Effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in Warsaw alcohol high-preferring rats

Abstract

RationalePharmacological treatment currently used for alcohol dependence is not sufficient for the all patients, and there is a crucial need to find more effective treatments. Recent studies indicate that topiramate is likely the most promising new medication for alcohol dependence. The rationale for topiramate as treatment for alcohol addiction is based on its multifaceted neurochemical activity that targets multiple neural pathways.ObjectivesThis study aims to assess the effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in rats selectively bred for high alcohol preference.MethodsInitially, Warsaw high preferring rats (N = 50) were given a 24-h/day free choice between a 10 % (v/v) alcohol solution and water for three consecutive weeks. Subsequently, rats were administered with topiramate (40 or 80 mg/kg b.w.) or vehicle for 14 days and ethanol intake was measured daily. Subsequently, we examined the effects of topiramate on plasma beta-endorphin levels, while alcohol was available and when it was not available for an extended period time.ResultsWe observed significantly increase in the levels of beta-endorphin in rats with free access to alcohol both in a topiramate- or vehicle-treated group. However, in topiramate-treated group, a voluntary consumption of alcohol diminished in comparison with the vehicle-treated rats.ConclusionThe results from this study indicated that topiramate reduces voluntary alcohol intake and support our previous findings that the increase of beta-endorphin level is responsible at least partly for the effectiveness of drugs in treating the alcohol addiction.

Novel anticonvulsants for reducing alcohol consumption: A review of evidence from preclinical rodent drinking models

“…Future studies should address the issues that most of the drugs only reduced drinking when the drug was onboard, not many studies have examined anticonvulsants in relapse models, and some of the studies demonstrated tolerance to the effects of the drugs. Some of the anticonvulsants only reduced consumption in alcohol-preferring(9, 10), high-drinking(5), or alcohol-dependent rodents(17). This suggests that genetics and/or chronic alcohol induced neuroadaptations may affect the efficacy of these drugs.…”

“…Topiramate also reduced stress-induced escalation of alcohol consumption and preference in C57BL/6J mice(8). In Warsaw high preferring (WHP) and P rats, repeated treatment (5 - 14 days) with topiramate significantly diminished voluntary consumption and preference for 10% alcohol in a standard two-bottle choice paradigm(9, 10). Tolerance to repeated administration was not observed in these studies, as topiramate was equally effective at reducing drinking throughout the treatment period.…”

Glutamatergic targets for new alcohol medications

“…Topiramate is often used, off-label, as a treatment for alcoholism, and inhibits glutamate release and blocks L-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPAR)/ kainate receptors (KAR) as part of a complex pharmacological profile. In rodents, topiramate promotes alcohol intoxication and reduces alcohol drinking and withdrawal, but does not disrupt alcohol place preference (Breslin et al 2010; Cagetti et al 2004; Chen and Holmes 2009; Farook et al 2007; Gremel et al 2006; Hargreaves and McGregor 2007; Knapp et al 2007; Lynch et al 2011; Nguyen et al 2007; Zalewska-Kaszubska et al 2013). Topiramate also reduces craving, withdrawal and drinking in alcoholics (Baltieri et al 2008; Florez et al 2008; Johnson et al 2004; Johnson et al 2003a; Johnson et al 2007; Komanduri 2003; Krupitsky et al 2007b; Miranda et al 2008; Paparrigopoulos et al 2011; Rubio et al 2004; Rustembegovic et al 2002).…”

Molecular basis of alcoholism

“…Another PPAR agonist, clofibrate, prevents the acquisition of nicotine self-administration in naïve rats and monkeys and decreases nicotine self-administration in nicotine-dependent rats and monkeys, suggesting that the PPAR agonist might be viable options for treating the neuroimmune pathologies in alcoholism and other forms of addiction. The pharmacologic blockade of neuroimmune activation reduces alcohol reward and decreases consumption using many types of anti-inflammatory drugs like minocycline, doxycycline, topiramate, anakinra, indomethacin, and CAPE (Agarwal, 2001; Pascual et al, 2007; Breslin et al, 2010; Wu et al, 2011; McIver et al, 2012; Blednov et al, 2013; Zalewska-Kaszubska et al, 2013). Taken together, these findings have built substantial evidence for neuroimmune modulation of acute and chronic alcohol consumption and offer unique unexplored targets for therapeutic intervention.…”