Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors
Open accessAbstract
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 (Drd2(loxP/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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D2 receptors inhibit cAMP signalling, are stimulated by phasic and tonic dopamine, and are not deemed necessary for drug reward.
“By contrast, D2 receptors, which inhibit cAMP signalling, are stimulated by both phasic and tonic dopamine and are not deemed necessary for drug reward.”
From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [64]
The Introduction and Discussion distinguish D2 autoreceptors from D2 receptors generally. They report that mice lacking all D2 receptors have impaired or absent drug-reward responses, contrary to the claim that D2 receptors are not deemed necessary for drug reward; mice lacking only D2 autoreceptors instead show enhanced cocaine reward. The cited passages do not establish the cAMP or tonic-dopamine parts of the sentence. (LLM, conf=0.85)
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References 52 · Cited by 364
Research works printed but not linked: 1
- [23]Mercuri NB Loss of autoreceptor function in dopaminergic neurons from dopamine D2 receptor deficient mice Neuroscience 79 323 327 1997 9200717
- Authors
- Bello, E. P., Mateo, Y., Gelman, D. M., Noaín, D., Shin, J. H., Low, M. J., Alvarez, V. A., Lovinger, D. M., & Rubinstein, M.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- National Institutes of Health (US)
- University of Michigan (US)
- Corresponding author
- Rubinstein, Marcelo
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2011-07-10
- Volume
- 14
- Issue
- 8
- Pages
- 1033-1038
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3175737
- OpenAlex
- W2008762508
- Cited by
- 364
- References
- 52
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 8 · 2023: 17 · 2022: 29 · 2021: 38 · 2020: 22 · 2019: 24 · 2018: 24 · 2017: 17 · 2016: 32 · 2015: 24 · 2014: 47 · 2013: 30 · 2012: 18
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Funders
- National Science Foundation (9901278)
- Howard Hughes Medical Institute
- Consejo Nacional de Investigaciones Científicas y Técnicas
- Universidad de Buenos Aires
- National Institutes of Health
- Agencia Nacional de Promoción Científica y Tecnológica
- National Institute on Alcohol Abuse and Alcoholism (ZIAAA000416, ZIAAA000421)
- National Institute of Mental Health (R01-MH61326, R01MH061326)
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- dopamine D2 autoreceptors, cocaine reward, dopamine release, dopamine synthesis, hyperlocomotion, negative feedback regulation, midbrain dopaminergic neurons
- MeSH terms
- Analysis of Variance, Animals, Autoradiography, Baclofen, Choice Behavior, Cocaine, Conditioning, Operant, Dihydroxyphenylalanine, Dopamine, Drug Interactions, Enzyme Inhibitors, Exploratory Behavior, Food, Hydrazines, Hyperkinesis, Membrane Potentials, Mesencephalon, Motivation, Motor Activity, Neurons, Reinforcement Schedule, Reward, Sulpiride, Receptors, Dopamine D2, Mice, Knockout, Dopamine Agonists, Dopamine Antagonists, Dopamine Uptake Inhibitors, Maze Learning, Quinpirole, Mice, GABA-B Receptor Agonists, In Vitro Techniques
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