The present study indicates that topiramate reduces consumption and preference of alcohol in WHP rats. Similar findings have been reported by other research group that used different strains of rats and mice (Gabriel and Cunningham 2005
; Breslin et al. 2010
). Studies by Hargreaves and McGregor (2007
) have found that topiramate (in doses of 40 and 80 mg/kg) tended to transiently reduce alcohol consumption under ad libitum access. Such reduction of consumption ceased with repeated (7-day) administration of the drug.
In our study, based on the use of topiramate in doses of 40 and 80 mg/kg b.w. for the period of 2 weeks, we did not observe any development of tolerance to the suppressant effect of the topiramate on alcohol intake. Decreased alcohol consumption was accompanied by significant increase in water intake in both the 40 and 80 mg/kg doses of topiramate treated groups. However, in contrast to the studies by Hargreaves and McGregor (2007
) and by Gabriel and Cunningham (2005
), we observed a reduced overall consumption of all fluids. The mechanism by which topiramate reduces total fluid intake is unclear. This noticeable decrease in total fluid intake complicates our conclusion with regard to the effect of topiramate on ethanol intake as topiramate reduces appetitive behavior, for all fluids. It is probable that topiramate disrupts the regulation of the ingestive process.
Breslin et al. (2010
) examined the effects of acutely administered topiramate on ethanol consumption in ethanol-preferring (P) rats and their background strain Wistar in order to assess the relationship between the level of consumption and a treatment effect. They observed that topiramate treatment produced a modest, but persistent (average of 5 days), reduction in ethanol consumption only in alcohol preferring rats. Conversely, in Wistar rats, topiramate had no effect on ethanol consumption or preference. They concluded that effectiveness of topiramate may depend on genetic vulnerability but not on the level of drinking.
This is consistent with our previous study where we observed that the administration of topiramate may have different effects on the opioid system depending on the individual genetic susceptibility to alcoholism (Zalewska-Kaszubska et al. 2007
). In alcohol preferring rats (WHP), which differ in the basic plasma beta endorphin concentration from non-preferring rats (WLP), a single application of ethanol resulted in a smaller increase in beta-endorphin in the rats previously treated with topiramate as compared with control rats treated with vehicle. By contrast, in WLP rats, topiramate treatment did not influence the ethanol effect. It has been suggested that topiramate has a modulating effect on the opioid system depending on genetic vulnerability. We agree with Breslin et al. (2010
) that the genetic vulnerability may be essential to understanding topiramate’s efficacy in decreasing alcohol intake. That opinion that topiramate may have a different impact based on genetic predisposition to alcoholism opens up a possibility of optimizing the treatment of alcoholics. Our study provides only preliminary suggestions regarding the efficacy of topiramate. Further studies are required to confirm our assumptions and correct our omissions. Thus, the subsequent research should concentrate on other lines of preferring alcohol rats as well as on clinical trials in patients with genetically determined susceptibility to alcohol abuse.
Among major challenges in the treatment of alcoholism are the diminution of physical withdrawal syndrome and craving, and the prevention of relapse into heavy drinking. As some studies suggest, a low level of endorphins may be related the increased craving for alcohol (Van Ree 1996
; Kiefer and Wiedemann 2004
), as well as to the tendency for alcohol abuse (Zalewska-Kaszubska and Czarnecka 2005
). Although we observed differences in reduction of alcohol consumption between the two studied doses of the drug, our observation that topiramate increases the beta-endorphin levels leads us to conclude that even low dose of the drug may be effectively used in the treatment of alcohol dependence. The overall decrease in the alcohol intake at a dose of 80 mg/kg was significantly lower; however, that noticeable difference in the drug’s effectiveness was observed only on first and third day of topiramate application. There was no significant difference in the effect on the beta-endorphin concentration between the two doses of topiramate, as a dose 40 mg/kg was at the limit of significance in comparison to the control group (p
The results obtained in this study may support conclusion from our previous research that the effectiveness of treatment of alcoholics may be in part dependent on the means available to increase the beta-endorphin level. We agree with the study by Chiu et al. (2007
), which suggested that even a low dose of topiramate can be beneficial in preventing alcohol relapse as even lower doses of the drug partially increased the beta-endorphin level. Miranda et al. (2008
) studied effects of topiramate in target doses of 200 and 300 mg/day that were administered to patients within a 32-day titration period to study the stimulating effects of alcohol ingestion. In this laboratory human study, topiramate did not show any effect on the frequency of drinking; however, as a result of its application, subject patients had significantly lower amount of alcohol intake during their drinking episodes as compared to those treated with placebo. On the basis of observation during the titration period, the authors suggested that doses of topiramate as low as 100–175 mg may be effective in reducing heavy drinking. They also observed that significant effect of the drug occurred as early as in the second week of the treatment at the level of only 75 mg a dose, in subjects treated with target dose of 200 mg. However, no significant effect was observed in group receiving 300 mg. Miranda et al. (2008
) concluded that the lowering of alcohol intake caused by topiramate is not dependent on the attenuation craving for alcohol. The authors suggested that topiramate may exert its beneficial effects by altering the subjective experiences of alcohol consumption. In addition, Paparrigopoulos et al. (2011
) suggested that low-dose topiramate as an adjunct to psychotherapeutic treatment is effective in reducing alcohol craving, as well as in reducing the symptoms of depression and anxiety observed during the early phase of alcohol withdrawal.
Several trials revealed that topiramate is more efficacious than naltrexone. One study of topiramate versus naltrexone in the treatment of alcohol dependence lead to a conclusion that both medicines were effective; however, topiramate was superior to naltrexone on critical measures of drinking, although the study did not have adequate statistical power to establish this fact (Flórez et al. 2008
). Suggestive evidence for superiority of topiramate over naltrexone was obtained by Baltieri et al. (2008
). Last clinical trial has shown that topiramate at a mean dose of 200 mg/day was better than naltrexone at a usually used dose of 50 mg/day at reducing alcohol intake and cravings throughout a 6-month evaluation (Flórez et al. 2011
). Previously, we observed that naltrexone after repeated treatment increased the beta-endorphin level with concomitant reduction in alcohol consumption (Zalewska-Kaszubska et al. 2008b
). While topiramate also increases levels of beta-endorphin, its mechanism of action is multidirectional and targets multiple neuronal pathways. Alcohol dependence involves adaptive changes in various neurotransmitters, which makes continuation of abstinence difficult. Due to its versatile action, topiramate may be more effective than naltrexone. In contrast, fluoxetine that does not influence the beta-endorphin level has only limited value in the treatment of alcohol dependence (Zalewska-Kaszubska et al. 2008a
In summary, the current study supports previous findings that topiramate reduces alcohol consumption, and that the mechanisms underlying this effect may involve, at least in part, modulation of the opioid system. Since all currently used drugs present only moderate effectiveness, this study allow us to look more optimistically into the future of alcohol addiction treatment.