A 5-HT1A agonist and a 5-HT2c antagonist reduce social interaction deficit induced by multiple ethanol withdrawals in rats.
BACKGROUND
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-HT(2C) antagonists or 5-HT(1A) agonists.


OBJECTIVE
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-HT(2C) antagonist; buspirone, a 5-HT(1A) partial agonist; WAY-100635, a 5-HT(1A) antagonist; ketanserin, a 5-HT(2A) antagonist; ritanserin, a mixed 5-HT(2A/2C) antagonist; and Ro-601075, a 5-HT(2C) 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-HT(2C) 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-HT(1A) agonists and 5-HT(2C) antagonists in reducing anxiety-like behavior induced by ethanol withdrawal and reducing the adaptive changes associated with repeated withdrawals.
Overstreet
David H
DH
Department of Psychiatry, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, CB #7178, Chapel Hill, NC 27599-7178, USA. dhover@med.unc.edu
Knapp
Darin J
DJ
Moy
Sheryl S
SS
Breese
George R
GR
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000523:psychology*; D002065:Buspirone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005021:Ethylamines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012919:Social Behavior; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005021:Ethylamines; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D016713:Ritanserin; D000431:Ethanol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D002065:Buspirone