Acute Cocaine Induces Fast Activation of D1 Receptor and Progressive Deactivation of D2 Receptor Striatal Neurons:In Vivo Optical Microprobe [Ca2+]iImaging
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Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine's reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca(2+)](i)) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R- versus D2R-expressing neurons in striatum. Acute cocaine (8 mg/kg, i.p.) rapidly increased [Ca(2+)](i) in D1R-expressing neurons (10.6 ± 3.2%) in striatum within 8.3 ± 2.3 min after cocaine administration after which the increases plateaued; these fast [Ca(2+)](i) increases were blocked by pretreatment with a D1R antagonist (SCH23390). In contrast, cocaine induced progressive decreases in [Ca(2+)](i) in D2R-expressing neurons (10.4 ± 5.8%) continuously throughout the 30 min that followed cocaine administration; these slower [Ca(2+)](i) decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R-expressing neurons (direct-pathway) enhances cocaine reward, whereas activation of D2R-expressing neurons suppresses it (indirect-pathway) (Lobo et al., 2010), this suggests that cocaine's rewarding effects entail both its fast stimulation of D1R (resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R (resulting in longer-lasting deactivation of indirect-pathway neurons). We also provide direct in vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration.
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For drug reward, an imbalance between enhanced D1 and decreased D2 receptor signaling facilitates compulsive drug intake.
“For drug reward, studies have also shown that an imbalance between D1 receptor signaling (enhanced) and D2 receptor signaling (decreased) facilitates compulsive drug intake (36);”
From The Addictive Dimensionality of Obesity (2013) · cites this paper as [36]
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Optical Neuroimaging: Studies of the Neuronal and Vascular Effects of Cocaine
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Pathophysiological role of Pyk2 in the nervous system
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- Authors
- Luo, Z., Volkow, N. D., Heintz, N., Pan, Y., & Du, C.
- Affiliations
- Stony Brook University (US)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-09-14
- Volume
- 31
- Issue
- 37
- Pages
- 13180-13190
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3214624
- OpenAlex
- W2131751421
- Cited by
- 90
- References
- 54
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 5 · 2020: 4 · 2019: 12 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 3 · 2013: 10 · 2012: 1
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy
- National Institutes of Health (5rc1da028534-02, 1RC1DA028534)
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Drug Abuse (R21DA032228, K25DA021200, RC1 DA028534, 1RC1DA028534, R01DA029718)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK059265)
- Laboratory Directed Research and Development
- Brookhaven National Laboratory (LDRD 10-023)
- 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
- cocaine, dopamine D1 receptor, dopamine D2 receptor, striatum, intracellular calcium imaging, direct pathway, indirect pathway, neuronal activation, cocaine reward, receptor antagonists
- MeSH terms
- Animals, Benzazepines, Calcium, Cerebral Cortex, Cocaine, Corpus Striatum, Mice, Transgenic, Microscopy, Fluorescence, Neurons, Time Factors, Receptors, Dopamine D1, Receptors, Dopamine D2, Dopamine Antagonists, Dopamine Uptake Inhibitors, Raclopride, Green Fluorescent Proteins, Mice, Voltage-Sensitive Dye Imaging, Dopamine D2 Receptor Antagonists
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