Abstract
Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine–induced downregulation of the insulin receptor substrate 2 (IRS2)–thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine's rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward.
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References
Shippenberg, T.S., Emmett-Oglesby, M.W., Ayesta, F.J. & Herz, A. Tolerance and selective cross-tolerance to the motivational effects of opioids. Psychopharmacology (Berl.) 96, 110–115 (1988).
Walker, J.R., Chen, S.A., Moffitt, H., Inturrisi, C.E. & Koob, G.F. Chronic opioid exposure produces increased heroin self-administration in rats. Pharmacol. Biochem. Behav. 75, 349–354 (2003).
Glass, M.J., Kruzich, P.J., Kreek, M.J. & Pickel, V.M. Decreased plasma membrane targeting of NMDA-NR1 receptor subunit in dendrites of medial nucleus tractus solitarius neurons in rats self-administering morphine. Synapse 53, 191–201 (2004).
Ahmed, S.H., Walker, J.R. & Koob, G.F. Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22, 413–421 (2000).
Kenny, P.J., Chen, S.A., Kitamura, O., Markou, A. & Koob, G.F. Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J. Neurosci. 26, 5894–5900 (2006).
Koob, G.F. & Le Moal, M. Plasticity of reward neurocircuitry and the 'dark side' of drug addiction. Nat. Neurosci. 8, 1442–1444 (2005).
Harris, G.C. & Aston-Jones, G. Altered motivation and learning following opiate withdrawal: evidence for prolonged dysregulation of reward processing. Neuropsychopharmacology 28, 865–871 (2003).
Harris, G.C. & Aston-Jones, G. Enhanced morphine preference following prolonged abstinence: association with increased Fos expression in the extended amygdala. Neuropsychopharmacology 28, 292–299 (2003).
Sklair-Tavron, L. et al. Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons. Proc. Natl. Acad. Sci. USA 93, 11202–11207 (1996).
Spiga, S., Serra, G.P., Puddu, M.C., Foddai, M. & Diana, M. Morphine-induced abnormalities in the VTA: confocal laser microscopy. Eur. J. Neurosci. 17, 605–612 (2003).
Wise, R.A. Opiate reward: sites and substrates. Neurosci. Biobehav. Rev. 13, 129–133 (1989).
Nestler, E.J. Molecular mechanisms of drug addiction. J. Neurosci. 12, 2439–2450 (1992).
Izzo, E., Martin-Fardon, R., Koob, G.F., Weiss, F. & Sanna, P.P. Neural plasticity and addiction: PI3-kinase and cocaine behavioral sensitization. Nat. Neurosci. 5, 1263–1264 (2002).
Horger, B.A. et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J. Neurosci. 19, 4110–4122 (1999).
Pierce, R.C. & Bari, A.A. The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity. Rev. Neurosci. 12, 95–110 (2001).
Hall, F.S., Drgonova, J., Goeb, M. & Uhl, G.R. Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuropsychopharmacology 28, 1485–1490 (2003).
Lu, L., Dempsey, J., Liu, S.Y., Bossert, J.M. & Shaham, Y. A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J. Neurosci. 24, 1604–1611 (2004).
Bolanos, C.A. & Nestler, E.J. Neurotrophic mechanisms in drug addiction. Neuromolecular Med. 5, 69–83 (2004).
Berhow, M.T. et al. Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system. Neuroscience 68, 969–979 (1995).
Wolf, D.H., Numan, S., Nestler, E.J. & Russell, D.S. Regulation of phospholipase Cgamma in the mesolimbic dopamine system by chronic morphine administration. J. Neurochem. 73, 1520–1528 (1999).
Muller, D.L. & Unterwald, E.M. In vivo regulation of extracellular signal-regulated protein kinase (ERK) and protein kinase B (Akt) phosphorylation by acute and chronic morphine. J. Pharmacol. Exp. Ther. 310, 774–782 (2004).
