Skip to main content

Advertisement

SpringerLink
Log in

N6-substituated adenosine analog J4 attenuates anxiety-like behaviors in mice

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Withdrawal from chronic alcohol exposure produces various physical and mental withdrawal symptoms. Activation of adenosine receptors is known to inhibit withdrawal-induced excitation. However, limited studies investigate how adenosine analogs may prove helpful tools to alleviate alcohol withdrawal-related affective behaviors.

Objectives

This study aimed to investigate the effects of J4 compared with saline using the mice vapor or voluntary ethanol drinking model on behavioral endpoints representing ethanol-withdrawal negative emotionality commonly observed during abstinence from chronic alcohol use.

Methods

We subjected C57BL/6 J mice to chronic intermittent ethanol (CIE) exposure schedule to investigate how 72-h withdrawal from alcohol alters affective-like behavior. Next, we determined how treatment with J4, a second-generation adenosine analog, influenced affective behaviors produced by alcohol withdrawal. Finally, we determined how J4 treatment alters voluntary ethanol drinking using the two-bottle-choice drinking paradigm.

Results

Our results show that 72-h withdrawal from chronic intermittent ethanol exposure produces limited affective-like disturbances in male C57BL/6 J mice exposed to 4 cycles ethanol vapor. Most importantly, J4 treatment irrespective of ethanol exposure decreases innate anxiety-like behavior in mice.

Conclusions

Withdrawal from chronic intermittent ethanol exposure and subsequent behavioral testing 72 h later produces minimal affective-like behavior. J4 treatment did however reduce marble-burying behavior and increased time spent in open arms of the elevated plus maze, suggesting J4 may be useful as a general anxiolytic.

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.

Institutional subscriptions

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

Similar content being viewed by others

References

  • Angoa-Pérez M, Kane MJ, Briggs DI, Francescutti DM, Kuhn DM (2013) Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. J Vis Exp (82):e50978. https://doi.org/10.3791/50978

  • Asatryan L, Nam HW, Lee MR, Thakkar MM, Saeed Dar M, Davies DL, Choi DS (2011) Implication of the purinergic system in alcohol use disorders. Alcohol Clin Exp Res 35:584–594

    CAS  PubMed  PubMed Central  Google Scholar 

  • Association AP (2013) Diagnostic and statistical manual of mental disorders : DSM-5. American Psychiatric Association, Arlington

    Google Scholar 

  • Augusto E, Matos M, Sévigny J, El-Tayeb A, Bynoe MS, Müller CE, Cunha RA, Chen J-F (2013) Ecto-5′-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A; receptor functions. J Neurosci 33:11390

    CAS  PubMed  PubMed Central  Google Scholar 

  • Borroto-Escuela DO, Rodriguez D, Romero-Fernandez W, Kapla J, Jaiteh M, Ranganathan A, Lazarova T, Fuxe K, Carlsson J (2018) Mapping the interface of a GPCR dimer: a structural model of the A(2A) adenosine and D(2) dopamine receptor heteromer. Front Pharmacol 9:829

    PubMed  PubMed Central  Google Scholar 

  • Burnstock G (2008) Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov 7:575–590

    CAS  PubMed  Google Scholar 

  • Chang C-P, Chang Y-G, Chuang P-Y, Nguyen TNA, Wu K-C, Chou F-Y, Cheng S-J, Chen H-M, Jin L-W, Carvalho K, Huin V, Buée L, Liao Y-F, Lin C-J, Blum D, Chern Y (2021) Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy. Acta Neuropathol Commun 9:112

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheffer A, Castillo ARG, Corrêa-Velloso J, Gonçalves MCB, Naaldijk Y, Nascimento IC, Burnstock G, Ulrich H (2018) Purinergic system in psychiatric diseases. Mol Psychiatry 23:94–106

    CAS  PubMed  Google Scholar 

  • Chen J, Rinaldo L, Lim SJ, Young H, Messing RO, Choi DS (2007) The type 1 equilibrative nucleoside transporter regulates anxiety-like behavior in mice. Genes Brain Behav 6:776–783

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen WC, Lai YS, Lin SH, Lu KH, Lin YE, Panyod S, Ho CT, Sheen LY (2016) Anti-depressant effects of Gastrodia elata Blume and its compounds gastrodin and 4-hydroxybenzyl alcohol, via the monoaminergic system and neuronal cytoskeletal remodeling. J Ethnopharmacol 182:190–199

    CAS  PubMed  Google Scholar 

  • Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, McMahon T, Diamond I, Bonci A, Messing RO (2004) The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat Neurosci 7:855–861

    CAS  PubMed  Google Scholar 

  • de Brouwer G, Fick A, Harvey BH, Wolmarans DW (2019) A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive–compulsive disorder: mapping the way forward. Cogn Affect Behav Neurosci 19:1–39

