Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The lateral habenula is not required for ethanol dependence-induced escalation of drinking

Neuropsychopharmacology (2022)Cite this article

Subjects

Abstract

The lateral habenula (LHb) is an epithalamic nuclei that has been shown to signal the aversive properties of ethanol. The present study tested the hypothesis that activity of the LHb is required for the acquisition and/or expression of dependence-induced escalation of ethanol drinking and somatic withdrawal symptoms. Male Sprague–Dawley rats completed 4 weeks of baseline drinking under a standard intermittent access two-bottle choice (2BC) paradigm before undergoing 2 weeks of daily chronic intermittent ethanol (CIE) via vapor inhalation. Following this CIE exposure period, rats resumed 2BC drinking to assess dependence-induced changes in voluntary ethanol consumption. CIE exposed rats exhibited a significant increase in ethanol drinking that was associated with high levels of blood alcohol and a reduction in somatic symptoms of ethanol withdrawal. However, despite robust cFos activation in the LHb during ethanol withdrawal, chemogenetic inhibition of the LHb did not alter either ethanol consumption or somatic signs of ethanol withdrawal. Consistent with this observation, ablating LHb outputs via electrolytic lesions of the fasciculus retroflexus (FR) did not alter the acquisition of somatic withdrawal symptoms or escalation of ethanol drinking in CIE-exposed rats. The LHb controls activity of the rostromedial tegmental nucleus (RMTg), a midbrain nucleus activated by aversive experiences including ethanol withdrawal. During ethanol withdrawal, both FR lesioned and sham control rats exhibited similar cFos activation in the RMTg, suggesting that RMTg activation during ethanol withdrawal does not require LHb input. These data suggest that, at least in male rats, the LHb is not necessary for the acquisition or expression of escalation of ethanol consumption or expression of somatic symptoms of ethanol withdrawal. Overall, our findings provide evidence that the LHb is dispensable for some of the negative consequences of ethanol withdrawal.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1: Escalation of ethanol drinking and somatic signs of withdrawal following CIE exposure.
Fig. 2: Chemogenetic inhibition of the LHb does not alter ethanol dependence-induced escalation of drinking or somatic signs of withdrawal.
Fig. 3: The LHb is activated during withdrawal from chronic ethanol exposure.
Fig. 4: Lesioning the FR does not alter the acquisition of somatic withdrawal symptoms or escalated ethanol intake in ethanol dependence.
Fig. 5: Lesioning the fasciculus retroflexus does not alter withdrawal-induced cFos expression in the RMTg.

References

  1. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217–38.

    PubMed  Article  Google Scholar 

  2. Gilpin NW, et al. Operant behavior and alcohol levels in blood and brain of alcohol-dependent rats. Alcohol Clin Exp Res. 2009;33:2113–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Vendruscolo LF, Roberts AJ. Operant alcohol self-administration in dependent rats: Focus on the vapor model. Alcohol. 2014;48:277–86.

    CAS  PubMed  Article  Google Scholar 

  4. O’Dell LE, Roberts AJ, Smith RT, Koob GF. Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure. Alcohol Clin Exp Res. 2004;28:1676–82.

    PubMed  Article  Google Scholar 

  5. Rassnick S, Heinrichs SC, Britton KT, Koob GF. Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res. 1993;605:25–32.

    CAS  PubMed  Article  Google Scholar 

  6. Roberts AJ, Cole M, Koob GF. Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats. Alcohol Clin Exp Res. 1996;20:1289–98.

    CAS  PubMed  Article  Google Scholar 

  7. de Guglielmo G, et al. Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats. Nat Commun. 2019;10:1238.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Cunningham CL, Fidler TL, Murphy KV, Mulgrew JA, Smitasin PJ. Time-dependent negative reinforcement of ethanol intake by alleviation of acute withdrawal. Biol Psychiatry. 2013;73:249–55.

    CAS  PubMed  Article  Google Scholar 

  9. Aizawa H, Kobayashi M, Tanaka S, Fukai T, Okamoto H. Molecular characterization of the subnuclei in rat habenula. J Comp Neurol. 2012;520:4051–66.

