Selective Serotonin Reuptake Inhibitors: Effects of Chronic Treatment on Ethanol-Reinforced Behavior In Mice (original) (raw)
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Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats
Alcohol, 1994
Serotonin 5-HT~ antagonists fail to affect ethanol self-administration of rats. ALCOHOL 11(5) [389][390][391][392][393][394][395] 1994.-Five Long-Evans hooded rats were trained to lever press according to fixed-ratio 5 reinforcement schedules for 0.06 mi dipper deliveries of 8aTe w/v ethanol during daily (M-F) 0.5-h experimental sessions. After ethanol self-administration was established, doses of the serotonin 5-HT3 antagonists, ondansetron (0,03-3.0 mg/kg), granisetron (0.01-1.0 mg/kg), and SC-51296 (0.1-10.0 mg/kg) were administered prior to ethanol sessions to determine their effects on ethanol self-administration. None of the doses of the antagonists had significant effects on numbers of obtained ethanol deliveries. Subsequently, each antagonist (ondansetron, 0.1 mg/kg; granisetron, 0.3 mg/kg; SC-51296, 0.1 mg/kg) was administered b.i.d, for five consecutive daily sessions. During none of these chronic tests with the 5-HT3 antagonists were there significant main effects of drug administration. Overall, these results do not support the hypothesis that the serotonin 5-HT3 antagonists would have robust therapeutic efficacy in the treatment of alcoholism.
The serotonin-2 receptor modulator, (-)-trans-PAT, decreases voluntary ethanol consumption in rats
European Journal of Pharmacology, 2013
Serotonin (5-HT) 5-HT 2C receptor agonists have shown promise as novel alcoholism pharmacotherapies, but developing selective agonists has been problematic. Female Sprague Dawley rats were given ethanol in a palatable gel vehicle during operant sessions. 5-HT 2C receptor modulators (Ro60-0175, SB242,084, and (−)-trans-PAT) were administered before operant sessions. As a control for the effects of 5-HT 2C receptor agonism on caloric intake, drugs were also tested using non-ethanol containing gelatin. Ro60-0175, a 5-HT 2 family receptor agonist, decreased both ethanol and vehicle responding while (−)-trans-PAT, a 5-HT 2C receptor agonist with 5-HT 2A-2B receptor inverse agonist activity, selectively reduced only ethanol responding. The effect of 5-HT 2C receptor agonists on self-administration after reinstatement of ethanol after a three week deprivation was also determined. (−)-trans-PAT eliminated increases in ethanol intake following ethanol deprivation whereas Ro60-0175 had no effect. These results emphasize the need for caloric controls and further support the idea that selective modulation of 5-HT 2 family receptors is a potential pharmacotherapeutic approach in the treatment of alcoholism.
Pharmacology, biochemistry, and behavior, 1993
The present study investigated the effect of the 5-HT2/1C receptor antagonist ritanserin, and of the 5-HT2/D2 receptor antagonist risperidone on ethanol preference in Sardinian alcohol-preferring (sP) rats. Rats were offered free access to both tap water and 8% (in one experiment 3%) ethanol solution. Subchronic (10 or 1 mg/kg/day, for 10 days) or chronic (1 mg/kg/day, for 30 days) subcutaneous (SC) ritanserin treatment failed to reduce 8% ethanol preference. Risperidone doses that produce marked 5-HT2, but low dopamine D2, receptor blockade (1 and 0.1 mg/kg/day, SC, for 9 and 10 days, respectively) did not modify 8% ethanol preference. On the other hand, a high risperidone dose (10 mg/kg/day, SC, for 14 days), which produces pronounced dopamine D2 receptor blockade, reduced 8% ethanol preference, like the dopamine receptor antagonist haloperidol. Previous studies have shown that both ritanserin and risperidone evoke long-lasting and pronounced suppression of 3% ethanol preference i...
Behavioral effects induced by 8-hydroxy-2-(din -propylamino)tetralin (8-OH-DPAT; i.e., lower lip retraction, flat body posture, and forepaw treading) were examined in rats during ethanol withdrawal following a 2-week period of access to a liquid diet containing 9% (v/v) ethanol. After an 18 h withdrawal period, tolerance to 8-OH-DPAT-induced fiat body posture and, conversely, sensitization to the effects of 8-OH-DPAT on lower lip retraction were observed in the 9% ethanol group as compared to control rats fed an isocaloric diet. In contrast, 8-OH-DPAT-induced forepaw treading in the 9% ethanol group was not significantly different in comparison to control rats. Plasma corticosterone levels were significantly higher in the ethanol-exposed group than in control animals, an effect which was not additive with the increase in corticosterone levels normally observed after the administration of low doses of 8-OH-DPAT. Altered flat body posture and lower lip retraction responses to a submaximal dose of 8-OH-DPAT (2.5 mg/kg i.p.) were still observed as late as 3 days after withdrawal of the 9% ethanol liquid diet, but were no longer apparent at 7 days. Interestingly, prominent ethanol withdrawal signs such as tremor and rigidity, while occurring on the first day, were completely absent on the third day. Taken together, these results indicate that chronic ethanol exposure differentially alters sensitivity to several pharmacological effects of the 5-HTaA receptor ligand 8-OH-DPAT. They further support the involvement of 5-HT (5-hydroxytryptamine, serotonin) systems in alcohol abuse and therapeutic interventions using 5-HTlA ligands.
