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Reduction in repeated ethanol-withdrawal-induced anxiety-like behavior by site-selective injections of 5-HT1A and 5-HT2C ligands

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Abstract

Rationale

Anxiety-like behavior resulting from repeated withdrawals from chronic ethanol diets is counteracted by systemic administration of a 5-HT2C receptor antagonist or a 5-HT1A receptor partial agonist.

Objectives

This study investigated whether prior treatment with these agents into the amygdala, dorsal raphe nucleus, nucleus accumbens, or paraventricular nucleus during early withdrawals would ameliorate the social interaction deficits observed after a subsequent withdrawal.

Methods

Sprague–Dawley rats were exposed to three cycles of 5 days of forced ethanol diet (4.5%, w/v), with 2 days of control diet after the first and second cycles. Drugs were administered into one of four brain sites 4 h after removal of ethanol on the first and 2nd cycles but not the third. The social interaction test was performed 5 h after removal of ethanol on the third cycle. Drugs tested included SB-243213, a 5-HT2C receptor inverse agonist; buspirone, a 5-HT1A receptor partial agonist; and Ro 60 1075, a 5-HT2C receptor agonist.

Results

Only SB-243213 (at 3 μg, but not at 1 and 0.3 μg) counteracted the social interaction deficits after injections into the amygdala, while buspirone (at 0.3 and 1 μg but not at 0.1 μg) reduced deficits only when given into the dorsal raphe nucleus. In contrast, the 5-HT2C receptor agonist, Ro 60 1075, accentuated the behavioral deficit after two weekly injections into the amygdala.

Conclusions

These results are consistent with the involvement of 5-HT2C receptors in the amygdala and 5-HT1A autoreceptors in the dorsal raphe nucleus in repeated ethanol withdrawal-induced sensitization of anxiety-like behavior.

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Acknowledgements

We wish to thank Qi Yu, Mili Senapati and Lara Marr for technical assistance and Martyn Wood of GlaxoSmithKline for supporting this project. This work was financially supported by NIAAA grants AA 14284, AA 11605, and AA 14949.

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Authors and Affiliations

  1. Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina School of Medicine, CB #7178, Chapel Hill, NC, 27599-7178, USA

    David H. Overstreet, Darin J. Knapp, Robert A. Angel, Montserrat Navarro & George R. Breese

  2. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7178, USA

    David H. Overstreet, Darin J. Knapp & George R. Breese

  3. Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7178, USA

    George R. Breese

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  1. David H. Overstreet
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  2. Darin J. Knapp
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  5. George R. Breese
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Correspondence to David H. Overstreet.

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Overstreet, D.H., Knapp, D.J., Angel, R.A. et al. Reduction in repeated ethanol-withdrawal-induced anxiety-like behavior by site-selective injections of 5-HT1A and 5-HT2C ligands. Psychopharmacology 187, 1–12 (2006). https://doi.org/10.1007/s00213-006-0389-0

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