Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats
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RATIONALE: The serotonin 5-HT(2A) and 5-HT(2C) receptors regulate the capacity of acute cocaine to augment behavior and monoamine levels within the nucleus accumbens (NAC), a brain region involved in cocaine's addictive and psychotogenic properties. OBJECTIVES: In the present study, we tested the hypothesis that NAC 5-HT(2A) and 5-HT(2C) receptor activation is involved in the expression of cocaine-induced neuroplasticity following protracted withdrawal from a sensitizing repeated cocaine regimen (days 1 and 7, 15 mg/kg; days 2-6, 30 mg/kg, i.p.). METHODS: The effects of intra-NAC infusions of the 5-HT(2A) antagonist R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907; 0, 50, 100, 500 nM) or the 5-HT(2C) antagonist [6-chloro-5-methyl-1-(6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] inodoline dihydrochloride (SB 242084; 0, 50, 100, 500 nM) were first assessed upon the expression of locomotor activity elicited by a 15-mg/kg cocaine challenge injection administered at 3-week withdrawal. A follow-up in vivo microdialysis experiment then compared the effects of the local perfusion of 0, 50, or 100 nM of each antagonist upon cocaine-induced dopamine and glutamate sensitization in the NAC. RESULTS: Although neither MDL 100907 nor SB 242084 altered acute cocaine-induced locomotion, SB 242084 reduced acute cocaine-elevated NAC dopamine and glutamate levels. Intra-NAC perfusion with either compound blocked the expression of cocaine-induced locomotor and glutamate sensitization, but only MDL 100907 pretreatment prevented the expression of cocaine-induced dopamine sensitization. CONCLUSIONS: These data provide the first evidence that NAC 5-HT(2A) and 5-HT(2C) receptors are critical for the expression of cocaine-induced neuroplasticity following protracted withdrawal, which has relevance for their therapeutic utility in the treatment of addiction.
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MDMA strongly affects 5-HT2A receptors, which are important mediators of behavioral sensitization.
“MDMA also strongly affects 5-HT2A receptors, which are important mediators of behavioral sensitization (47–49).”
From MDMA-Assisted Therapy as a Means to Alter Affective, Cognitive, Behavioral, and Neurological Systems Underlying Social Dysfunction in Social Anxiety Disorder (2021) · cites this paper as [49]
The Results (page unavailable) report that blocking nucleus accumbens 5-HT2A receptors prevented the expression of cocaine-induced locomotor sensitization in rats, supporting a role for these receptors in behavioral sensitization. The paper does not establish that MDMA strongly affects 5-HT2A receptors; its reference to MDMA appears in a cited study’s title. (LLM, conf=0.88)
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References 78 · Cited by 64
- Authors
- Zayara, A. E., McIver, G., Valdivia, P. N., Lominac, K. D., McCreary, A. C., & Szumlinski, K. K.
- Affiliations
- University of California, Santa Barbara (US)
- Solvay (Netherlands) (NL)
- Corresponding author
- Szumlinski, Karen K.
- Venue
- Psychopharmacology
- Published
- 2010-09-03
- Volume
- 213
- Issue
- 2-3
- Pages
- 321-335
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC3032203
- OpenAlex
- W2151277620
- Cited by
- 64
- References
- 78
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 3 · 2013: 6 · 2012: 7
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Psychopharmacology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Drug Abuse (R01DA024038)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- nucleus accumbens, 5-HT2A receptor, 5-HT2C receptor, serotonin receptors, cocaine sensitization, cocaine withdrawal, locomotor sensitization, dopamine sensitization, SB242084, cocaine dependence, neuroplasticity, microdialysis, receptor antagonists
- MeSH terms
- Aminopyridines, Animals, Behavior, Animal, Cocaine, Dopamine, Dose-Response Relationship, Drug, Fluorobenzenes, Indoles, Male, Neuronal Plasticity, Nucleus Accumbens, Piperidines, Rats, Sprague-Dawley, Microdialysis, Glutamic Acid, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Rats, Serotonin 5-HT2 Receptor Antagonists
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