Psychopharmacology, 2005
Rationale: Previous studies show that selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, have a greater effect on ethanol-maintained responding compared with an alternative reinforcer. However, none of these studies matched baseline responding for reinforcers. Because behavioral effects of many drugs depend on the baseline response rate, the preferential effects of SSRIs may be due to different baseline response rates. Objectives: Fluvoxamine effects on ethanol-and foodmaintained responding were compared using a multiple schedule of behavior, providing matched baseline responding and allowing within-subject analysis in two strains of rats. Methods: The multiple schedule consisted of three consecutive 5-min, fixed-ratio five components (Food1, Ethanol, Food2). Fluvoxamine (3-30 mg/kg, i.p.) was administered 30 min presession. In Lewis rats, fluvoxamine effects were determined at several available ethanol concentrations [8, 16, 32, and 8% (w/v) redetermination]. In Sprague-Dawley rats, fluvoxamine effects were determined when the available ethanol concentration was 8% (w/v). Results: Baseline responding was stable and well matched under all conditions except 32% ethanol, when responding for ethanol was lower than for food. After the administration of 17.8 mg/kg fluvoxamine, ethanol-maintained responding was 15-33% lower than food-maintained responding in four of the five conditions tested. Breath ethanol assessments indicated that rats had blood ethanol levels of 33 mg/dl following responding for 8% ethanol. Conclusions: These results are in agreement with previous findings that SSRIs preferentially reduce ethanolmaintained responding and suggest this is not likely due to different baseline levels of responding between the comparison conditions. Further, these results support the hypothesis that alteration of synaptic serotonin can modulate ethanol reinforcement.
Serotonin-3 Receptors in the Actions of Alcohol, Alcohol Reinforcement, and Alcoholism
Alcoholism: Clinical & Experimental Research, 2004
This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The organizers and chairs were William J. McBride and David M. Lovinger. The presentations were (1) Mechanisms of alcohol potentiation of 5-HT 3 receptor function, by David M. Lovinger and Tina Machu;
Ethanol does not affect serotonin receptor binding in rodent brain
Alcohol, 1989
ALCOHOL 6(4) 277-280, 1989.-The effects of ethanol on serotonin (5-hydroxytryptamine, 5-HT) receptor binding in rat and mouse brain were determined under in vitro conditions and in mouse brain following seven days of ethanol ingestion. 5-HT~A receptor characteristics were measured utilizing the agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]DPAT), and 5HT 2 receptorbinding studies utilized the antagonist [3H]ketanserin. At the highest concentration of ethanol tested in vitro (680 mM), there was only 25% inhibition of [3H]DPAT binding in rat and mouse brain and 14% inhibition of [3H]ketanserin binding in rat brain. Effects of an anesthetic concentration of ethanol (100 mM) on agonist binding in the presence and absence of the guanine nucleotide GTP were also evaluated in vitro in mouse brain. In no case did ethanol (100 mM) significantly affect 5-HT~A or 5-HT 2 receptor-binding characteristics. When 5-HT receptor characteristics were measured after mice consumed ethanol for seven days, there was no change in either 5-HT~A or 5-HT 2 receptor-binding properties in any of the brain areas examined.
Influence of fluoxetine and paroxetine in behavioral sensitization induced by ethanol in mice
Pharmacology Biochemistry and Behavior, 2005
The serotonergic system is involved in depression, anxiety and alcoholism. The rewarding properties of ethanol, mainly its anxiolytic and stimulant effects, as well as the development of dependence on ethanol have been related to the serotonergic system. Consequently, the use of selective serotonergic reuptake inhibitors (SSRI) has been proposed in the treatment of alcoholism. In this study we investigated whether acute administration of the SSRIs fluoxetine or paroxetine is able to (i) reverse the behavioral effects induced by chronic ethanol consumption, and conversely, (ii) to determine whether acute ethanol is able to substitute for the chronically induced behavioral effects of fluoxetine or paroxetine. Four groups of male Swiss mice (n = 60/group) received daily i.p. saline, ethanol (2 g/kg), fluoxetine (10 mg/kg) or paroxetine (5 mg/kg) for 27 days. On the 28th day, each group was challenged with saline, ethanol, fluoxetine or paroxetine. The 14 groups (SS, SE, SP, SF, EE, ES, EP, EF, PP, PE, PS, FF, FE, and FS) were then tested in open field, activity cage and plus-maze. EP and EF groups were able to reverse the behavioral sensitization to the psychomotor stimulant effects of chronic ethanol administration. In contrast, a sensitized stimulatory effect was observed in chronically fluoxetine-or paroxetine treated mice challenged with ethanol (PE and FE). An anxiolytic effect was observed whether ethanol was substituted for SSRI or, conversely, SSRI was substituted for ethanol. SSRIs facilitated ethanol-induced locomotor sensitization, although SSRIs by themselves are unable to produce the locomotor stimulation similar to that induced by ethanol. Finally, SSRIs are unable to interfere in the ethanol anxiolytic effect. D
Psychopharmacology, 1994
Previous work has reported that the 5-hydroxytryptamine (5-HT)I A agonist, 8-hydroxy 2-(di-n-propylamino)tetralin (8-OH DPAT), reduces ethanol intake by rats. However, as 8-OH DPAT reduces 5-HT neurotransmission, these findings are inconsistent with the proposed inhibitory role of central 5-HT neurons on ethanol intake. We examined the effect of 8-OH DPAT on ethanol, water and food intake in rats maintained on a limited access schedule using a lower dose range (6-250 gg/kg) and by assessing concomitant changes in behaviour. Low doses of 8-OH DPAT enhanced ethanol intake even when food and water were offered as alternatives. Suppression in ethanol intake was observed at higher doses where elements of the 5-HT syndrome were apparent. Similar observations were made in both fluid and nonfluid deprived water drinking rats, suggesting the latter effect is non-selective. Therefore 8-OH DPAT may both increase or decrease ethanol consumption in the rat depending on the dose used.