. Ramos A, Pereira E, Martins GC, Wehrmeister TD, Izídio GS. Integrating the open field, elevated plus maze and light/dark box to assess different types of emotional behaviors in one single trial. Behav Brain Res. 2008;193:277–88.

    Article  PubMed  Google Scholar 

  57. Ceylan-Isik AF, McBride SM, Ren J. Sex difference in alcoholism: Who is at a greater risk for development of alcoholic complication? Life Sci 2010;87(5–6):133–8. https://doi.org/10.1016/j.lfs.2010.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pohjalainen T, Rinne JO, Någren K, Syvälahti E, Hietala J. Sex differences in the striatal dopamine D2 receptor binding characteristics in vivo. Am J Psychiatry. 1998;155:768–73.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Tinne Buelens and Ann Van Santvoort for their excellent technical assistance and the local radiopharmacy team for the tracer productions.

Funding

This work was funded by a research grant to JC from the Research Foundation Flanders (FWO/1508415 N). JC is a postdoctoral fellow from FWO (FWO/12R1619N). YEK is a SB PhD fellow at FWO (FWO/1S50320N), BdL received a PhD fellowship from the Flemish Agency for Innovation by Science and Technology, and KVL is senior clinical research fellow for the FWO. GS, MO, JMH, and GB have no competing financial interests to report in relation to this work.

Author information

Author notes

  1. Bart de Laat and Yvonne E. Kling contributed equally to this work.

Authors and Affiliations

  1. Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium

    Bart de Laat, Koen Van Laere & Jenny Ceccarini

  2. Department of Neurosciences, KU Leuven, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium

    Yvonne E. Kling

  3. Center for Brain & Disease Research, Laboratory of Neurobiology, VIB, Leuven, Belgium

    Yvonne E. Kling

  4. Department of Imaging and Pathology, Translational MRI, KU Leuven, Leuven, Belgium

    Gwen Schroyen

  5. Laboratory for Radiopharmaceutical Research, KU Leuven, Leuven, Belgium

    Maarten Ooms & Guy Bormans

  6. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Jacob M. Hooker

  7. Division of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium

    Koen Van Laere

  8. University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Jenny Ceccarini

Authors
  1. Bart de Laat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yvonne E. Kling
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gwen Schroyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maarten Ooms
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jacob M. Hooker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guy Bormans
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koen Van Laere
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jenny Ceccarini
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The experimental setup was designed by BdL and JC. BdL, GS and MO performed data collection. Data analysis was conducted by YEK and JC. The manuscript was written by YEK and JC, supported by BdL, GS, MO, JMH, GB and KVL. All authors revised the manuscript and accepted the final version.

Corresponding author

Correspondence to Jenny Ceccarini.

Ethics declarations

Ethics approval

All animal experiments were conducted according to the European Communities Council Directive of November 24, 1986 (86/609/EEC) and approved by the Animal Ethics Committees of the University of Leuven.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's note

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

This article is part of the Topical Collection on Preclinical Imaging.

Supplementary Information

ESM 1

(DOCX 469 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Laat, B., Kling, Y.E., Schroyen, G. et al. Effects of chronic voluntary alcohol consumption on PDE10A availability: a longitudinal behavioral and [18F]JNJ42259152 PET study in rats. Eur J Nucl Med Mol Imaging 49, 492–502 (2022). https://doi.org/10.1007/s00259-021-05448-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-021-05448-3

Keywords

Search

Navigation