Skip to main content
SpringerLink
Log in

Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats

  • Article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of ionotropic N-methyl-d-aspartate (NMDA) receptors or metabotropic receptors’ type 5 (mGlu5) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide.

Methods

In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N-ω-propyl-l-arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated.

Results

Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5–5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue.

Conclusions

Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats.

Graphical abstract

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

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon request.

References

  1. Global report on cocaine 2023. Glob Rep Cocaine. 2023.

  2. Czeisler MÉ, Lane RI, Petrosky E, Wiley JF, Christensen A, Njai R, et al. Mental health, substance use, and suicidal ideation during the COVID-19 pandemic—United States, June 24–30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1049–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kampman KM. The treatment of cocaine use disorder. Sci Adv. 2019;5(10):1–8.

    Article  Google Scholar 

  4. Cleva RM, Olive MF. mGlu receptors and drug addiction. Wiley Interdiscip Rev Membr Transp Signal. 2012;1:281–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, et al. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci. 2003;6(7):743–9.

    Article  CAS  PubMed  Google Scholar 

  6. Pomierny-Chamiolo L, Miszkiel J, Frankowska M, Pomierny B, Niedzielska E, Smaga I, et al. Withdrawal from cocaine self-administration and yoked cocaine delivery dysregulates glutamatergic mGlu5 and NMDA receptors in the rat brain. Neurotox Res. 2015;27(3):246–58.

    Article  CAS  PubMed  Google Scholar 

  7. Smaga I, Gawlińska K, Frankowska M, Wydra K, Sadakierska-Chudy A, Suder A, et al. Extinction training after cocaine self-administration influences the epigenetic and genetic machinery responsible for glutamatergic transporter gene expression in male rat brain. Neuroscience. 2020;451:99–110.

    Article  CAS  PubMed  Google Scholar 

  8. Martin G, Nie Z, Siggins GR. Metabotropic glutamate receptors regulate N-methyl-d-aspartate-mediated synaptic transmission in nucleus accumbens. J Neurophysiol. 1997;78(6):3028–38.

    Article  CAS  PubMed  Google Scholar 

  9. Attucci S, Albani-Torregrossa S, Moroni F, Pellegrini-Giampietro DE. Metabotropic glutamate receptors stimulate phospholipase D via different pathways in the adult and neonate rat hippocampus. Neurochem Res. 2001;26(10):1151–5.

    Article  CAS  PubMed  Google Scholar 

  10. Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, et al. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-d-aspartate responses in medium spiny striatal neurons. Neuroscience. 2001;106(3):579–87.

    Article  CAS  PubMed  Google Scholar 

  11. Ferraguti F, Shigemoto R. Metabotropic glutamate receptors. Cell Tissue Res. 2006;326(2):483–504.

    Article  CAS  PubMed  Google Scholar 

  12. Stefani MR, Moghaddam B. Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade. Eur J Pharmacol. 2010;639(1–3):26–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Spencer S, Kalivas PW. Glutamate transport: a new bench to bedside mechanism for treating drug abuse. Int J Neuropsychopharmacol. 2017;20(10):797–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry. 2003;8(4):373–82.

    Article  CAS  PubMed  Google Scholar 

  15. Kew JNC, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology. 2005;179(1):4–29.

    Article  CAS  PubMed  Google Scholar 

  16. Smaga I, Sanak M, Filip M. Cocaine-induced changes in the expression of NMDA receptor subunits. Curr Neuropharmacol. 2019;17(11):1039–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Smaga I, Wydra K, Suder A, Frankowska M, Sanak M, Caffino L, et al. The NMDA receptor subunit (GluN1 and GluN2A) modulation following different conditions of cocaine abstinence in rat brain structures. Neurotox Res. 2021;39(3):556–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Smaga I, Wydra K, Piechota M, Caffino L, Fumagalli F, Sanak M, et al. Cocaine abstinence modulates NMDA receptor subunit expression: an analysis of the GluN2B subunit in cocaine-seeking behavior. Prog Neuro-Psychopharmacol Biol Psychiatry. 2021;109: 110248.

    Article  CAS  Google Scholar 

  19. DePoy LM, Zimmermann KS, Marvar PJ, Gourley SL. Induction and blockade of adolescent cocaine-induced habits. Biol Psychiatry. 2017;81(7):595–605.

