Abstract
Cocaine abusers remain vulnerable to drug craving and relapse for many years after abstinence is achieved. We have recently shown that ondansetron (a 5-HT3 receptor antagonist) given 3.5 h after each daily cocaine injection reverses previously established behavioral sensitization. The purpose of the present investigation was two-fold. First, as cocaine cannot be used as therapy, we examined whether pergolide (a D1/D2 receptor agonist with reduced abuse potential) and ondansetron could reverse behavioral sensitization. Second, we investigated whether these behavioral changes were associated with parallel alterations in expression levels and/or phosphorylation changes in the NR2B and GluR1 subunits of the respective NMDA and AMPA receptors. Rats were injected for 5 consecutive days with cocaine or saline followed by 9 days of withdrawal. Starting on withdrawal day 10, animals were given vehicle, pergolide/saline, or pergolide/ondansetron for 5 consecutive days. Following a second 9-day period of withdrawal, all animals were challenged with cocaine for assessment of behavioral sensitization and tissues were collected on the following day for Western blot. Sensitization was associated with increased NR2B expression in the accumbens (NAc) shell and decreased Tyr1472 phosphorylation in the NAc core, as well as increased Ser845 phosphorylation of the GluR1 subunit in prefrontal cortex, NAc core, and shell. Pergolide/ondansetron treatment, but not pergolide alone, consistently reversed both the behavioral sensitization and the associated changes in the NMDA and AMPA receptor subunits. To the extent that sensitization plays a role in chronic cocaine abuse, a combination of these clinically available drugs may be useful in treatment of the disorder.
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Acknowledgements
We are grateful to Dr Qiang Chen and Mrs Xueying Xiong for their excellent technical assistance. We also acknowledge the statistical assistance from Dr Ramona M Rodriguiz in the Department of Psychiatry and Behavioral Sciences at the Duke University Medical Center. This study was supported by grants from the National Institute of Drug Abuse (DA-10327 and DA-14323 to EHE and DA-06519 to THL).
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Zhang, X., Lee, T., Davidson, C. et al. Reversal of Cocaine-Induced Behavioral Sensitization and Associated Phosphorylation of the NR2B and GluR1 Subunits of the NMDA and AMPA Receptors. Neuropsychopharmacol 32, 377–387 (2007). https://doi.org/10.1038/sj.npp.1301101
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DOI: https://doi.org/10.1038/sj.npp.1301101
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