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Serum- and glucocorticoid-inducible kinase 1 activity in ventral tegmental area dopamine neurons regulates cocaine conditioned place preference but not cocaine self-administration

Abstract

Drugs of abuse regulate the activity of the mesolimbic dopamine (DA) system, and drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation are linked to behavioral outputs associated with addiction. Previous work from our lab determined that VTA serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription and catalytic activity were increased by repeated cocaine administration; however, it was unknown if these biochemical changes contributed to cocaine-elicited behaviors. Using transgenic and viral-mediated manipulations, we investigated the role of VTA SGK1 catalytic activity in regulating cocaine conditioned place preference and self-administration. We showed intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine conditioned place preference (CPP). Further, we found that K127Q expression in VTA DA neurons significantly decreased cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. However, blunted VTA DA SGK1 catalytic activity did not alter cocaine self-administration. Altogether, these studies identify the specific VTA cells critical for SGK1-mediated effects on cocaine CPP but not self-administration.

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Fig. 1: VTA SGK1-K127Q expression is capable of modulating cocaine CPP.
Fig. 2: SGK1-K127Q expression in VTA DA, but not GABA, neurons drives impaired cocaine CPP.
Fig. 3: Cocaine-elicited locomotor activity is altered by K127Q expression in VTA DA neurons.
Fig. 4: VTA SGK1-K127Q expression does not alter sucrose preference.
Fig. 5: Cocaine intake and motivation to earn a reward are not altered by K127Q expression in VTA DA neurons.

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Acknowledgements

We would like to thank Ken Moon for his significant assistance with mouse genotyping and breeding and Drs. Sarah Simmons and Sophia Kaska for their contribution in training on the molecular and behavioral techniques used to obtain data for this manuscript. We would also like to thank Cristina Rivera Quiles and Samantha Caico for assistance with viral targeting and validation.

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MAD: conceptualization, investigation, formal analysis, visualization, writing–original draft; VB: investigation, validation, writing–review and editing; ALE: investigation; ARS: investigation, validation; BF: validation; RLN: resources; AJR; writing–review and editing; MSM-R: conceptualization, methodology, writing–review and editing, supervision, project administration, funding acquisition.

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Correspondence to Michelle S. Mazei-Robison.

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Doyle, M.A., Bali, V., Eagle, A.L. et al. Serum- and glucocorticoid-inducible kinase 1 activity in ventral tegmental area dopamine neurons regulates cocaine conditioned place preference but not cocaine self-administration. Neuropsychopharmacol. 46, 1574–1583 (2021). https://doi.org/10.1038/s41386-021-01032-3

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