Cocaine Modulation of Frontostriatal Expression of Zif268, D2, and 5-HT2c Receptors in High and Low Impulsive Rats
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Impulsivity shares high comorbidity with substance abuse in humans, and high impulsivity (HI) in rats has been identified as a predictive factor for cocaine addiction-like behavior. Despite the evidence that high impulsivity is associated with altered function of corticostriatal networks, the specific neural substrates underlying the increased vulnerability of impulsive individuals to develop cocaine addiction remain unknown. We therefore investigated specific neural correlates of HI within the corticostriatal circuitry and determined how they interact with a protracted history of cocaine self-administration. We used in situ hybridization to map brain expression of two major genes implicated in impulsivity, encoding the dopamine D2 receptor (DA D2R) and the 5-HT2c receptor (5-HT2cR), and an immediate early gene associated with neuronal plasticity, zif268, in groups of rats selected for HI and low impulsivity (LI) on a 5-choice serial reaction time task (5-CSRTT) immediately after 5-CSRTT training, and following 10 or 50 days of cocaine self-administration. HI rats exhibited decreased DA D2R mRNA in the mesolimbic pathway, and increased 5-HT2cR mRNA in the orbitofrontal cortex compared with LI rats. HI rats also showed decreased zif268 mRNA in the ventral and dorsomedial striatum. Cocaine exposure decreased striatal D2R mRNA in both HI and LI rats, decreased 5-HT2cR mRNA differentially in striatal and prefrontal areas between HI and LI rats, and selectively decreased zif268 mRNA in the orbitofrontal and infralimbic cortices of HI animals. These findings implicate novel markers underlying the vulnerability of impulsive rats to cocaine addiction that localize to the OFC, infralimbic cortex, and striatum.
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The decrease in striatal D2 receptor binding in impulsive animals is related to decreased mRNA expression in the nucleus accumbens shell and VTA.
“Besson et al. (Besson et al., 2013) recently provided evidence that the decrease in striatal D2 receptor binding in impulsive animals is related to decreased mRNA expression in the nucleus accumbens shell as well as in the VTA.”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Besson et al., 2013
Drug exposure worsens the decrease in D2 receptor mRNA levels throughout the striatum in both high and low impulsive animals.
“Importantly, similarly to dopamine transmission, drug exposure worsens the decrease in D2 receptor mRNA levels throughout the striatum in both high and low impulsive animals (Besson et al., 2013).”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Besson et al., 2013
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- Authors
- Besson, M., Pelloux, Y., Dilleen, R., Theobald, D. E., Lyon, A., Belin-Rauscent, A., Robbins, T. W., Dalley, J. W., Everitt, B. J., & Belin, D.
- Affiliations
- University of Cambridge (GB)
- Institut de Neurosciences de la Timone (FR)
- Inserm (FR)
- Corresponding author
- Everitt, Barry J
- Venue
- Neuropsychopharmacology
- Published
- 2013-05-01
- Volume
- 38
- Issue
- 10
- Pages
- 1963-1973
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3746704
- OpenAlex
- W2016521885
- Cited by
- 81
- References
- 55
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 3 · 2022: 7 · 2021: 3 · 2020: 2 · 2019: 12 · 2018: 7 · 2017: 8 · 2016: 6 · 2015: 12 · 2014: 9 · 2013: 5
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (089589/Z/09/Z, 093875/Z/10/Z, 093875)
- University of Cambridge
- Institut National de la Santé et de la Recherche Médicale
- AXA Research Fund
- Medical Research Council (G1002231, G0701500, G9536855, 089589/Z/09/Z, G1000183)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- impulsivity, cocaine self-administration, Zif268, dopamine D2 receptor, 5-HT2C receptor, frontostriatal circuits, orbitofrontal cortex, infralimbic cortex, striatum, mesolimbic system, 5-choice serial reaction time task, gene expression
- MeSH terms
- Animals, Cerebral Cortex, Cocaine, Conditioning, Operant, Corpus Striatum, Impulsive Behavior, Male, Neural Pathways, Rats, Inbred Strains, Self Administration, Gene Expression, Receptors, Dopamine D2, Receptor, Serotonin, 5-HT2C, Rats, Early Growth Response Protein 1
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