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Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors

Abstract

Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2loxP/loxP; Dat+/IRES−cre, referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.

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Figure 1: Selective ablation of DA D2 autoreceptors prevents somatodendritic D2 like–mediated inhibition of midbrain DA neurons.
Figure 2: Increased DA release and DA synthesis in autoDrd2KO mice.
Figure 3: Spontaneous locomotor hyperactivity in autoDrd2KO mice.
Figure 4: Normal DA reuptake and supersensitivity for cocaine in autoDrd2KO mice.
Figure 5: AutoDrd2KO mice displayed supramaximal DA release during train stimulation.
Figure 6: AutoDrd2KO mice displayed increased motivation to work for a natural reward.

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Acknowledgements

We thank J. Sztein, G. Levin, C. Bäckman, V. Rodríguez, R. Lorenzo, S. Nemirovsky, M. Peper, S. Merani, C. Carbone, F. Maschi and M. Baetscher for their scientific and technical assistance. This work was supported in part by an International Research Scholar Grant of the Howard Hughes Medical Institute (M.R.), Universidad de Buenos Aires (M.R.) and Agencia Nacional de Promoción Científica y Tecnológica (M.R.), National Science Foundation grant INT-9901278 (M.J.L. and M.R.) and US National Institutes of Health grant R01-MH61326 (M.J.L.). E.P.B., D.N. and D.M.G. received doctoral fellowships from the Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. Y.M., J.H.S., V.A.A. and D.M.L. were supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism. J.H.S. and V.A.A. received support from the Intramural Program of the National Institute of Neurological Disorders and Stroke.

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D.M.G. and M.R. generated the conditional mutant mice. D.N. and E.P.B. characterized, raised and maintained mouse colonies and performed backcrossing. E.P.B. and D.N. conducted neurochemical, histological and behavioral experiments. Y.M. and J.H.S. conducted electrochemical and electrophysiological experiments. E.P.B., Y.M., J.H.S., D.N. and M.R. prepared the figures. E.P.B., Y.M. and M.R. wrote the manuscript. All of the authors designed experiments, analyzed data and edited the manuscript.

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Correspondence to Marcelo Rubinstein.

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Bello, E., Mateo, Y., Gelman, D. et al. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci 14, 1033–1038 (2011). https://doi.org/10.1038/nn.2862

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