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.
Subscribe to Journal
Get full journal access for 1 year
only $30.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
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.
Sinha, R, Catapano, D, O’Malley S. Stress-induced craving and stress response in cocaine dependent individuals. Psychoneuroendocrinology.1999; 142:343–51.
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.
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.
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.
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.
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.
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.
Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Anaesthesia. 1999;54:146–65.
Seedat YK. Clonidine and guanfacine—comparison of their effects on haemodynamics in hypertension. South Afr Med J. 1985;67:557–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gilsbach R, Albarrán-Juárez J, Hein L. Pre- versus Postsynaptic Signaling by α 2-Adrenoceptors. Curr Top Membr. 2011;67:139–60.
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.
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.
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.
Paxinos G, Franklin B. The mouse brain in stereotaxic coordinates. Academic Press; 2004.
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.
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.
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.
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.
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.
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.
Avery SN, Clauss JA, Blackford JU. The Human BNST: Functional Role in Anxiety and Addiction. Neuropsychopharmacology. 2016;41:126–41.
Clauss JA, Avery SN, Benningfield MM, Blackford JU. Social anxiety is associated with BNST response to unpredictability. Depress Anxiety. 2019; 36:666–75.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Winter JC, Rabin RA. Yohimbine as a serotonergic agent: evidence from receptor binding and drug discrimination. J Pharm Exp Ther. 1992;263:682–9.
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.
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.
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.
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.
We thank Drs. John D. Allison and Bob Matthews, for technical assistance.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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