Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats.
BACKGROUND
Previous work from our laboratory indicated that Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA) and that 5-HT(3) antagonists will inhibit EtOH-stimulated somatodendritic release of dopamine within the VTA.


OBJECTIVE
The objective of this study was to use the intracranial self-administration procedure to determine the involvement of 5-HT(3)receptors in mediating the reinforcing effects of EtOH within the VTA, and to increase our understanding of central nervous system mechanisms involved in the rewarding effects of EtOH.


METHODS
Adult female Wistar rats were stereotaxically implanted with guide cannulae aimed at the posterior VTA. After 1 week, rats were placed into standard two-lever experimental chambers for a total of seven sessions (4-h sessions separated by 48 h) and allowed to self-administer vehicle alone, a 5-HT(3) antagonist alone, 200 mg% EtOH alone, or combinations of 200 mg% EtOH with different concentrations of a 5-HT(3) antagonist ( n=6-9 per group).


RESULTS
Throughout all seven sessions, Wistar rats self-infused more 200 mg% ETOH (25+/-5 infusions) than vehicle (5+/-4 infusions) or 5-HT(3) antagonist (6+/-4 infusions) ( P<0.05), and responded significantly more ( P<0.05) on the active than inactive lever (e.g., 50+/-12 vs 12+/-8 responses in session 1). Co-administration of 50 micro M or 100 micro M ICS 205,930 with 200 mg% EtOH completely prevented the acquisition and maintenance of EtOH self-infusion into the posterior VTA. Similarly, co-administration of either 25-100 micro M LY-278-584 or 10-100 micro M zacopride with 200 mg% EtOH completely blocked EtOH-maintained intracranial self-administration behavior.


CONCLUSIONS
The results of this study suggest that the reinforcing effects of EtOH within the posterior VTA of Wistar rats require activation of local 5-HT(3) receptors.
Rodd-Henricks
Zachary A
ZA
Department of Psychiatry, Institute of Psychiatric Research, Indiana School of Medicine, 791 Union Drive, Indianapolis, IN 46202-4887, USA. zrodd@iupui.edu
McKinzie
David L
DL
Melendez
Roberto I
RI
Berry
Nada
N
Murphy
James M
JM
McBride
William J
WJ
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3; D012646:Self Administration; D012702:Serotonin Antagonists / Q000494:pharmacology; D013237:Stereoisomerism; D014326:Tropanes / Q000494:pharmacology; D000077526:Tropisetron; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002492:Central Nervous System Depressants; D007191:Indazoles; D007211:Indoles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D014326:Tropanes; C061531:LY 278584; D000431:Ethanol; D000077526:Tropisetron; C055971:zacopride