    Article  CAS  PubMed  Google Scholar 

  20. Smaga I, Wydra K, Witek K, Surówka P, Suder A, Pieniążek R, et al. Intravenous administration of Tat-NR2B9c peptide, a PSD95 inhibitor, attenuates reinstatement of cocaine-seeking behavior in rats. Behav Brain Res. 2022;416: 113537.

    Article  CAS  PubMed  Google Scholar 

  21. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001;357(3):593–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Garthwaite J, Garthwaite G, Palmer RMJ, Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol Mol Pharmacol. 1989;172(4–5):413–6.

    Article  CAS  Google Scholar 

  23. Harada K, Aota M, Inoue T, Matsuda R, Mihara T, Yamaji T, et al. Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: a comparison with diazepam and buspirone. Eur J Pharmacol. 2006;553(1–3):171–84.

    Article  CAS  PubMed  Google Scholar 

  24. Kim HS, Park WK. Nitric oxide mediation of cocaine-induced dopaminergic behaviors: ambulation-accelerating activity, reverse tolerance and conditioned place preference in mice. J Pharmacol Exp Ther. 1995;275:551–7.

    CAS  PubMed  Google Scholar 

  25. Orsini C, Izzo E, Koob GF, Pulvirenti L. Blockade of nitric oxide synthesis reduces responding for cocaine self-administration during extinction and reinstatement. Brain Res. 2002;925(2):133–40.

    Article  CAS  PubMed  Google Scholar 

  26. Balda MA, Anderson KL, Itzhak Y. Adolescent and adult responsiveness to the incentive value of cocaine reward in mice: role of neuronal nitric oxide synthase (nNOS) gene. Neuropharmacology. 2006;51(2):341–9.

    Article  CAS  PubMed  Google Scholar 

  27. Smith ACW, Scofield MD, Heinsbroek JA, Gipson CD, Neuhofer D, Roberts-Wolfe DJ, et al. Accumbens nNOS interneurons regulate cocaine relapse. J Neurosci. 2017;37(4):742–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Siemsen BM, McFaddin JA, Haigh K, Brock AG, Nan Leath M, Hooker KN, et al. Amperometric measurements of cocaine cue and novel context-evoked glutamate and nitric oxide release in the nucleus accumbens core. J Neurochem. 2020;153(5):599–616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR. Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test. Eur Neuropsychopharmacol. 2008;18(5):323–32.

    Article  CAS  PubMed  Google Scholar 

  30. Beamer E, Otahal J, Sills GJ, Thippeswamy T. Nw-Propyl-l-arginine (L-NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural, EEG and immunohistochemical analyses. Eur J Neurosci. 2012;36(9):3194–203.

    Article  PubMed  Google Scholar 

  31. Srebro DP, Vučković S, Milovanović A, Vujović KS, Vučetić Č, Prostran M. Preventive treatment with dizocilpine attenuates oedema in a carrageenan model of inflammation: the interaction of glutamatergic and nitrergic signaling. Inflammopharmacology. 2019;27(1):121–8.

    Article  CAS  PubMed  Google Scholar 

  32. Frankowska M, Filip M, Przegaliński E. Effects of GABAB receptor ligands in animal tests of depression and anxiety. Pharmacol Rep. 2007;59(6):645–55.

    CAS  PubMed  Google Scholar 

  33. Gawlińska K, Frankowska M, Gawliński D, Piechota M, Korostyński M, Filip M. Cocaine administration and its abstinence conditions modulate neuroglia. Int J Mol Sci. 2020;21(21):7970.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. San Diego: Elsevier Academic Press; 2007.

    Google Scholar 

  35. Bagetta G, Rodinò P, Arabia A, Massoud R, Paoletti AM, Nisticò R, et al. Systemic administration of cocaine, given alone or in combination with sensory stimuli, differentially affects l-arginine-nitric oxide metabolism in discrete regions of the brain of rat. Neurosci Lett. 1999;266(3):153–6.

    Article  CAS  PubMed  Google Scholar 

  36. Loftis JM, Janowsky A. Regulation of NMDA receptor subunits and nitric oxide synthase expression during cocaine withdrawal. J Neurochem. 2000;75(5):2040–50.

    Article  CAS  PubMed  Google Scholar 

  37. Itzhak Y, Ali SF, Martin JL, Black MD, Huang PL. Resistance of neuronal nitric oxide synthase-deficient mice to cocaine-induced locomotor sensitization. Psychopharmacology. 1998;140(3):378–86.

