Abstract
The GABAergic tail of the ventral tegmental area (tVTA), also named rostromedial tegmental nucleus (RMTg), exerts an inhibitory control on dopamine neurons of the VTA and substantia nigra. The tVTA has been implicated in avoidance behaviors, response to drugs of abuse, reward prediction error, and motor functions. Stimulation of the lateral habenula (LHb) inputs to the tVTA, or of the tVTA itself, induces avoidance behaviors, which suggests a role of the tVTA in processing aversive information. Our aim was to test the impact of aversive stimuli on the molecular recruitment of the tVTA, and the behavioral consequences of tVTA lesions. In rats, we assessed Fos response to lithium chloride (LiCl), β-carboline, naloxone, lipopolysaccharide (LPS), inflammatory pain, neuropathic pain, foot-shock, restraint stress, forced swimming, predator odor, and opiate withdrawal. We also determined the effect of tVTA bilateral ablation on physical signs of opiate withdrawal, and on LPS- and LiCl-induced conditioned taste aversion (CTA). Naloxone-precipitated opiate withdrawal induced Fos in μ-opioid receptor-positive (15%) and -negative (85%) tVTA cells, suggesting the presence of both direct and indirect mechanisms in tVTA recruitment during withdrawal. However, tVTA lesion did not impact physical signs of opiate withdrawal. Fos induction was also present with repeated, but not single, foot-shock delivery. However, such induction was mostly absent with other aversive stimuli. Moreover, tVTA ablation had no impact on CTA. Although stimulation of the tVTA favors avoidance behaviors, present findings suggest that this structure may be important to the response to some, but not all, aversive stimuli.
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
Balcita-Pedicino JJ, Omelchenko N, Bell R, Sesack SR (2011). The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial mesopontine tegmental nucleus. J Comp Neurol 519: 1143–1164.
Benbouzid M, Pallage V, Rajalu M, Waltisperger E, Doridot S, Poisbeau P et al (2008). Sciatic nerve cuffing in mice: a model of sustained neuropathic pain. Eur J Pain 12: 591–599.
Bourdy R, Barrot M (2012). A new control center for dopaminergic systems: pulling the VTA by the tail. Trends Neurosci 35: 681–690.
Bourdy R, Sánchez-Catalán MJ, Kaufling J, Balcita-Pedicino JJ, Freund-Mercier MJ, Veinante P et al (2014). Control of the nigrostriatal dopamine neuron activity and motor function by the tail of the ventral tegmental area. Neuropsychopharmacology 39: 2788–2798.
Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010). Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68: 815–834.
Brown PL, Shepard PD (2013). Lesions of the fasciculus retroflexus alter foot-shock-induced cFos expression in the mesopontine rostromedial tegmental area of rats. PLoS One 8: e60678.
Castanon N, Bluthé RM, Dantzer R (2001). Chronic treatment with the atypical antidepressant tianeptine attenuates sickness behavior induced by peripheral but not central lipopolysaccharide and interleukin-1beta in the rat. Psychopharmacology 154: 50–60.
Cornish JL, Hunt GE, Robins L, McGregor IS (2012). Regional c-Fos and FosB/ΔFosB expression associated with chronic methamphetamine self-administration and metamphetamine-seeking behavior in rats. Neuroscience 206: 100–114.
Cui W, Mizukami H, Yanagisawa M, Aida T, Nomura M, Isomura Y et al (2014). Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. J Neurosci 34: 16273–16285.
File SE, Baldwin HA (1987). Effects of beta-carbolines in animal models of anxiety. Brain Res Bull 19: 293–299.
Geisler S, Marinelli M, Degarmo B, Becker ML, Freiman AJ, Beales M et al (2008). Prominent activation of brainstem and pallidal afferents of the ventral tegmental area by cocaine. Neuropsychopharmacology 33: 2688–2700.
Gellert VF, Holtzman SG (1978). Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions. J Pharmacol Exp Ther 205: 536–546.
Hong S, Jhou TC, Smith M, Saleem KS, Hikosaka O (2011). Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J Neurosci 31: 11457–11471.
