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A 5-HT1A agonist and a 5-HT2c antagonist reduce social interaction deficit induced by multiple ethanol withdrawals in rats

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Abstract

Rationale

Repeated withdrawals from chronic forced ethanol exposure sensitize animals to withdrawal-induced deficits in social interaction behavior. The deficits in social interaction behavior following withdrawal from continuous ethanol exposure can be reduced following acute treatments with 5-HT2C antagonists or 5-HT1A agonists.

Objectives

The present study investigated whether prior treatment with these serotonergic agents during early withdrawals in rats subjected to repeated withdrawals from ethanol exposure would ameliorate the social interaction deficits observed following the final withdrawal.

Methods

Sprague-Dawley rats were exposed to three cycles of 5 days forced ethanol (7%, w/v), with 2 days of control diet after the first and second cycles. Drugs were administered IP 4 h after removal of ethanol on the first and second cycles but not the third in one group and 4.5 h after removal of ethanol on the third cycle in another. The social interaction test was performed 5 h after removal of ethanol on the third cycle. Drugs tested included SB-242084, a 5-HT2C antagonist; buspirone, a 5-HT1A partial agonist; WAY-100635, a 5-HT1A antagonist; ketanserin, a 5-HT2A antagonist; ritanserin, a mixed 5-HT2A/2C antagonist; and Ro-601075, a 5-HT2C agonist.

Results

Both SB-242084 and buspirone reduced ethanol withdrawal-induced deficits in social interaction when given either acutely 30 min before the test or at 4 h after withdrawal from the first and second cycles. WAY-100635 and ketanserin were completely ineffective regardless of mode of treatment. In contrast, the 5-HT2C agonist, Ro-601075, accentuated the withdrawal-induced deficit in social interaction behavior in rats exposed to either 4.5 or 7% ethanol diet.

Conclusions

These results support the utility of 5-HT1A agonists and 5-HT2C antagonists in reducing anxiety-like behavior induced by ethanol withdrawal and reducing the adaptive changes associated with repeated withdrawals.

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Acknowledgements

We wish to thank Matthew Crist, Dhritiman Mukherjee, Rebecca Overstreet, Leo Orlov, and Qi Yu for technical assistance. We thank the Case Western University web site for information about the affinity of the various serotonergic drugs (www.pdsp.cwru.edu/pdsp/asp). This work was supported by NIAAA grants AA 00243, AA 11605, and AA 00214.

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Authors and Affiliations

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

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

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

    George R. Breese

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

    George R. Breese

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  1. David H. Overstreet
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Correspondence to David H. Overstreet.

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Overstreet, D.H., Knapp, D.J., Moy, S.S. et al. A 5-HT1A agonist and a 5-HT2c antagonist reduce social interaction deficit induced by multiple ethanol withdrawals in rats. Psychopharmacology 167, 344–352 (2003). https://doi.org/10.1007/s00213-003-1425-y

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