Effect of 5-HT(1B) receptor ligands on self-administration of ethanol in an operant procedure in rats.
Recent evidence suggests that 5-HT(1B) receptor activation modifies ethanol's reinforcing, intoxicating and discriminative stimulus effects. The present study further explored the role played by 5-HT(1A/1B) receptors by examining their influence on oral ethanol self-administration. Male Wistar rats were trained on an FR 4 schedule to obtain a reinforcer of 0.1 12% w/v ethanol solution. Once responding was stable, the effect of the 5-HT(1A/1B) agonist RU24969 alone and in combination with the 5-HT(1B) antagonist GR127935 or the 5-HT(1A) antagonists (+) WAY100135 and (+) WAY100635 was assessed. The effect of RU24969 on ethanol's pharmacokinetic profile and on operant oral saline self-administration was also examined to assess if alterations in oral ethanol self-administration were due to nonspecific effects on level pressing. For comparison, we examined the effect of another 5-HT(1A/1B) agonist, CGS12066B, on oral ethanol self-administration. Both RU24969 (0.1 to 1 mg/kg) and CGS12066B (0.1 to 1 mg/kg) significantly suppressed oral ethanol self-administration. Administration of GR127935 (1 mg/kg), significantly reversed the effects elicited by RU24969, whereas neither WAY100635 (1 mg/kg) nor (+)WAY100135 (1 mg/kg) had any effect. The effects of lower doses of RU24969 on oral ethanol self-administration were selective as oral saline self-administration and blood ethanol levels were not altered by these doses. These data demonstrate that 5-HT(1B) receptor activation suppresses oral ethanol self-administration. These studies provide further evidence that 5-HT(1B) receptors play a modulatory role in ethanol's behavioral effects.
Tomkins
D M
DM
Centre for Addiction and Mental Health, Toronto, Ontario, Canada. denise_tomkins@camh.net
O'Neill
M F
MF
D000428:Alcohol Drinking; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D000431:Ethanol / Q000493:pharmacokinetics; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000502:physiology*; D012646:Self Administration
D007211:Indoles; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D011810:Quinoxalines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; C052561:CGS 12066B; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; C090701:GR 127935; D000431:Ethanol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide