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α2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference

Abstract

The α2a-adrenergic receptor (α2a-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages α2a-AR autoreceptors, it also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α2a-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST Gi-coupled α2a-AR heteroreceptor signaling using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.

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Fig. 1: Full or heteroreceptor α2A-AR KO does not disrupt the acquisition or extinction of cocaine CPP.
Fig. 2: Full or heteroreceptor α2A-AR KO disrupts stress-induced reinstatement of cocaine CPP.
Fig. 3: Full or heteroreceptor deletion of α2A-ARs does not induce stress-dependent biases in side occupancy in cocaine-naïve mice.
Fig. 4: Activation of Gi signaling within the BNST reinstates cocaine CPP.
Fig. 5: A dose of guanfacine that does not increase BNST cFOS blocks stress-induced reinstatement of cocaine CPP.

References

  1. 1.

    Karlsgodt KH, Lukas SE, Elman I. Psychosocial stress and the duration of cocaine use in non-treatment seeking individuals with cocaine dependence. Am J Drug Alcohol Abus. 2003;29:539–51.

    Google Scholar 

  2. 2.

    Levandowski ML, Tractenberg SG, de Azeredo LA, De Nardi T, Rovaris DL, Bau CHD, et al. Crack cocaine addiction, early life stress and accelerated cellular aging among women. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;71:83–9.

    CAS  Google Scholar 

  3. 3.

    Sinha, R, Catapano, D, O’Malley S. Stress-induced craving and stress response in cocaine dependent individuals. Psychoneuroendocrinology.1999; 142:343–51.

  4. 4.

    Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J. Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology. 2000;23:138–50.

    CAS  PubMed  Google Scholar 

  5. 5.

    Shaham Y, Highfield D, Delfs J, Leung S, Stewart J. Clonidine blocks stress-induced reinstatement of heroin seeking in rats: An effect independent of locus coeruleus noradrenergic neurons. Eur J Neurosci. 2000;12:292–302.

    CAS  PubMed  Google Scholar 

  6. 6.

    Lê AD, Harding S, Juzytsch W, Funk D, Shaham Y. Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacol (Berl). 2005;179:366–73.

    Google Scholar 

  7. 7.

    Mantsch JR, Baker DA, Funk D, Lê AD, Shaham Y. Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology. 2016;41:335–56.

    CAS  PubMed  Google Scholar 

  8. 8.

    Fox HC, Seo D, Tuit K, Hansen J, Kimmerling A, Morgan PT, et al. Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: Preliminary findings. J Psychopharmacol. 2012;26:958–72.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Fox H, Sinha R. The role of guanfacine as a therapeutic agent to address stress-related pathophysiology in cocaine-dependent individuals. vol. 69. 1st edn. Elsevier Inc.; 2014.

  10. 10.

    Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Anaesthesia. 1999;54:146–65.

    CAS  PubMed  Google Scholar 

  11. 11.

    Seedat YK. Clonidine and guanfacine—comparison of their effects on haemodynamics in hypertension. South Afr Med J. 1985;67:557–9.

    CAS  Google Scholar 

  12. 12.

    Fox HC, Morgan PT, Sinha R. Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals. Neuropsychopharmacology. 2014;39:1527–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    McKee SA, Potenza MN, Kober H, Sofuoglu M, Arnsten AFT, Picciotto MR, et al. A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. J Psychopharmacol. 2015;29:300–11.

    CAS  PubMed  Google Scholar 

  14. 14.

    Krupitsky E, Zvartau E, Blokhina E, Verbitskaya E, Tsoy M, Wahlgren V, et al. Naltrexone with or without guanfacine for preventing relapse to opiate addiction in St.-Petersburg, Russia. Drug Alcohol Depend. 2013;132:674–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Haney M, Cooper ZD, Bedi G, Herrmann E, Comer SD, Reed SC, et al. Guanfacine decreases symptoms of cannabis withdrawal in daily cannabis smokers. Addict Biol. 2019;24:707–16.

    CAS  PubMed  Google Scholar 

  16. 16.

    Brown J, Doxey JC, Handley S. Effects of α-adrenoceptor agonists and antagonists and of antidepressant drugs on pre- and postsynaptic a-adrenoceptors. Eur J Pharm. 1980;67:33–40.

    CAS  Google Scholar 

  17. 17.

    Okada M, Fukuyama K, Kawano Y, Shiroyama T, Suzuki D, Ueda Y. Effects of acute and sub-chronic administrations of guanfacine on catecholaminergic transmissions in the orbitofrontal cortex. Neuropharmacology. 2019;156:107547.

    CAS  PubMed  Google Scholar 

  18. 18.

    Lee AM, Calarco CA, McKee SA, Mineur YS, Picciotto MR. Variability in nicotine conditioned place preference, stress‐induced reinstatement, and effects of guanfacine in male and female mice. Genes, Brain Behav. 2019;e12601:1–17.

  19. 19.

    Mantsch JR, Weyer A, Vranjkovic O, Beyer CE, Baker Da, Caretta H. Involvement of noradrenergic neurotransmission in the stress- but not cocaine-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: role for β−2 adrenergic receptors. Neuropsychopharmacology. 2010;35:2165–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Vranjkovic O, Gasser PJ, Gerndt CH, Baker DA, Mantsch JR. Stress-Induced Cocaine Seeking Requires a Beta-2 Adrenergic Receptor-Regulated Pathway from the Ventral Bed Nucleus of the Stria Terminalis That Regulates CRF Actions in the Ventral Tegmental Area. J Neurosci. 2014;34:12504–14.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Leri F, Flores J, Rodaros D, Stewart J. Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci. 2002;22:5713–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    McReynolds JR, Vranjkovic O, Thao M, Baker DA, Makky K, Lim Y, et al. Beta-2 adrenergic receptors mediate stress-evoked reinstatement of cocaine-induced conditioned place preference and increases in CRF mRNA in the bed nucleus of the stria terminalis in mice. Psychopharmacol (Berl). 2014;231:3953–63.

    CAS  Google Scholar 

  23. 23.

    Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, et al. α2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007;129:397–410.

    CAS  PubMed  Google Scholar 

  24. 24.

    Gilsbach R, Albarrán-Juárez J, Hein L. Pre- versus Postsynaptic Signaling by α 2-Adrenoceptors. Curr Top Membr. 2011;67:139–60.

    CAS  PubMed  Google Scholar 

  25. 25.

    Alamo C, López-Muñoz F, Sánchez-García J. Mechanism of action of guanfacine: a postsynaptic differential approach to the treatment of attention deficit hyperactivity disorder (adhd). Actas Esp Psiquiatr. 2016;44:107–12.

    PubMed  Google Scholar 

  26. 26.

    Harris NA, Isaac AT, Günther A, Merkel K, Melchior J, Eguakun E, et al. Dorsal BNST α2A -adrenergic receptors produce HCN-dependent excitatory actions that initiate anxiogenic behaviors. J Neurosci. 2018;38:8922–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Gilsbach R, Röser C, Beetz N, Brede M, Hadamek K, Haubold M, et al. Genetic dissection of α2-adrenoceptor functions in adrenergic versus nonadrenergic cells. Mol Pharmacol. 2009;75:1160–70.

    CAS  PubMed  Google Scholar 

  28. 28.

    Paxinos G, Franklin B. The mouse brain in stereotaxic coordinates. Academic Press; 2004.

  29. 29.

    Fetterly TL, Basu A, Nabit BP, Awad E, Williford KM, Centanni SW, et al. α 2A-adrenergic receptor activation decreases parabrachial nucleus excitatory drive onto BNST CRF neurons and reduces their activity In vivo. J Neurosci 2018;39:472–84.

    PubMed  Google Scholar 

  30. 30.

    Conrad KL, Davis AR, Silber.man Y, Sheffler DJ, Shields AD, Saleh Sa, et al. Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes. Neuropsychopharmacology. 2012;37:2253–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Davis AR, Shields AD, Brigman JL, Norcross M, McElligott ZA, Holmes A, et al. Yohimbine impairs extinction of cocaine-conditioned place preference in an α2-adrenergic receptor independent process. Learn Mem. 2008;15:667–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Erb S, Stewart J. A role for the bed nucleus of the stria terminalis, but not the amygdala, in the effects of corticotropin-releasing factor on stress-induced reinstatement of cocaine seeking. J Neurosci. 1999;19:1–6.

    Google Scholar 

  33. 33.

    Vranjkovic O, Pina M, Kash TL, Winder DG. The bed nucleus of the stria terminalis in drug-associated behavior and affect: a circuit-based perspective. Neuropharmacology. 2017;122:100–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Crowley NA, Bloodgood DW, Hardaway JA, Kendra AM, McCall JG, Al-Hasani R, et al. Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit. Cell Rep. 2016;14:2774–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Avery SN, Clauss JA, Blackford JU. The Human BNST: Functional Role in Anxiety and Addiction. Neuropsychopharmacology. 2016;41:126–41.

    CAS  PubMed  Google Scholar 

  36. 36.

    Clauss JA, Avery SN, Benningfield MM, Blackford JU. Social anxiety is associated with BNST response to unpredictability. Depress Anxiety. 2019; 36:666–75.

  37. 37.

    Mineur YS, Bentham MP, Zhou WL, Plantenga ME, McKee SA, Picciotto MR. Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice. Psychopharmacol (Berl). 2015;232:3539–49.

    CAS  Google Scholar 

  38. 38.

    Mineur YS, Cahuzac EL, Mose TN, Bentham MP, Plantenga ME, Thompson DC, et al. Interaction between noradrenergic and cholinergic signaling in amygdala regulates anxiety- and depression-related behaviors in mice. Neuropsychopharmacology. 2018;43:2118–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Fiks AG, Mayne SL, Song L, Steffes J, Liu W, McCarn B, et al. Changing patterns of alpha agonist medication use in children and adolescents 2009–11. J Child Adolesc Psychopharmacol. 2015;25:362–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Gowing L, Farrell M, Ali R, Jm W. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database of Systematic Reviews 2009. https://doi.org/10.1002/14651858.CD002024.pub3.

  41. 41.

    Cecchi M, Khoshbouei H, Javors M, Morilak DA. Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuroscience. 2002;112:13–21.

    CAS  PubMed  Google Scholar 

  42. 42.

    Schmidt KT, Makhijani VH, Boyt KM, Cogan ES, Pati D, Pina MM, et al. Stress-Induced Alterations of Norepinephrine Release in the Bed Nucleus of the Stria Terminalis of Mice. ACS Chem Neurosci. 2019;10:1908–14.

    CAS  PubMed  Google Scholar 

  43. 43.

    Pleil KE, Rinker Ja, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, et al. NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci 2015;18:545–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Rinker JA, Marshall SA, Mazzone CM, Lowery-Gionta EG, Gulati V, Pleil KE, et al. Extended amygdala to ventral tegmental area corticotropin-releasing factor circuit controls binge ethanol intake. Biol Psychiatry. 2017;81:930–40.

    CAS  PubMed  Google Scholar 

  45. 45.

    Pina MM, Young EA, Ryabinin AE, Cunningham CL. The bed nucleus of the stria terminalis regulates ethanol-seeking behavior in mice. Neuropharmacology. 2015;99:627–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Companion MA, Thiele TE. Assessment of ventral tegmental area-projecting GABAergic neurons from the bed nucleus of the stria terminalis in modulating binge-like ethanol intake. Eur J Neurosci. 2018;48:3335–43.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Abercrombie ED, Keller RW, Zigmond MJ. Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies. Neuroscience. 1988;27:897–904.

    CAS  PubMed  Google Scholar 

  48. 48.

    Winter JC, Rabin RA. Yohimbine as a serotonergic agent: evidence from receptor binding and drug discrimination. J Pharm Exp Ther. 1992;263:682–9.

    CAS  Google Scholar 

  49. 49.

    Nair SG, Navarre BM, Cifani C, Pickens CL, Bossert JM, Shaham Y. Role of dorsal medial prefrontal cortex dopamine D1-family receptors in relapse to high-fat food seeking induced by the anxiogenic drug Yohimbine. Neuropsychopharmacology. 2011;36:497–510.

    CAS  PubMed  Google Scholar 

  50. 50.

    Dzung Lê A, Funk D, Harding S, Juzytsch W, Fletcher PJ. The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats. Psychopharmacol (Berl). 2009;204:477–88.

    Google Scholar 

  51. 51.

    Verplaetse TL, Roberts W, Moore KE, Peltier MR, Oberleitner LM, McKee SA. Pharmacokinetics and pharmacodynamics of immediate-release versus extended-release guanfacine in adult daily smokers. J Clin Psychopharmacol. 2019;39:124–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Barcelos NM, Van Ness PH, Wagner AF, MacAvoy MG, Mecca AP, Anderson GM, et al. Guanfacine treatment for prefrontal cognitive dysfunction in older participants: a randomized clinical trial. Neurobiol Aging. 2018;70:117–24.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Drs. John D. Allison and Bob Matthews, for technical assistance.

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R.E.P. conceived the study, designed and performed experiments, and co-wrote the paper. A.B. analyzed data, validated viral deposits, and contributed to writing. B.P.N. piloted behavioral studies. N.A.H. performed surgery, assisted in experimental design, and analysis. O.M.F. performed surgery. S.P., R.G., and L.H. provided materials and resources. D.G.W. conceived the study, designed experiments, and co-wrote the paper.

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Correspondence to Danny G. Winder.

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Perez, R.E., Basu, A., Nabit, B.P. et al. α2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference. Neuropsychopharmacol. 45, 1473–1481 (2020). https://doi.org/10.1038/s41386-020-0641-z

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