Repeated cocaine exposure decreases dopamine D2‐like receptor modulation of Ca2+homeostasis in rat nucleus accumbens neurons
Open accessAbstract
The nucleus accumbens (NAc) is a limbic structure in the forebrain that plays a critical role in cognitive function and addiction. Dopamine modulates activity of medium spiny neurons (MSNs) in the NAc. Both dopamine D 1‐like and D 2‐like receptors (including D1R or D 1,5 R and D2R or D 2,3,4 R, respectively) are thought to play critical roles in cocaine addiction. Our previous studies demonstrated that repeated cocaine exposure (which alters dopamine transmission) decreases excitability of NAc MSNs in cocaine‐sensitized, withdrawn rats. This decrease is characterized by a reduction in voltage‐sensitive Na+currents and high voltage‐activated Ca 2+currents, along with increased voltage‐gated K+currents. These changes are associated with enhanced activity in the D1R/cAMP/PKA/protein phosphatase 1 pathway and diminished calcineurin function. Although D1R‐mediated signaling is enhanced by repeated cocaine exposure, little is known whether and how the D2R is implicated in the cocaine‐induced NAc dysfunction. Here, we performed a combined electrophysiological, biochemical, and neuroimaging study that reveals the cocaine‐induced dysregulation of Ca 2+homeostasis with involvement of D2R. Our novel findings reveal that D2R stimulation reduced Ca 2+influx preferentially via the L‐type Ca 2+channels and evoked intracellular Ca 2+release, likely via inhibiting the cAMP/PKA cascade, in the NAc MSNs of drug‐free rats. However, repeated cocaine exposure abolished the D 2 R effects on modulating Ca 2+homeostasis with enhanced PKA activity and led to a decrease in whole‐cell Ca 2+influx. These adaptations, which persisted for 21 days during cocaine abstinence, may contribute to the mechanism of cocaine withdrawal. Synapse, 2011. © 2010 Wiley‐Liss, Inc.
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Chronic cocaine exposure is associated with decreases in tonic D2R signaling involved in drug withdrawal, compulsive intake, and reinstatement of drug-seeking behavior.
“The same chronic cocaine exposure is associated with decreases in tonic D2R signaling, and these decreases are involved in drug withdrawal, compulsive intake, and reinstatement of drug-seeking behavior (Nestler et al 1990; Self et al 1996; Perez et al 2011; Grieder et al 2012).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Perez et al 2011
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Addiction circuitry in the human brain
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“The same chronic cocaine exposure is associated with decreases in tonic D2R signaling, and these decreases are involved in drug withdrawal, compulsive intake, and reinstatement of drugseeking behavior (Nestler et al. 1990; Self et al. 1996; Perez et al. 2011; Grieder et al. 2012).”
- Authors
- Perez, M. F., Ford, K. A., Goussakov, I., Stutzmann, G. E., & Hu, X.
- Affiliations
- Rosalind Franklin University of Medicine and Science (US)
- Rush University Medical Center (US)
- Corresponding author
- Hu, Xiu‐Ti
- Venue
- Synapse
- Publisher
- Wiley
- Published
- 2010-12-03
- Volume
- 65
- Issue
- 2
- Pages
- 168-180
- ISSN
- 0887-4476 (ISSN-L)
- 1098-2396
- PMC
- PMC3686293
- OpenAlex
- W2063981565
- Cited by
- 40
- References
- 62
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 3 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Synapse (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Conicet (submittedVersion, cc-by-nc-sa)
- Funders
- U.S. Public Health Service
- National Institute on Drug Abuse (DA-04093, R01DA004093, DA026746, R03DA026746, R37DA004093)
- 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 › Ion channel regulation and function
- Keywords
- cocaine, dopamine D2 receptor, nucleus accumbens, medium spiny neurons, calcium homeostasis, L-type calcium channels, cAMP/PKA signaling, cocaine withdrawal, cocaine dependence, calcium influx, calcium release
- MeSH terms
- Analysis of Variance, Animals, Calcium, Cocaine, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Interactions, Electric Stimulation, Enzyme Inhibitors, Homeostasis, Male, Membrane Potentials, Neurons, Nucleus Accumbens, Salicylamides, Time Factors, Calcium Channels, Rats, Sprague-Dawley, Cyclic AMP-Dependent Protein Kinases, Patch-Clamp Techniques, Dopamine Agonists, Dopamine Antagonists, Dopamine Uptake Inhibitors, Quinpirole, Calcineurin, Rats, In Vitro Techniques
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