    Article  CAS  PubMed  Google Scholar 

  38. Ohno M, Arai I, Watanabe S. N-Methyl-d-aspartate stimulates dopamine release through nitric oxide formation in the nucleus accumbens of rats. Brain Res. 1995;699(2):332–5.

    Article  CAS  PubMed  Google Scholar 

  39. Mungrue IN, Bredt DS. nNOS at a glance: implications for brain and brawn. J Cell Sci. 2004;117(13):2627–9.

    Article  CAS  PubMed  Google Scholar 

  40. Christopherson KS, Hillier BJ, Lim WA, Bredt DS. PSD-95 assembles a ternary complex with the N-methyl-d-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem. 1999;274(39):27467–73.

    Article  CAS  PubMed  Google Scholar 

  41. Hillier W, Wydrzynski T. The affinities for the two substrate water binding sites in the O2 evolving complex of photosystem II vary independently during S-state turnover. Biochemistry. 2000;39(15):4399–405.

    Article  CAS  PubMed  Google Scholar 

  42. Wydra K, Gołembiowska K, Suder A, Kamińska K, Fuxe K, Filip M. On the role of adenosine (A)2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats. Psychopharmacology. 2015;232(2):421–35.

    Article  CAS  PubMed  Google Scholar 

  43. Kalivas PW, Stewart J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev. 1991;16(3):223–44.

    Article  CAS  PubMed  Google Scholar 

  44. Smaga I, Zaniewska M, Gawliński D, Faron-Górecka A, Szafrański P, Cegła M, et al. Changes in the cannabinoids receptors in rats following treatment with antidepressants. Neurotoxicology. 2017;63:13–20.

    Article  CAS  PubMed  Google Scholar 

  45. Wydra K, Witek K, Suder A, Filip M. Esketamine inhibits cocaine-seeking behaviour subsequent to various abstinence conditions in rats. Biomolecules. 2023;13(9):1411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Frankowska M, Miszkiel J, Pomierny-Chamioło L, Pomierny B, Giannotti G, Suder A, et al. Alternation in dopamine D2-like and metabotropic glutamate type 5 receptor density caused by differing housing conditions during abstinence from cocaine self-administration in rats. J Psychopharmacol. 2019;33(3):372–82.

    Article  CAS  PubMed  Google Scholar 

  47. Frankowska M, Miszkiel J, Pomierny-Chamioło L, Pomierny B, Borelli AC, Suder A, et al. Extinction training following cocaine or MDMA self-administration produces discrete changes in D(2)-like and mGlu(5) receptor density in the rat brain. Pharmacol Rep. 2019;71(5):870–8.

    Article  CAS  PubMed  Google Scholar 

  48. Knackstedt LA, Schwendt M. mGlu5 receptors and relapse to cocaine-seeking: the role of receptor trafficking in postrelapse extinction learning deficits. Neural Plast. 2016;2016:9312508.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Knackstedt LA, Moussawi K, Lalumiere R, Schwendt M, Klugmann M, Kalivas PW. Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J Neurosci. 2010;30(23):7984–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Neuhofer D, Spencer SM, Chioma VC, Beloate LN, Schwartz D, Kalivas PW. The loss of NMDAR-dependent LTD following cannabinoid self-administration is restored by positive allosteric modulation of CB1 receptors. Addict Biol. 2020;25(6):1–21.

    Article  Google Scholar 

  51. McLeod AA. Later management of documented ischaemic heart disease: secondary prevention and rehabilitation. Br Med Bull. 2001;59:113–33.

    Article  CAS  PubMed  Google Scholar 

  52. Sales AJ, Hiroaki-Sato VA, Joca SRL. Participation of hippocampal nitric oxide synthase and soluble guanylate cyclase in the modulation of behavioral responses elicited by the rat forced swimming test. Behav Pharmacol. 2017;28(1):19–29.

    Article  CAS  PubMed  Google Scholar 

  53. Jefferys D, Funder J. Nitric oxide modulates retention of immobility in the forced swimming test in rats. Eur J Pharmacol. 1996;295(2–3):131–5.

    Article  CAS  PubMed  Google Scholar 

  54. Morato GS, Ortiga RM, Ferreira VMM. Involvement of nitric oxide-dependent pathways of dorsolateral periaqueductal gray in the effects of ethanol in rats submitted to the elevated plus-maze test. Behav Brain Res. 2004;153(2):341–9.