    PubMed  Google Scholar 

  • Deacon RMJ (2006) Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protoc 1:122–124

    CAS  PubMed  Google Scholar 

  • Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55

    CAS  PubMed  Google Scholar 

  • Eissa N, Jayaprakash P, Azimullah S, Ojha SK, Al-Houqani M, Jalal FY, Łażewska D, Kieć-Kononowicz K, Sadek B (2018) The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism. Sci Rep 8:13077

    PubMed  PubMed Central  Google Scholar 

  • Ferré S, Karcz-Kubicha M, Hope BT, Popoli P, Burgueño J, Gutiérrez MA, Casadó V, Fuxe K, Goldberg SR, Lluis C, Franco R, Ciruela F (2002) Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proc Natl Acad Sci 99:11940

    PubMed  PubMed Central  Google Scholar 

  • Fredholm BB, Svenningsson P (2020) Why target brain adenosine receptors? A historical perspective. Parkinsonism Relat Disord 80:S3–S6

    PubMed  Google Scholar 

  • Fredholm BB, Cunha RA, Svenningsson P (2003) Pharmacology of adenosine A2A receptors and therapeutic applications. Curr Top Med Chem 3:413–426

    CAS  PubMed  Google Scholar 

  • Fredholm BB, Chen JF, Masino SA, Vaugeois JM (2005) Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Annu Rev Pharmacol Toxicol 45:385–412

    CAS  PubMed  Google Scholar 

  • Fredholm BB, Chern Y, Franco R, Sitkovsky M (2007) Aspects of the general biology of adenosine A2A signaling. Prog Neurobiol 83:263–276

    CAS  PubMed  Google Scholar 

  • Heilig M, Egli M, Crabbe JC, Becker HC (2010) Review: acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol 15:169–184

    PubMed  PubMed Central  Google Scholar 

  • Ho S-Y, Chen I-C, Chang K-C, Lin H-R, Tsai C-W, Lin C-J, Liou H-H (2020) Equilibrative nucleoside transporters-1 inhibitors act as anti-epileptic agents by inhibiting glutamatergic transmission. Front Neurosci 14:610898. https://doi.org/10.3389/fnins.2020.610898

  • Hong S-I, Kang S, Chen J-F, Choi D-S (2019a) Indirect medium spiny neurons in the dorsomedial striatum regulate ethanol-containing conditioned reward seeking. J Neurosci 39:7206

    PubMed  PubMed Central  Google Scholar 

  • Hong S-I, Peyton L, Chern Y, Choi D-S (2019b) Novel adenosine analog, N6-(4-hydroxybenzyl)-adenosine, dampens alcohol drinking and seeking behaviors. J Pharmacol Exp Ther 371:260

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu W-H, Shiao Y-J, Chao Y-M, Huang Y-J, Lin Y-L (2020) T1–11, an adenosine derivative, ameliorates aging-related behavioral physiology and senescence markers in aging mice. Aging 12:10556–10577

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang N-K, Lin J-H, Lin J-T, Lin C-I, Liu EM, Lin C-J, Chen W-P, Shen Y-C, Chen H-M, Chen J-B, Lai H-L, Yang C-W, Chiang M-C, Wu Y-S, Chang C, Chen J-F, Fang J-M, Lin Y-L, Chern Y (2011) A new drug design targeting the adenosinergic system for Huntington’s disease. PLoS One 6:e20934

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jia Y-F, Vadnie CA, Ho AM-C, Peyton L, Veldic M, Wininger K, Matveyenko A, Choi D-S (2020a) Type 1 equilibrative nucleoside transporter (ENT1) regulates sex-specific ethanol drinking during disruption of circadian rhythms. Addict Biol 25:e12801

    CAS  PubMed  Google Scholar 

  • Jia Y-F, Wininger K, Ho AM-C, Peyton L, Baker M, Choi D-S (2020b) Astrocytic glutamate transporter 1 (GLT1) deficiency reduces anxiety- and depression-like behaviors in mice. Front Behav Neurosci 14:57. https://doi.org/10.3389/fnbeh.2020.00057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang S, Hong S-I, Lee J, Peyton L, Baker M, Choi S, Kim H, Chang S-Y, Choi D-S (2020) Activation of astrocytes in the dorsomedial striatum facilitates transition from habitual to goal-directed reward-seeking behavior. Biol Psychiatry 88:797–808

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kao YH, Lin MS, Chen CM, Wu YR, Chen HM, Lai HL, Chern Y, Lin CJ (2017) Targeting ENT1 and adenosine tone for the treatment of Huntington’s disease. Hum Mol Genet 26:467–478

