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IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates

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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Figure 1: Chronic opiate administration inhibits IRS2-Akt signaling and decreases VTA dopamine neuronal size.
Figure 2: Chronic morphine exposure decreases place conditioning to morphine at an early withdrawal (w.d.) time point.
Figure 3: Chronic morphine induces long-lasting decreases in VTA dopamine cell size and morphine reward.
Figure 4: Viral-mediated expression of IRS2dn regulates Akt signaling and VTA dopamine neuron morphology.
Figure 5: The rewarding and locomotor activating effects of morphine are altered by viral-mediated disruption of the IRS2-Akt pathway.

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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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Correspondence to Eric J Nestler.

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The authors declare no competing financial interests.

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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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