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


OBJECTIVE
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 microg, but not at 1 and 0.3 microg) counteracted the social interaction deficits after injections into the amygdala, while buspirone (at 0.3 and 1 microg but not at 0.1 microg) 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.
Overstreet
David H
DH
Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina School of Medicine, CB #7178, Chapel Hill, NC 27599-7178, USA. dhover@med.unc.edu
Knapp
Darin J
DJ
Angel
Robert A
RA
Navarro
Montserrat
M
Breese
George R
GR
D000818:Animals; D001007:Anxiety / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D002065:Buspirone / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000009:adverse effects*; D005021:Ethylamines / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
D005021:Ethylamines; D007211:Indoles; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D000431:Ethanol; C406343:SB 243213; D002065:Buspirone