    CAS  PubMed  Google Scholar 

  • Karadayian AG, Busso MJ, Feleder C, Cutrera RA (2013) Alterations in affective behavior during the time course of alcohol hangover. Behav Brain Res 253:128–138

    PubMed  Google Scholar 

  • Kimbrough A, Lurie DJ, Collazo A, Kreifeldt M, Sidhu H, Macedo GC, D’Esposito M, Contet C, George O (2020) Brain-wide functional architecture remodeling by alcohol dependence and abstinence. Proc Natl Acad Sci 117:2149

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koob GF (2017) Antireward, compulsivity, and addiction: seminal contributions of Dr. Athina Markou to motivational dysregulation in addiction. Psychopharmacology 234:1315–1332

    CAS  PubMed  Google Scholar 

  • Latini S, Pedata F (2001) Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J Neurochem 79:463–484

    CAS  PubMed  Google Scholar 

  • Lewis MH, Rajpal H, Muehlmann AM (2019) Reduction of repetitive behavior by co-administration of adenosine receptor agonists in C58 mice. Pharmacol Biochem Behav 181:110–116

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lowery-Gionta EG, Marcinkiewcz CA, Kash TL (2015) Functional alterations in the dorsal raphe nucleus following acute and chronic ethanol exposure. Neuropsychopharmacology 40:590–600

    CAS  PubMed  Google Scholar 

  • Mason BJ (2017) Emerging pharmacotherapies for alcohol use disorder. Neuropharmacology 122:244–253

    CAS  PubMed  PubMed Central  Google Scholar 

  • McCaul ME, Hutton HE, Stephens MAC, Xu X, Wand GS (2017) Anxiety, anxiety sensitivity, and perceived stress as predictors of recent drinking, alcohol craving, and social stress response in heavy drinkers. Alcohol Clin Exp Res 41:836–845

    CAS  PubMed  PubMed Central  Google Scholar 

  • McCool BA, Chappell AM (2015) Chronic intermittent ethanol inhalation increases ethanol self-administration in both C57BL/6J and DBA/2J mice. Alcohol 49:111–120

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nam HW, Lee MR, Zhu Y, Wu J, Hinton DJ, Choi S, Kim T, Hammack N, Yin JC, Choi DS (2011) Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-D-aspartate receptor signaling. Biol Psychiatry 69:1043–1051

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nam HW, McIver SR, Hinton DJ, Thakkar MM, Sari Y, Parkinson FE, Haydon PG, Choi DS (2012) Adenosine and glutamate signaling in neuron-glial interactions: implications in alcoholism and sleep disorders. Alcohol Clin Exp Res 36:1117–1125

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nam HW, Bruner RC, Choi DS (2013a) Adenosine signaling in striatal circuits and alcohol use disorders. Mol Cells 36:195–202

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nam HW, Hinton DJ, Kang NY, Kim T, Lee MR, Oliveros A, Adams C, Ruby CL, Choi DS (2013b) Adenosine transporter ENT1 regulates the acquisition of goal-directed behavior and ethanol drinking through A2A receptor in the dorsomedial striatum. J Neurosci 33:4329–4338

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okhuarobo A, Bolton JL, Igbe I, Zorrilla EP, Baram TZ, Contet C (2020) A novel mouse model for vulnerability to alcohol dependence induced by early-life adversity. Neurobiol Stress 13:100269

    PubMed  PubMed Central  Google Scholar 

  • Overstreet DH, Knapp DJ, Breese GR (2004) Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors. Pharmacol Biochem Behav 77:405–413

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perez EE, De Biasi M (2015) Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment. Alcohol 49:237–243

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roberto M, Kirson D, Khom S (2021) The role of the central amygdala in alcohol dependence. Cold Spring Harb Perspect Med 11(2):a039339. https://doi.org/10.1101/cshperspect.a039339

  • Rose JH, Karkhanis AN, Chen R, Gioia D, Lopez MF, Becker HC, McCool BA, Jones SR (2016) Supersensitive kappa opioid receptors promotes ethanol withdrawal-related behaviors and reduce dopamine signaling in the nucleus accumbens. Int J Neuropsychopharmacol 19:pyv127

    PubMed  Google Scholar 

  • Ruby CL, Walker D, An J, Kim J, Choi D (2011) Sex-specific regulation of depression, anxiety-like behaviors and alcohol drinking in mice lacking ENT1. J Addict Res Ther S4:004. https://doi.org/10.4172/2155-6105.S4-004

  • Sebastião AM, Ribeiro JA (2000) Fine-tuning neuromodulation by adenosine. Trends Pharmacol Sci 21:341–346

