Abstract
Compulsion-like alcohol drinking (CLAD), where consumption continues despite negative consequences, is a major obstacle to treating alcohol use disorder. The locus coeruleus area in the brainstem and norepinephrine receptor (NER) signaling in forebrain cortical regions have been implicated in adaptive responding under stress, which is conceptually similar to compulsion-like responding (adaptive responding despite the presence of stress or conflict). Thus, we examined whether anterior insula (aINS)-to-brainstem connections and alpha-1 NERs regulated compulsion-like intake and alcohol-only drinking (AOD). Halorhodopsin inhibition of aINS–brainstem significantly reduced CLAD, with no effect on alcohol-only or saccharin intake, suggesting a specific aINS–brainstem role in aversion-resistant drinking. In contrast, prazosin inhibition of alpha-1 NERs systemically reduced both CLAD and AOD. Similar to systemic inhibition, intra-aINS alpha-1-NER antagonism reduced both CLAD and AOD. Global aINS inhibition with GABAR agonists also strongly reduced both CLAD and AOD, without impacting saccharin intake or locomotion, while aINS inhibition of calcium-permeable AMPARs (with NASPM) reduced CLAD without impacting AOD. Finally, prazosin inhibition of CLAD and AOD was not correlated with each other, systemically or within aINS, suggesting the possibility that different aINS pathways regulate CLAD versus AOD, which will require further study to definitively address. Together, our results provide important new information showing that some aINS pathways (aINS–brainstem and NASPM-sensitive) specifically regulate compulsion-like alcohol consumption, while aINS more generally may contain parallel pathways promoting CLAD versus AOD. These findings also support the importance of the adaptive stress response system for multiple forms of alcohol drinking.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
G.B.D. 2019 Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1223–49.
Carvalho AF, Heilig M, Perez A, Probst C, Rehm J. Alcohol use disorders. Lancet. 2019;394:781–92.
Epstein DH, Kowalczyk WJ. Compulsive seekers: our take. Two clinicians’ perspective on a new animal model of addiction. Neuropsychopharmacology. 2017;43:677–9.
Larimer ME, Palmer RS, Marlatt GA. Relapse prevention. An overview of Marlatt’s cognitive-behavioral model. Alcohol Res Health. 1999;23:151–60.
Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217–38.
Everitt BJ, Robbins TW. Drug addiction: updating actions to habits to compulsions ten years on. Annu Rev Psychol. 2016;67:23–50.
Hopf FW, Lesscher HM. Rodent models for compulsive alcohol intake. Alcohol. 2014;48:253–64.
Hopf FW. Do specific NMDA receptor subunits act as gateways for addictive behaviors? Genes Brain Behav. 2017;16:118–38.
Naqvi NH, Gaznick N, Tranel D, Bechara A. The insula: a critical neural substrate for craving and drug seeking under conflict and risk. Ann N Y Acad Sci. 2014;1316:53–70.
Wilcox CE, Pommy JM, Adinoff B. Neural circuitry of impaired emotion regulation in substance use disorders. Am J Psychiatry. 2016;173:344–61.
Chen NM, Lasek AM. Perineuronal nets in the insula regulate aversion-resistant alcohol drinking. Addict Biol. 2020;25:e12821–32.
Seif T, Chang SJ, Simms JA, Gibb SL, Dadgar J, Chen BT, et al. Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. Nat Neurosci. 2013;16:1094–100.
Jaramillo AA, Randall PA, Stewart S, Fortino B, Van Voorhies K, Besheer J. Functional role for cortical-striatal circuitry in modulating alcohol self-administration. Neuropharmacology. 2018;130:42–53.
Seif T, Simms JA, Lei K, Wegner S, Bonci A, Messing RO, et al. D-serine and D-cycloserine reduce compulsive alcohol intake in rats. Neuropsychopharmacology. 2015;40:2357–67.
Grodin EN, Sussman L, Sundby K, Brennan GM, Diazgranados N, Heilig M, et al. Neural correlates of compulsive alcohol seeking in heavy drinkers. Biol Psych Cogn Neuro Neuroimag. 2018;2:1022–31.
Arcurio LR, Finn PR, James TW. Neural mechanisms of high-risk decisions-to-drink in alcohol-dependent women. Addict Biol. 2015;20:390–406.
Tiffany ST, Conklin CA. A cognitive processing model of alcohol craving and compulsive alcohol use. Addiction. 2000;95 Suppl 2:S145–53.
Gehrlach DA, Weiand C, Gaitanos TN, Cho E, Klein AS, Hennrich AA, et al. A whole-brain connectivity map of mouse insular cortex. Elife. 2020;9:e55585–610.
Valentino RJ, Van, Bockstaele E. Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharm. 2008;583:194–203.