Kumar, V., Zhang, M.X., Swank, M.W., Kunz, J. & Wu, G.Y. Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J. Neurosci. 25, 11288–11299 (2005).
Jaworski, J., Spangler, S., Seeburg, D.P., Hoogenraad, C.C. & Sheng, M. Control of dendritic arborization by the phosphoinositide-3'-kinase–Akt–mammalian target of rapamycin pathway. J. Neurosci. 25, 11300–11312 (2005).
Bechara, A. & van der Kooy, D. Chronic exposure to morphine does not alter the neural tissues subserving its acute rewarding properties: apparent tolerance is overshadowing. Behav. Neurosci. 106, 364–373 (1992).
Self, D.W., McClenahan, A.W., Beitner-Johnson, D., Terwilliger, R.Z. & Nestler, E.J. Biochemical adaptations in the mesolimbic dopamine system in response to heroin self-administration. Synapse 21, 312–318 (1995).
Robinson, T.E., Gorny, G., Savage, V.R. & Kolb, B. Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats. Synapse 46, 271–279 (2002).
Ziolkowska, B. et al. Contingency does not contribute to the effects of cocaine self-administration on prodynorphin and proenkephalin gene expression in the rat forebrain. Brain Res. 1069, 1–9 (2006).
Paladini, C.A., Mitchell, J.M., Williams, J.T. & Mark, G.P. Cocaine self-administration selectively decreases noradrenergic regulation of metabotropic glutamate receptor-mediated inhibition in dopamine neurons. J. Neurosci. 24, 5209–5215 (2004).
Barrot, M. et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc. Natl. Acad. Sci. USA 99, 11435–11440 (2002).
Bolaños, C.A. et al. Viral-mediated expression of phospholipase Cγ in distinct regions of the ventral tegmental area differentially modulates mood-related behaviors. J. Neurosci. 23, 7569–7576 (2003).
Olson, V.G. et al. Regulation of drug reward by CREB: Evidence for two functionally distinct subregions of the ventral tegmental area. J. Neurosci. 25, 5553–5562 (2005).
Georges, F., Le Moine, C. & Aston-Jones, G. No effect of morphine on ventral tegmental dopamine neurons during withdrawal. J. Neurosci. 26, 5720–5726 (2006).
Bechara, A., Nader, K. & van der Kooy, D. A two-separate-motivational-systems hypothesis of opioid addiction. Pharmacol. Biochem. Behav. 59, 1–17 (1998).
Aston-Jones, G. & Harris, G.C. Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology 47 (Suppl. 1): 167–179 (2004).
Beaulieu, J.M. et al. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122, 261–273 (2005).
Rasmussen, K., Beitner-Johnson, D.B., Krystal, J.H., Aghajanian, G.K. & Nestler, E.J. Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological, and biochemical correlates. J. Neurosci. 10, 2308–2317 (1990).
Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Academic Press, San Diego, 1997).
Zachariou, V. et al. Essential role for RGS9 in opiate action. Proc. Natl. Acad. Sci. USA 100, 13656–13661 (2003).
Russo, S.J. et al. Gonadal hormones differentially modulate cocaine-induced conditioned place preference in male and female rats. Neuroscience 120, 523–533 (2003).
Rosenthal, R. & Rosnow, R.L. Statistical procedures and the justification of knowledge in psychological science. Am. Psychol. 44, 1276–1284 (1989).
Acknowledgements
We thank R. Kalb and T. Franke for Akt plasmids, M. Cobb for ERK2 plasmids and D. Wolfe for IRS2 plasmids. This work was supported by grants from the US National Institute on Drug Abuse and National Institute of Mental Health.
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Supplementary Fig. 1
Timeline of drug and viral treatments for morphine conditioned place preference experiments. (PDF 366 kb)
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Russo, S., Bolanos, C., Theobald, D. et al. IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nat Neurosci 10, 93–99 (2007). https://doi.org/10.1038/nn1812
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DOI: https://doi.org/10.1038/nn1812
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