    CAS  PubMed  Article  Google Scholar 

  10. Namboodiri VMK, Rodriguez-Romaguera J, Stuber GD. The habenula. Curr Biol. 2016;26:R873–77.

    CAS  PubMed  Article  Google Scholar 

  11. Zahm DS, Root DH. Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving. Pharmacol Biochem Behav. 2017;162:3–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Brinschwitz K, et al. Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain. Neuroscience. 2010;168:463–76.

    CAS  PubMed  Article  Google Scholar 

  13. Hu H, Cui Y, Yang Y. Circuits and functions of the lateral habenula in health and in disease. Nat Rev Neurosci. 2020;21:277–95.

    CAS  PubMed  Article  Google Scholar 

  14. Quina LA, et al. Efferent pathways of the mouse lateral habenula: efferent pathways of the mouse lateral habenula. J Comp Neurol. 2015;523:32–60.

    PubMed  Article  Google Scholar 

  15. Zhou L, et al. Organization of functional long-range circuits controlling the activity of serotonergic neurons in the dorsal raphe nucleus. Cell Rep. 2017;18:3018–32.

    CAS  PubMed  Article  Google Scholar 

  16. Matsumoto M, Hikosaka O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature. 2007;447:1111–5.

    CAS  PubMed  Article  Google Scholar 

  17. Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12:77–84.

    CAS  PubMed  Article  Google Scholar 

  18. Hong S, Jhou TC, Smith M, Saleem KS, Hikosaka O. Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J Neurosci. 2011;31:11457–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Laurent V, Wong FL, Balleine BW. The lateral habenula and its input to the rostromedial tegmental nucleus mediates outcome-specific conditioned inhibition. J Neurosci. 2017;37:10932–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Li H, et al. Three rostromedial tegmental afferents drive triply dissociable aspects of punishment learning and aversive valence encoding. Neuron. 2019;104:987–99.e4

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Proulx CD, et al. A neural pathway controlling motivation to exert effort. Proc Natl Acad Sci. 2018;115:5792–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Stamatakis AM, Stuber GD. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci. 2012;15:1105–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Coffey KR, Marx RG, Vo EK, Nair SG, Neumaier JF. Chemogenetic inhibition of lateral habenula projections to the dorsal raphe nucleus reduces passive coping and perseverative reward-seeking in rats. Neuropsychopharmacology. 2020;45:1115–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Lammel S, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012;491:212–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Li B, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470:535–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Szőnyi A, et al. Median raphe controls acquisition of negative experience in the mouse. Science. 2019;366:eaay8746.

    PubMed  Article  CAS  Google Scholar 

  27. Clerke JA, Congiu M, Mameli M. Neuronal adaptations in the lateral habenula during drug withdrawal: Preclinical evidence for addiction therapy. Neuropharmacology. 2021;192:108617.

    CAS  PubMed  Article  Google Scholar 

  28. Mathis V, Kenny PJ. From controlled to compulsive drug-taking: The role of the habenula in addiction. Neurosci Biobehav Rev. 2019;106:102–11.

    PubMed  Article  Google Scholar 

  29. Shah A, et al. The lateral habenula and alcohol: Role of glutamate and M-type potassium channels. Pharmacol Biochem Behav. 2017;162:94–102.

    CAS  PubMed  Article  Google Scholar 

  30. Valentinova K, et al. Morphine withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability. Nat Neurosci. 2019;22:1053–6.

    CAS  PubMed  Article  Google Scholar 

  31. Haack AK, et al. Lesions of the lateral habenula increase voluntary ethanol consumption and operant self-administration, block yohimbine-induced reinstatement of ethanol seeking, and attenuate ethanol-induced conditioned taste aversion. PLoS ONE. 2014;9:e92701.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Glover EJ, McDougle MJ, Siegel GS, Jhou TC, Chandler LJ. Role for the rostromedial tegmental nucleus in signaling the aversive properties of alcohol. Alcohol Clin Exp Res. 2016;40:1651–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Tandon S, Keefe KA, Taha SA. Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion: LHb activity mediates ethanol-induced aversion. J Physiol. 2017;595:1393–412.

    CAS  PubMed  Article  Google Scholar 

  34. Zuo W, et al. Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor-mediated activation of lateral habenula neurons: LHb and alcohol addiction. Addict Biol. 2017;22:103–16.

