Abstract
Bilateral stereotactic lesioning of the nucleus accumbens (NAc) core reduces relapse rates in alcohol-dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the NAc core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the NAc using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.
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Acknowledgements
We thank Michael Krashes, Brad Lowell, Bryan Roth, and Jürgen Wess for sharing DREADD constructs and reagents. CNO was obtained from the NIH as part of the Rapid Access to Investigative Drug Program funded by the NINDS. We also thank Michael Long and Dmitriy Aronov for advice on electrolytic lesions, Charles Hoeffer and the NYU rodent behavior core facility for help with behavioral assays, and Jens Hjerling-Leffler for valuable comments on the manuscript. This work was supported by funds from the NYU Physician Scientist Training Program (LS); the NYU Dean’s Undergraduate Research Fund (DC); NIH grants R01 MH068469, R01 MH071679, R01 MH095147, and R01 NS081297 to GF; and grant UL1 TR000038 from the National Center for Advancing Translational Sciences, National Institutes of Health.
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Cassataro, D., Bergfeldt, D., Malekian, C. et al. Reverse Pharmacogenetic Modulation of the Nucleus Accumbens Reduces Ethanol Consumption in a Limited Access Paradigm. Neuropsychopharmacol 39, 283–290 (2014). https://doi.org/10.1038/npp.2013.184
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DOI: https://doi.org/10.1038/npp.2013.184
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