Vazey EM, den Hartog CR, Moorman DE. Central noradrenergic interactions with alcohol and regulation of alcohol-related behaviors. Handb Exp Pharm. 2018;248:239–60.
Luppi PH, Aston-Jones G, Akaoka H, Chouvet G, Jouvet M. Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin. Neuroscience. 1995;65:119–60.
Clavier RM. Afferent projections to the self-stimulation regions of the dorsal pons, including the locus coeruleus, in the rat as demonstrated by the horseradish peroxidase technique. Brain Res Bull. 1979;4:497–504.
Yasui Y, Breder CD, Saper CB, Cechetto DF. Autonomic responses and efferent pathways from the insular cortex in the rat. J Comp Neurol. 1991;303:355–74.
Cedarbaum JM, Aghajanian GK. Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. J Comp Neurol. 1978;178:1–16.
Sinha R, Wemm S, Fogelman N, Milivojevic V, Morgan PM, Angarita GA, et al. Moderation of Prazosin’s efficacy by alcohol withdrawal symptoms. Am J Psychiatry. 2020;178:447–58.
Wilcox CE, Adinoff B, Clifford J, Ling J, Witkiewitz K, Mayer AR, et al. Brain activation and subjective anxiety during an anticipatory anxiety task is related to clinical outcome during prazosin treatment for alcohol use disorder. Neuroimage Clin. 2020;26:102162.
Skelly MJ, Weiner JL. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain Behav. 2014;4:468–83.
Le AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, et al. Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology. 2012;218:89–99.
Walker BM, Rasmussen DD, Raskind MA, Koob GF. alpha1-noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol. Alcohol. 2008;42:91–7.
Verplaetse TL, Rasmussen DD, Froehlich JC, Czachowski CL. Effects of prazosin, an alpha1-adrenergic receptor antagonist, on the seeking and intake of alcohol and sucrose in alcohol-preferring (P) rats. Alcohol Clin Exp Res. 2012;36:881–6.
Rasmussen DD, Beckwith LE, Kincaid CL, Froehlich JC. Combining the alpha1-adrenergic receptor antagonist, prazosin, with the beta-adrenergic receptor antagonist, propranolol, reduces alcohol drinking more effectively than either drug alone. Alcohol Clin Exp Res. 2014;38:1532–9.
Darevsky D, Gill TM, Vitale KR, Hu B, Wegner SA, Hopf FW. Drinking despite adversity: behavioral evidence for a head down and push strategy of conflict-resistant alcohol drinking in rats. Addict Biol. 2019;24:426–37.
Darevsky D, Hopf FW. Behavioral indicators of succeeding and failing under higher-challenge compulsion-like alcohol drinking in rat. Behav Brain Res. 2020;393:112768.
Wegner SA, Hu B, De Oliveira Sergio T, Darevsky D, Kwok CC, Lei K, et al. A novel NMDA receptor-based intervention to suppress compulsion-like alcohol drinking. Neuropharmacology. 2019;157:107681.
Fuchs RA, Evans KA, Parker MP, See RE. Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. J Neurosci. 2004;24:6600–10.
Li X, Zeric T, Kambhampati S, Bossert JM, Shaham Y. The central amygdala nucleus is critical for incubation of methamphetamine craving. Neuropsychopharmacology. 2015;40:1297–306.
Lei K, Kwok C, Darevsky D, Wegner SA, Yu J, Nakayama L, et al. Nucleus accumbens shell Orexin-1 receptors are critical mediators of binge intake in excessive-drinking individuals. Front Neurosci. 2019;13:88.
den Hartog C, Zamudio-Bulcock P, Nimitvilai S, Gilstrap M, Eaton B, Fedarovich H, et al. Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice. Neuropharmacology. 2016;107:451–9.
Hopf FW, Mangieri RA. Do alcohol-related AMPA-type glutamate receptor adaptations promote intake? Handb Exp Pharm. 2018;248:157–86.
McBain CJ, Fisahn A. Interneurons unbound. Nat Rev Neurosci. 2001;2:11–23.
Aston-Jones G, Cohen JD. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci. 2005;28:403–50.
Varazzani C, San-Galli A, Gilardeau S, Bouret S. Noradrenaline and dopamine neurons in the reward/effort trade-off: a direct electrophysiological comparison in behaving monkeys. J Neurosci. 2015;35:7866–77.
Jahn CI, Gilardeau S, Varazzani C, Blain B, Sallet J, Walton ME, et al. Dual contributions of noradrenaline to behavioural flexibility and motivation. Psychopharmacology. 2018;235:2687–702.
Ullsperger M, Harsay HA, Wessel JR, Ridderinkhof KR. Conscious perception of errors and its relation to the anterior insula. Brain Struct Funct. 2010;214:629–43.