    CAS  PubMed  Article  Google Scholar 

  35. Sheth C, Furlong TM, Keefe KA, Taha SA. The lateral hypothalamus to lateral habenula projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption. Behav Brain Res. 2017;328:195–208.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Kang S, et al. Ethanol withdrawal drives anxiety-related behaviors by reducing m-type potassium channel activity in the lateral habenula. Neuropsychopharmacology. 2017;42:1813–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Kang S, Li J, Bekker A, Ye J-H. Rescue of glutamate transport in the lateral habenula alleviates depression- and anxiety-like behaviors in ethanol-withdrawn rats. Neuropharmacology. 2018;129:47–56.

    CAS  PubMed  Article  Google Scholar 

  38. Li J, et al. Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats. Neuropharmacology. 2017;126:108–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Zuo W, et al. Ethanol potentiates both GABAergic and glutamatergic signaling in the lateral habenula. Neuropharmacology. 2017;113:178–87.

    CAS  PubMed  Article  Google Scholar 

  40. Shiwalkar, N, Zuo, W, Bekker A, Ye J-H, The role of the lateral habenula circuitries in alcohol use disorders. In Neuroscience of Alcohol 153-61 (Elsevier, 2019). https://doi.org/10.1016/B978-0-12-813125-1.00016-7.

  41. Glover EJ, Starr EM, Chao Y, Jhou TC, Chandler LJ. Inhibition of the rostromedial tegmental nucleus reverses alcohol withdrawal-induced anxiety-like behavior. Neuropsychopharmacology (2019). https://doi.org/10.1038/s41386-019-0406-8.

  42. Smith RJ, Anderson RI, Haun HL, Mulholland PJ, Griffin WC 3rd, Lopez MF, et al. Dynamic c-Fos changes in mouse brain during acute and protracted withdrawal from chronic intermittent ethanol exposure and relapse drinking. Addict. Biol. 2020;25:e12804. https://doi.org/10.1111/adb.12804.

    CAS  Article  PubMed  Google Scholar 

  43. Brown PL, Shepard PD. Lesions of the fasciculus retroflexus alter footshock-induced cfos expression in the mesopontine rostromedial tegmental area of rats. PLoS ONE. 2013;8:e60678.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Jhou TC, et al. Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways. J Neurosci. 2013;33:7501–12.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Meye FJ, et al. Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse. Nat Neurosci. 2016;19:1019–24.

    CAS  PubMed  Article  Google Scholar 

  46. Lahti L, et al. Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei. Development. 129957 (2015). https://doi.org/10.1242/dev.129957.

  47. Smith RJ, Vento PJ, Chao YS, Good CH, Jhou TC. Gene expression and neurochemical characterization of the rostromedial tegmental nucleus (RMTg) in rats and mice. Brain Struct Funct. 2019;224:219–38.

    CAS  PubMed  Article  Google Scholar 

  48. Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC. The Rostromedial Tegmental Nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron. 2009;61:786–800.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Funding

This work was supported by funding from the National Institutes on Alcohol Abuse and Alcoholism grants AA019967 and AA027706 (LJC), T32 AA007474 (TBN), and F31 AA029622 (TBN), P50 AA010761 (JJW), and from the National Institute of Drug Abuse grant F31 DA045485 (KMB). The authors have nothing to disclose.

Author information

Author notes

  1. Dylan T. Vaughan

    Present address: Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

  2. Kevin M. Braunscheidel

    Present address: Department of Neuroscience Mount Sinai, New York, NY, USA

Authors and Affiliations

  1. Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA

    Todd B. Nentwig, Dylan T. Vaughan, Kevin M. Braunscheidel, Brittney D. Browning, John J. Woodward & L. Judson Chandler

Authors
  1. Todd B. Nentwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dylan T. Vaughan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin M. Braunscheidel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brittney D. Browning
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John J. Woodward
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Judson Chandler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TBN and LJC designed the experiments and co-wrote the manuscript. TBN performed the experiments, carried out the statistical analysis, and graphed the data. DTV assisted with behavioral experiments. KMB performed slice electrophysiology experiments and analysis with oversight by JJW. BDB assisted with the immunofluorescence experiments.

Corresponding author

Correspondence to L. Judson Chandler.

Ethics declarations

Competing interests

The 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.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nentwig, T.B., Vaughan, D.T., Braunscheidel, K.M. et al. The lateral habenula is not required for ethanol dependence-induced escalation of drinking. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01357-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41386-022-01357-7

Search

Advanced search

Quick links