Serotonin (5-HT) receptor agonists, antagonists, and mixed agonist/antagonists have been implicated in the volitional intake of ethanol in the rat and other species. The present experiments were undertaken to determine whether FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate) would alter ethanol drinking in: genetic ethanol preferring (P) rats; and a new strain of high ethanol preferring (HEP) male and female rats derived from crossbreeding of P and a variant strain of Sprague-Dawley animals. After a preference test for solutions of 3 to 30% ethanol vs. water, each rat was given limited access to its maximally preferred concentration daily between 1600 and 1800 h; fluid intakes were recorded every 0.25 h. Once fluid consumption had stabilized over 4 days, saline vehicle, 2.5 mg/kg or 5.0 mg/kg FG5938 was injected subcutaneously 0.5 h prior to ethanol access on each of 3 consecutive days; thereafter, preference testing for ethanol continued for 4 additional days. Whereas the saline vehicle was without effect, FG5938 caused a fivefold decrease in total intake of ethanol from 1.7 to 0.3 g/kg and in proportion of ethanol to total fluid consumed from 0.42 to 0.03. The onset of the significant decline in ethanol drinking occurred during the latter 1.75-h interval. Further, both doses of FG5938, but not saline, increased the intake of food significantly. The decline in ethanol drinking was virtually identical in both P and HEP males and in female HEP rats. These results demonstrate that FG5938 affects ethanol drinking only after 0.5 h of its administration. Finally, it is envisaged that the ingestion of ethanol in genetic high drinking rats is mediated, in part, by central synapses utilizing both 5-HT1A and 5-HT2A receptors.

1996-09-01·Alcohol (Fayetteville, N.Y.)4区 · 医学

The mixed receptor drug FG5938 suppresses alcohol drinking while enhancing feeding in P rats

4区 · 医学

Article

作者: K.T. Piercy ; A.K. Björk ; R.D. Myers

The neurotransmitter serotonin (5-HT) has long been implicated in the etiology of aberrant consumption of alcohol. Several compounds thought to possess a potential therapeutic value to counteract drinking have high affinities for 5-HT1A and 5-HT2A receptors in the brain. For example, amperozide and FG5865 significantly reduce the volitional intake of alcohol, without altering food intake, both in rats genetically predisposed or chemically induced to drink alcohol. The present study was undertaken in the alcohol-preferring (P) rat to determine whether an amperozide like drug. FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate). exerts an action on the volitional drinking of alcohol as well as on the intakes of food and water. In 11 male P rats, the pattern of preference for different concentrations of alcohol was determined by an 11-day test for water vs. 3 to 30% alcohol solutions. After maximally preferred alcohol concentrations, i.e., 9 to 15% had stabilized for 4 days, saline or FG5938 was injected subcutaneously at 1600 and 2200 h in a dose of 2.5, 5.0, or 10.0 mg/kg over 4 consecutive days. Following treatment, preference testing for the same concentrations of alcohol was continued for 5 additional days. FG5938 caused a significant suppression in alcohol drinking in terms of both absolute g/kg and proportion to total fluid intake. During its administration, FG5938 also enhanced the ingestion of food and water of the P animals significantly, with the largest intake occurring on the initial day, while body weights increased. After FG5938 injections, food and water intakes returned to predrug levels. The saline control vehicle had no significant effect on the intakes of alcohol, food, or water of the P rats. Overall, these results show that FG5938 acts to attenuate alcohol preference while simultaneously increasing the ingestion of food paradoxically. To our knowledge, this is the first known drug to possess this unique property. Finally, these findings support the view that a compound having affinities to both 5-HT1A and 5-HT2A receptors may be useful as a therapeutic agent in the treatment of alcoholism.

100 项与 FG-5938 相关的药物交易

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