Datta D, Yang ST, Galvin VC, Solder J, Luo F, Morozov YM, et al. Noradrenergic alpha1-adrenoceptor actions in the primate dorsolateral prefrontal cortex. J Neurosci. 2019;39:2722–34.
Berridge CW, Shumsky JS, Andrzejewski ME, McGaughy JA, Spencer RC, Devilbiss DM, et al. Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic alpha(1)- and alpha(2)-receptors. Biol Psychiatry. 2012;71:467–73.
Berridge CW, Spencer RC. Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex. Brain Res. 2016;1641:189–96.
Porter BS, Li K, Hillman KL. Regional activity in the rat anterior cingulate cortex and insula during persistence and quitting in a physical-effort task. eNeuro. 2020;7:ENEURO.0243-20.2020.
Lustberg D, Iannitelli AF, Tillage RP, Pruitt M, Liles LC, Weinshenker D. Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder. Psychopharmacology. 2020;237:1973–87.
Owen SF, Liu MH, Kreitzer AC. Thermal constraints on in vivo optogenetic manipulations. Nat Neurosci. 2019;22:1061–5.
Corbetta M, Patel G, Shulman GL. The reorienting system of the human brain: from environment to theory of mind. Neuron. 2008;58:306–24.
Alnaes D, Sneve MH, Espeseth T, Endestad T, van de Pavert SH, Laeng B. Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in the dorsal attention network and the locus coeruleus. J Vis. 2014;14:1–20.
Puumala T, Riekkinen P Sr, Sirvio J. Modulation of vigilance and behavioral activation by alpha-1 adrenoceptors in the rat. Pharm Biochem Behav. 1997;56:705–12.
Schmidt KT, Schroeder JP, Foster SL, Squires K, Smith BM, Pitts EG, et al. Norepinephrine regulates cocaine-primed reinstatement via alpha1-adrenergic receptors in the medial prefrontal cortex. Neuropharmacology. 2017;119:134–40.
Forget B, Wertheim C, Mascia P, Pushparaj A, Goldberg SR, Le Foll B. Noradrenergic alpha1 receptors as a novel target for the treatment of nicotine addiction. Neuropsychopharmacology. 2010;35:1751–60.
Do-Monte FH, Souza RR, Wong TT, Carobrez Ade P. Systemic or intra-prelimbic cortex infusion of prazosin impairs fear memory reconsolidation. Behav Brain Res. 2013;244:137–41.
Fox HC, Anderson GM, Tuit K, Hansen J, Kimmerling A, Siedlarz KM, et al. Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res. 2012;36:351–60.
Funk D, Stewart J. Role of catecholamines in the frontal cortex in the modulation of basal and stress-induced autonomic output in rats. Brain Res. 1996;741:220–9.
Ye L, Orynbayev M, Zhu X, Lim EY, Dereddi RR, Agarwal A, et al. Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release. Nat Commun. 2020;11:6157.
Venniro M, Caprioli D, Zhang M, Whitaker LR, Zhang S, Warren BL, et al. The anterior insular cortex->central amygdala glutamatergic pathway is critical to relapse after contingency management. Neuron. 2017;96:414–27.e8.
Arguello AA, Wang R, Lyons CM, Higginbotham JA, Hodges MA, Fuchs RA. Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats. Psychopharmacology. 2017;234:2431–41.
Rotge JY, Cocker PJ, Daniel ML, Belin-Rauscent A, Everitt BJ, Belin D. Bidirectional regulation over the development and expression of loss of control over cocaine intake by the anterior insula. Psychopharmacology. 2017;234:1623–31.
Mendez-Ruette M, Linsambarth S, Moraga-Amaro R, Quintana-Donoso D, Mendez L, Tamburini G, et al. The role of the rodent insula in anxiety. Front Physiol. 2019;10:330.
Neill DB. Frontal–striatal control of behavioral inhibition in the rat. Brain Res. 1976;105:89–103.
Campbell EJ, Flanagan JPM, Walker LC, Hill M, Marchant NJ, Lawrence AJ. Anterior insular cortex is critical for the propensity to relapse following punishment-imposed abstinence of alcohol seeking. J Neurosci. 2019;39:1077–87.
Jaramillo AA, Agan VE, Makhijani VH, Pedroza S, McElligott ZA, Besheer J. Functional role for suppression of the insular-striatal circuit in modulating interoceptive effects of alcohol. Addict Biol. 2018;23:1020–31.
Joshi DD, Puaud M, Fouyssac M, Belin-Rauscent A, Everitt B, Belin D. The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse. Eur J Neurosci. 2020;52:4115–26.
Haaranen M, Scuppa G, Tambalo S, Jarvi V, Bertozzi SM, Armirotti A, et al. Anterior insula stimulation suppresses appetitive behavior while inducing forebrain activation in alcohol-preferring rats. Transl Psychiatry. 2020;10:150.