Jalabert M, Bourdy R, Courtin J, Veinante P, Manzoni OJ, Barrot M et al (2011). Neuronal circuits underlying acute morphine action on dopamine neurons. Proc Natl Acad Sci USA 108: 16446–16450.
Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC (2009b). The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61: 786–800.
Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS (2009a). The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol 513: 566–596.
Jhou TC, Xu SP, Lee MR, Gallen CL, Ikemoto S (2012). Mapping of reinforcing and analgesic effects of the mu opioid agonist endomorphin-1 in the ventral midbrain of the rat. Psychopharmacology 224: 303–312.
Jhou TC, Good CH, Rowley CS, Xu SP, Wang H, Burnham NW et al (2013). Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways. J Neurosci 33: 7501–7512.
Kaufling J, Veinante P, Pawlowski SA, Freund-Mercier MJ, Barrot M (2009). Afferents to the GABAergic tail of the ventral tegmental area in the rat. J Comp Neurol 513: 597–621.
Kaufling J, Veinante P, Pawlowski SA, Freund-Mercier MJ, Barrot M (2010a). Gamma-aminobutyric acid cells with cocaine-induced DeltaFosB in the ventral tegmental area innervate mesolimbic neurons. Biol Psychiatry 67: 88–92.
Kaufling J, Waltisperger E, Bourdy R, Valera A, Veinante P, Freund-Mercier MJ et al (2010b). Pharmacological recruitment of the GABAergic tail of the ventral tegmental area by acute drug exposure. Br J Pharmacol 161: 1677–1691.
Kaufling J, Aston-Jones G (2015). Persistent adaptations in afferents to ventral tegmental dopamine neurons after opiate withdrawal. J Neurosci 35: 10290–10303.
Konsman JP, Veeneman J, Combe C, Poole S, Luheshi GN, Dantzer R (2008). Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide. Eur J Neurosci 28: 2499–2510.
Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM et al (2012). Input-specific control of reward and aversion in the ventral tegmental area. Nature 491: 212–217.
Lavezzi HN, Parsley KP, Zahm DS (2012). Mesopontine rostromedial tegmental nucleus neurons projecting to the dorsal raphe and pedunculopontine tegmental nucleus: psychostimulant-elicited Fos expression and collateralization. Brain Struct Funct 217: 719–734.
Lavezzi HN, Parsley KP, Zahm DS (2015). Modulation of locomotor activation by the rostromedial tegmental nucleus. Neuropsychopharmacology 40: 676–687.
Lecca S, Melis M, Luchicchi A, Ennas MG, Castelli MP, Muntoni AL et al (2011). Effects of drugs of abuse on putative rostromedial tegmental neurons, inhibitory afferents to midbrain dopamine cells. Neuropsychopharmacology 36: 589–602.
Lecca S, Melis M, Luchicchi A, Muntoni AL, Pistis M (2012). Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse. Neuropsychopharmacology 37: 1164–1176.
Luis-Delgado OE, Barrot M, Rodeau JL, Ulery PG, Freund-Mercier MJ, Lasbennes F (2006a). The transcription factor DeltaFosB is recruited by inflammatory pain. J Neurochem 98: 1423–1431.
Luis-Delgado OE, Barrot M, Rodeau JL, Schott G, Benbouzid M, Poisbeau P et al (2006b). Calibrated forceps: a sensitive and reliable tool for pain and analgesia studies. J Pain 7: 32–39.
Marchand AR, Luck D, DiScala G (2003). Evaluation of an improved automated analysis of freezing behaviour in rats and its use in trace fear conditioning. J Neurosci Methods 126: 145–153.
Matsui A, Williams JT (2011). Opioid-sensitive GABA inputs from rostromedial tegmental nucleus synapse onto midbrain dopamine neurons. J Neurosci 31: 17729–17735.
Matsui A, Jarvie BC, Robinson BG, Hentges ST, Williams JT (2014). Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal. Neuron 82: 1346–1356.
Matsumoto M, Hikosaka O (2009). Representation of negative motivational value in the primate lateral habenula. Nat Neurosci 12: 77–84.
Melis M, Sagheddu C, De Felice M, Casti A, Madeddu C, Spiga S et al (2014). Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in Sardinian alcohol-preferring rats. J Neurosci 34: 12716–12724.
