Abstract
Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by α7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.
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
Alkondon M, Pereira EF, Barbosa CT, Albuquerque EX (1997). Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharmacol Exp Ther 283: 1396–1411.
Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EX (1999). Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices. J Neurosci 19: 2693–2705.
Atherton JF, Bevan MD (2005). Ionic mechanisms underlying autonomous action potential generation in the somata and dendrites of GABAergic substantia nigra pars reticulata neurons in vitro. J Neurosci 25: 8272–8281.
Balcita-Pedicino J, Omelchenko N, Bell R, Sesack SR (2009). The rostromedial mesopontine tegmentum as a relay between the lateral habenula and dopamine neurons in the ventral tegmental area: ultrastructural evidence in the rat program no 815.7/B91. 2009 Neuroscience Meeting Planner. Society for Neuroscience: Chicago, IL.
Brinschwitz K, Dittgen A, Madai VI, Lommel R, Geisler S, Veh RW (2010). Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain. Neuroscience 168: 463–476.
Brischoux F, Chakraborty S, Brierley DI, Ungless MA (2009). Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc Natl Acad Sci USA 106: 4894–4899.
Burke KA, Franz TM, Gugsa N, Schoenbaum G (2006). Prior cocaine exposure disrupts extinction of fear conditioning. Learn Mem 13: 416–421.
Cahusac PM, Morris R, Salt TE, Hill RG (1990). Sensory responses of caudal trigeminal neurons to thermal and mechanical stimuli and their behavioural correlates in the rat. Neuroscience 36: 543–551.
Chen BT, Hopf FW, Bonci A (2010). Synaptic plasticity in the mesolimbic system: therapeutic implications for substance abuse. Ann N Y Acad Sci 1187: 129–139.
Christoph GR, Leonzio RJ, Wilcox KS (1986). Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J Neurosci 6: 613–619.
Colussi-Mas J, Geisler S, Zimmer L, Zahm DS, Berod A (2007). Activation of afferents to the ventral tegmental area in response to acute amphetamine: a double-labelling study. Eur J Neurosci 26: 1011–1025.
Davila V, Yan Z, Craciun LC, Logothetis D, Sulzer D (2003). D3 dopamine autoreceptors do not activate G-protein-gated inwardly rectifying potassium channel currents in substantia nigra dopamine neurons. J Neurosci 23: 5693–5697.
Erhardt S, Schwieler L, Engberg G (2002). Excitatory and inhibitory responses of dopamine neurons in the ventral tegmental area to nicotine. Synapse 43: 227–237.
Fisher JL, Pidoplichko VI, Dani JA (1998). Nicotine modifies the activity of ventral tegmental area dopaminergic neurons and hippocampal GABAergic neurons. J Physiol Paris 92: 209–213.
Frazier CJ, Rollins YD, Breese CR, Leonard S, Freedman R, Dunwiddie TV (1998). Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells. J Neurosci 18: 1187–1195.
French ED, Dillon K, Wu X (1997). Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 8: 649–652.
Freund TF, Katona I, Piomelli D (2003). Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83: 1017–1066.
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.
Gessa GL, Melis M, Muntoni AL, Diana M (1998). Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors. Eur J Pharmacol 341: 39–44.
Glavinovic MI, Rabie HR (1998). Monte Carlo simulation of spontaneous miniature excitatory postsynaptic currents in rat hippocampal synapse in the presence and absence of desensitization. Pflugers Arch 435: 193–202.
Gordon MK, Rosen JB (1999). Lasting effect of repeated cocaine administration on acoustic and fear-potentiated startle in rats. Psychopharmacology (Berl) 144: 1–7.
Gould TJ, Wehner JM (1999). Nicotine enhancement of contextual fear conditioning. Behav Brain Res 102: 31–39.
Grace AA, Bunney BS (1983). Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—1. Identification and characterization. Neuroscience 10: 301–315.
Grace AA, Bunney BS (1984). The control of firing pattern in nigral dopamine neurons: burst firing. J Neurosci 4: 2877–2890.
Haney M, Miczek KA (1994). Ultrasounds emitted by female rats during agonistic interactions: effects of morphine and naltrexone. Psychopharmacology (Berl) 114: 441–448.
Hikosaka O, Sesack SR, Lecourtier L, Shepard PD (2008). Habenula: crossroad between the basal ganglia and the limbic system. J Neurosci 28: 11825–11829.
Hirasawa H, Shiells R, Yamada M (2001). Blocking AMPA receptor desensitization prolongs spontaneous EPSC decay times and depolarizes H1 horizontal cells in carp retinal slices. Neurosci Res 40: 217–225.
Hutchison MA, Riley AL (2008). Adolescent exposure to nicotine alters the aversive effects of cocaine in adult rats. Neurotoxicol Teratol 30: 404–411.
Ikemoto S (2010). Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev (in press, originally published online 10 February 2010, doi:10.1016/j.neubiorev.2010.02.001).
Ikemoto S, Qin M, Liu ZH (2006). Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J Neurosci 26: 723–730.
Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC (2009a). 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 (2009b). 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 S, Ikemoto S (2009c). Self-administration of a mu-opioid agonist into the rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons and other arousal systems Program No 683.1/GG66. 2009 Neuroscience Meeting Planner. Society for Neuroscience: Chicago, IL.
Ji H, Shepard PD (2007). Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism. J Neurosci 27: 6923–6930.
Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009). Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89: 309–380.
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.
Lesage F, Guillemare E, Fink M, Duprat F, Heurteaux C, Fosset M et al (1995). Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J Biol Chem 270: 28660–28667.
Lu Y, Marks MJ, Collins AC (1999). Desensitization of nicotinic agonist-induced [3H]gamma-aminobutyric acid release from mouse brain synaptosomes is produced by subactivating concentrations of agonists. J Pharmacol Exp Ther 291: 1127–1134.
Mansvelder HD, Keath JR, McGehee DS (2002). Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33: 905–919.
Marinelli M, Rudick CN, Hu XT, White FJ (2006). Excitability of dopamine neurons: modulation and physiological consequences. CNS Neurol Disord Drug Targets 5: 79–97.
Matsuda LA, Bonner TI, Lolait SJ (1993). Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol 327: 535–550.
Matsumoto M, Hikosaka O (2007). Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447: 1111–1115.
Melis M, Camarini R, Ungless MA, Bonci A (2002). Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure. J Neurosci 22: 2074–2082.
Melis M, Pillolla G, Luchicchi A, Muntoni AL, Yasar S, Goldberg SR et al (2008). Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors. J Neurosci 28: 13985–13994.
Mereu G, Yoon KW, Boi V, Gessa GL, Naes L, Westfall TC (1987). Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine. Eur J Pharmacol 141: 395–399.
Moreira FA, Aguiar DC, Campos AC, Lisboa SF, Terzian AL, Resstel LB et al (2009). Antiaversive effects of cannabinoids: is the periaqueductal gray involved? Neural Plast 2009: 625469.
Moreira FA, Lutz B (2008). The endocannabinoid system: emotion, learning and addiction. Addict Biol 13: 196–212.
Morrow BA, Taylor JR, Roth RH (1995). Prior exposure to cocaine diminishes behavioral and biochemical responses to aversive conditioning: reversal by glycine/N-methyl-D-aspartate antagonist co-treatment. Neuroscience 69: 233–240.
Nie Z, Schweitzer P, Roberts AJ, Madamba SG, Moore SD, Siggins GR (2004). Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303: 1512–1514.
Omelchenko N, Bell R, Sesack SR (2009). Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area. Eur J Neurosci 30: 1239–1250.
Pang Y, Kiba H, Jayaraman A (1993). Acute nicotine injections induce c-fos mostly in non-dopaminergic neurons of the midbrain of the rat. Brain Res Mol Brain Res 20: 162–170.
Paxinos G, Watson C (2007). The Rat Brain in Stereotaxic Coordinates, 7th edn. Elsevier Academic Press: London.
Perrotti LI, Bolanos CA, Choi KH, Russo SJ, Edwards S, Ulery PG et al (2005). DeltaFosB accumulates in a GABAergic cell population in the posterior tail of the ventral tegmental area after psychostimulant treatment. Eur J Neurosci 21: 2817–2824.
Pidoplichko VI, DeBiasi M, Williams JT, Dani JA (1997). Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390: 401–404.
Radcliffe KA, Fisher JL, Gray R, Dani JA (1999). Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal neurons. Ann N Y Acad Sci 868: 591–610.
Schilstrom B, Yaka R, Argilli E, Suvarna N, Schumann J, Chen BT et al (2006). Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors. J Neurosci 26: 8549–8558.
Schultz W (2007a). Behavioral dopamine signals. Trends Neurosci 30: 203–210.
Schultz W (2007b). Multiple dopamine functions at different time courses. Annu Rev Neurosci 30: 259–288.
Seguela P, Wadiche J, Dineley-Miller K, Dani JA, Patrick JW (1993). Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci 13: 596–604.
Simpson GR, Riley AL (2005). Morphine preexposure facilitates morphine place preference and attenuates morphine taste aversion. Pharmacol Biochem Behav 80: 471–479.
Ungless MA, Magill PJ, Bolam JP (2004). Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science 303: 2040–2042.
Vivian JA, Miczek KA (1998). Effects of mu and delta opioid agonists and antagonists on affective vocal and reflexive pain responses during social stress in rats. Psychopharmacology (Berl) 139: 364–375.
Wise RA, Yokel RA, DeWit H (1976). Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats. Science 191: 1273–1275.
Acknowledgements
We thank Stefano Carta and Angelo Casu for their skillful technical assistance and the Regione Autonoma della Sardegna, Assessorato alla Programmazione, for the support given to SL and AL through the program ‘Bursaries for Young Researchers.’
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Supplementary information
Rights and permissions
About this article
Cite this article
Lecca, S., Melis, M., Luchicchi, A. et al. Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells. Neuropsychopharmacol 36, 589–602 (2011). https://doi.org/10.1038/npp.2010.190
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2010.190
Keywords
This article is cited by
-
Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice
Nature Communications (2023)
-
The rostromedial tegmental nucleus RMTg is not a critical site for ethanol-induced motor activation in rats
Psychopharmacology (2023)
-
Inhibition of the rostromedial tegmental nucleus reverses alcohol withdrawal-induced anxiety-like behavior
Neuropsychopharmacology (2019)
-
Gene expression and neurochemical characterization of the rostromedial tegmental nucleus (RMTg) in rats and mice
Brain Structure and Function (2019)
-
Response of the Tail of the Ventral Tegmental Area to Aversive Stimuli
Neuropsychopharmacology (2017)