Haaranen M, Schafer A, Jarvi V, Hyytia P. Chemogenetic stimulation and silencing of the insula, amygdala, nucleus accumbens, and their connections differentially modulate alcohol drinking in rats. Front Behav Neurosci. 2020;14:580849.
Siciliano CA, Noamany H, Chang CJ, Brown AR, Chen X, Leible D, et al. A cortical-brainstem circuit predicts and governs compulsive alcohol drinking. Science. 2019;366:1008–12.
Alves FH, Crestani CC, Resstel LB, Correa FM. Both alpha1- and alpha2-adrenoceptors in the insular cortex are involved in the cardiovascular responses to acute restraint stress in rats. PLoS ONE. 2014;9:e83900.
Alves FH, Crestani CC, Resstel LB, Correa FM. Cardiovascular effects of noradrenaline microinjected into the insular cortex of unanesthetized rats. Auton Neurosci. 2011;160:90–8.
Ventura R, De Carolis D, Alcaro A, Puglisi-Allegra S. Ethanol consumption and reward depend on norepinephrine in the prefrontal cortex. Neuroreport. 2006;17:1813–7.
Rojas S, Diaz-Galarce R, Jerez-Baraona JM, Quintana-Donoso D, Moraga-Amaro R, Stehberg J. The insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat. Front Behav Neurosci. 2015;9:164.
Robertson SD, Plummer NW, Jensen P. Uncovering diversity in the development of central noradrenergic neurons and their efferents. Brain Res. 2016;1641:234–44.
Drouin C, Blanc G, Trovero F, Glowinski J, Tassin JP. Cortical alpha 1-adrenergic regulation of acute and sensitized morphine locomotor effects. Neuroreport. 2001;12:3483–6.
Darracq L, Blanc G, Glowinski J, Tassin JP. Importance of the noradrenaline–dopamine coupling in the locomotor activating effects of D-amphetamine. J Neurosci. 1998;18:2729–39.
Kang S, Li J, Zuo W, Fu R, Gregor D, Krnjevic K, et al. Ethanol withdrawal drives anxiety-related behaviors by reducing M-type potassium channel activity in the lateral habenula. Neuropsychopharmacology. 2017;42:1813–24.
Fu R, Mei Q, Shiwalkar N, Zuo W, Zhang H, Gregor D, et al. Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula. Neuropharmacology. 2020;163:107863.
Albrechet-Souza L, Schratz CL, Gilpin NW. Sex differences in traumatic stress reactivity in rats with and without a history of alcohol drinking. Biol Sex Differ. 2020;11:27.
George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen CD, et al. Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking. Proc Natl Acad Sci U S A. 2012;109:18156–61.
Li J, Bian W, Dave V, Ye JH. Blockade of GABA(A) receptors in the paraventricular nucleus of the hypothalamus attenuates voluntary ethanol intake and activates the hypothalamic-pituitary-adrenocortical axis. Addict Biol. 2011;16:600–14.
Steensland P, Fredriksson I, Holst S, Feltmann K, Franck J, Schilstrom B, et al. The monoamine stabilizer (-)-OSU6162 attenuates voluntary ethanol intake and ethanol-induced dopamine output in nucleus accumbens. Biol Psychiatry. 2012;72:823–31.
Acknowledgements
We thank Sarah Wean and Drs Andrea Jones and Simon Katner for assistance with intracranial prazosin experiments, and Molly Sazer-Hopf for help with brain images.
Author information
Authors and Affiliations
Contributions
TDOS, KL, SAW, and FWH designed the experiments; TDOS, KL, CK, SG, SAW, MW, JW, and FWH performed the experiments; TDOS, KL, SAW, DD, and FWH analyzed the data; TDOS and FWH wrote a first draft of the manuscript, all authors edited the manuscript and approved the final version. Raw data are available upon request.
Corresponding author
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
De Oliveira Sergio, T., Lei, K., Kwok, C. et al. The role of anterior insula–brainstem projections and alpha-1 noradrenergic receptors for compulsion-like and alcohol-only drinking. Neuropsychopharmacol. 46, 1918–1926 (2021). https://doi.org/10.1038/s41386-021-01071-w
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-021-01071-w
This article is cited by
-
Bad habits–good goals? Meta-analysis and translation of the habit construct to alcoholism
Translational Psychiatry (2024)
-
Punishment-resistant alcohol intake is mediated by the nucleus accumbens shell in female rats
Neuropsychopharmacology (2024)
-
Insular cortex subregions have distinct roles in cued heroin seeking after extinction learning and prolonged withdrawal in rats
Neuropsychopharmacology (2024)