    Article  CAS  PubMed  Google Scholar 

  55. Vila-Verde C, Marinho ALZ, Lisboa SF, Guimarães FS. Nitric oxide in the prelimbic medial prefrontal cortex is involved in the anxiogenic-like effect induced by acute restraint stress in rats. Neuroscience. 2016;320:30–42.

    Article  CAS  PubMed  Google Scholar 

  56. Frankowska M, Gołda A, Wydra K, Gruca P, Papp M, Filip M. Effects of imipramine or GABAB receptor ligands on the immobility, swimming and climbing in the forced swim test in rats following discontinuation of cocaine self-administration. Eur J Pharmacol. 2010;627(1–3):142–9.

    Article  CAS  PubMed  Google Scholar 

  57. Hámor PU, Gobin CM, Schwendt M. The role of glutamate mGlu5 and adenosine A2a receptor interactions in regulating working memory performance and persistent cocaine seeking in rats. Prog Neuro-Psychopharmacol Biol Psychiatry. 2020;103: 109979.

    Article  Google Scholar 

  58. Gobin C, Schwendt M. The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators. Psychopharmacology. 2020;237(1):115–25.

    Article  CAS  PubMed  Google Scholar 

  59. Lipaus IFS, Gomes EF, Martins CW, e Silva CM, Pires RGW, Malgarin F, et al. Impairment of spatial working memory and oxidative stress induced by repeated crack cocaine inhalation in rats. Behav Brain Res. 2019;359:910–7.

    Article  CAS  PubMed  Google Scholar 

  60. Fijał K, Nowak E, Leśkiewicz M, Budziszewska B, Filip M. Working memory deficits and alterations of ERK and CREB phosphorylation following withdrawal from cocaine self-administration. Pharmacol Rep. 2015;67(5):881–9.

    Article  PubMed  Google Scholar 

  61. Utkan T, Gocmez SS, Ozer C, Gacar N, Aricioglu F. Selective and nonselective neuronal NOS inhibitors impair cognitive function in the three panel runway and passive avoidance tasks in rats. Pharmacol Biochem Behav. 2012;101(4):515–9.

    Article  CAS  PubMed  Google Scholar 

  62. Cieślik P, Borska M, Wierońska JM. A comparative study of the impact of NO-related agents on MK-801- or scopolamine-induced cognitive impairments in the Morris water maze. Brain Sci. 2023;13(3):410.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Filip M, Przegaliński E. The role of the nitric oxide (NO) pathway in the discriminative stimuli of amphetamine and cocaine. Pharmacol Biochem Behav. 1998;59(3):703–8.

    Article  CAS  PubMed  Google Scholar 

  64. Brown GC, Bal-Price A. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol. 2003;27(3):325–55.

    Article  CAS  PubMed  Google Scholar 

  65. Hartung H, Threlfell S, Cragg SJ. Nitric oxide donors enhance the frequency dependence of dopamine release in nucleus accumbens. Neuropsychopharmacology. 2011;36(9):1811–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wiesinger H. Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol. 2001;64(4):365–91.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Karolina Wydra-Kolarska, Ph.D., Agata Suder, and Dawid Gawliński, Ph.D. for technical support.

Funding

This study was supported by statutory funds from the Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland.

Author information

Authors and Affiliations

  1. Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland

    Małgorzata Frankowska, Irena Smaga, Kinga Gawlińska, Renata Pieniążek & Małgorzata Filip

Authors
  1. Małgorzata Frankowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irena Smaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kinga Gawlińska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renata Pieniążek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Małgorzata Filip
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MF contributed to conceptualization, supervision, and funding acquisition; MFr, IS, and KG were involved in methodology and validation; MFr, IS, KG, and RP were involved in data curation; MFr, IS, and MF performed visualization; MF, MFr, IS, and KG were responsible for writing—original draft preparation; MF and MFr were responsible for writing—review and editing. All authors contributed to and proofread the manuscript and approved the final version.

Corresponding authors

Correspondence to Małgorzata Frankowska or Małgorzata Filip.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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

Frankowska, M., Smaga, I., Gawlińska, K. et al. Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats. Pharmacol. Rep 76, 338–347 (2024). https://doi.org/10.1007/s43440-024-00571-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43440-024-00571-y

Keywords

Search

Navigation