McGregor IS, Hargreaves GA, Apfelbach R, Hunt GE (2004). Neural correlates of cat odor-induced anxiety in rats: region-specific effects of the benzodiazepine midazolam. J Neurosci 24: 4134–4144.
Meye FJ, Valentinova K, Lecca S, Marion-Poll L, Maroteaux MJ, Musardo S et al (2015). Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula. Nat Neurosci 18: 376–378.
Nestler EJ (2015). Reflections on: ’A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function’. Brain Res 1645: 71–74.
Ossenkopp KP, Eckel LA (1995). Toxin-induced conditioned changes in taste reactivity and the role of the chemosensitive area postrema. Neurosci Biobehav Rev 19: 99–108.
Paxinos G, Watson C (2007) The Rat Brain in Stereotaxic Coordinates4th edn.Academic Press: San Diego, CA.
Perrotti LI, Bolaños CA, Choi KH, Russo SJ, Edwards S, Ulery PG et al (2005). ΔFosB accumulates in a GABAergic cell population in the posterior tail of the ventral tegmental area after psychostimulant treatment. Eur J Neurosci 21: 2817–2824.
Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA Jr (2001). Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci 21: 7397–7403.
Rotllant D, Marquez C, Nadal R, Armario A (2010). The brain pattern of c-fos induction by two doses of amphetamine suggests different brain processing pathways and minor contribution of behavioural traits. Neuroscience 168: 691–705.
Sánchez-Catalán MJ, Kaufling J, Georges F, Veinante P, Barrot M (2014). The antero-posterior heterogeneity of the ventral tegmental area. Neuroscience 282C: 198–216.
Slouzkey I, Rosenblum K, Maroun M (2013). Memory of conditioned taste aversion is erased by inhibition of PI3K in the insular cortex. Neuropsychopharmacology 38: 1143–1153.
Stamatakis AM, Stuber GD (2012). Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci 15: 1105–1107.
Tenk CM, Kavaliers M, Ossenkopp KP (2006). The effects of acute corticosterone on lithium chloride-induced conditioned place aversion and locomotor activity in rats. Life Sci 79: 1069–1080.
Thiébot MH, Soubrié P, Sanger D (1988). Anxiogenic properties of beta-CCE and FG 7142: a review of promises and pitfalls. Psychopharmacology 9: 452–463.
Wise RA (2004). Dopamine, learning and motivation. Nat Rev Neurosci 5: 483–494.
Yalcin I, Megat S, Barthas F, Waltisperger E, Kremer M, Salvat E et al (2014). The sciatic nerve cuffing model of neuropathic pain in mice. J Vis Exp 89.
Zahm DS, Becker ML, Freiman AJ, Strauch S, Degarmo B, Geisler S et al (2010). Fos after single and repeated self-administration of cocaine and saline in the rat: emphasis on the Basal forebrain and recalibration of expression. Neuropsychopharmacology 35: 445–463.
Acknowledgements
We thank the UMS3415 Chronobiotron for animal housing, and the Neuropôle ‘Plateforme imagerie in vitro’ for confocal facilities.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Supplementary information
Rights and permissions
About this article
Cite this article
Sánchez-Catalán, MJ., Faivre, F., Yalcin, I. et al. Response of the Tail of the Ventral Tegmental Area to Aversive Stimuli. Neuropsychopharmacol 42, 638–648 (2017). https://doi.org/10.1038/npp.2016.139
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2016.139
This article is cited by
-
Harm reduction approaches for the use of benzodiazepines: a scoping review
Harm Reduction Journal (2025)
-
Activation of the tail of the ventral tegmental area in response to pup predicting cues in maternal rats
Brain Structure and Function (2025)
-
Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice
Nature Communications (2023)
-
Rostromedial tegmental nucleus nociceptin/orphanin FQ (N/OFQ) signaling regulates anxiety- and depression-like behaviors in alcohol withdrawn rats
Neuropsychopharmacology (2023)
-
The rostromedial tegmental nucleus RMTg is not a critical site for ethanol-induced motor activation in rats
Psychopharmacology (2023)