    PubMed  Google Scholar 

  • Shen H-Y, Coelho JE, Ohtsuka N, Canas PM, Day Y-J, Huang Q-Y, Rebola N, Yu L, Boison D, Cunha RA, Linden J, Tsien JZ, Chen J-F (2008) A critical role of the adenosine A2A; receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A; receptor knock-outs. J Neurosci 28:2970

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen H-Y, Canas PM, Garcia-Sanz P, Lan J-Q, Boison D, Moratalla R, Cunha RA, Chen J-F (2013) Adenosine A2A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 8:e80902

    PubMed  PubMed Central  Google Scholar 

  • Shoji H, Miyakawa T (2021) Effects of test experience, closed-arm wall color, and illumination level on behavior and plasma corticosterone response in an elevated plus maze in male C57BL/6J mice: a challenge against conventional interpretation of the test. Mol Brain 14:34

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sidhu H, Kreifeldt M, Contet C (2018) Affective disturbances during withdrawal from chronic intermittent ethanol inhalation in C57BL/6J and DBA/2J male mice. Alcohol Clin Exp Res 42:1281–1290

    CAS  PubMed  PubMed Central  Google Scholar 

  • Starski P, Hong S-I, Peyton L, Oliveros A, Wininger K, Hutchison C, Kang S, Karpyak V, Choi D-S (2020) Ethanol induces maladaptive impulse control and decreased seeking behaviors in mice. Addict Biol 25:e12754

    PubMed  Google Scholar 

  • Tanimura Y, Vaziri S, Lewis MH (2010) Indirect basal ganglia pathway mediation of repetitive behavior: attenuation by adenosine receptor agonists. Behav Brain Res 210:116–122

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R (2009) Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology 204:361–373

    CAS  PubMed  PubMed Central  Google Scholar 

  • Towner TT, Varlinskaya EI (2020) Adolescent ethanol exposure: anxiety-like behavioral alterations, ethanol intake, and sensitivity. Front Behav Neurosci 14:45. https://doi.org/10.3389/fnbeh.2020.00045

  • Turner S, Mota N, Bolton J, Sareen J (2018) Self-medication with alcohol or drugs for mood and anxiety disorders: a narrative review of the epidemiological literature. Depress Anxiety 35:851–860

    PubMed  PubMed Central  Google Scholar 

  • van Calker D, Biber K, Domschke K, Serchov T (2019) The role of adenosine receptors in mood and anxiety disorders. J Neurochem 151:11–27

    PubMed  Google Scholar 

  • Wang N, Liu X, Li X-T, Li X-X, Ma W, Xu Y-M, Liu Y, Gao Q, Yang T, Wang H, Peng Y, Zhu X-F, Guan Y-Z (2021) 7,8-dihydroxyflavone alleviates anxiety-like behavior induced by chronic alcohol exposure in mice involving tropomyosin-related kinase B in the amygdala. Mol Neurobiol 58:92–105

    PubMed  Google Scholar 

  • Yamada K, Kobayashi M, Kanda T (2014) Chapter fifteen - involvement of adenosine A2A receptors in depression and anxiety. In: Mori A (ed) International review of neurobiology. Academic Press, Cambridge, pp 373–393

Download references

Acknowledgements

We thank all members of the DSC.’s laboratory for interest, help and comments.

Funding

This work was supported by the Samuel C. Johnson Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, and the National Institute on Alcohol Abuse and Alcoholism (AA018779, AA029258, AG072898).

Author information

Authors and Affiliations

  1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

    Lee Peyton, Hesham Essa & Doo-Sup Choi

  2. Regenerative Sciences Program, Center for Regenerative Medicine, Mayo Clinic College of Medicine Rochester, Rochester, MN, 55905, USA

    Brandon Emanuel León

  3. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Yijuang Chern

  4. Department of Psychiatry and Psychology, Mayo Clinic College of Medicine Rochester, Rochester, MN, 55905, USA

    Doo-Sup Choi

Authors
  1. Lee Peyton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brandon Emanuel León
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hesham Essa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yijuang Chern
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Doo-Sup Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the work presented in the paper. LP and DSC conceived the study; LP, BL, HE, and DSC designed experiments, performed the experiments; LP, BL, and HE analyzed the data. All authors wrote the manuscript.

Corresponding author

Correspondence to Doo-Sup Choi.

Ethics declarations

Conflict of interest

D-S Choi is a scientific advisory board member to Peptron Inc. Peptron had no role in preparation, review, or approval of the manuscript. Y Chern holds patents on treating neurodegenerative diseases and pain by J4. All the other 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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peyton, L., León, B.E., Essa, H. et al. N6-substituated adenosine analog J4 attenuates anxiety-like behaviors in mice. Psychopharmacology 239, 887–895 (2022). https://doi.org/10.1007/s00213-022-06079-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-022-06079-8

Keywords

Search

Navigation