Severity of drinking as a predictor of efficacy of the combination of ondansetron and topiramate in rat models of ethanol consumption and relapse

Abstract

Rationale Alcohol dependence is the third leading cause of preventable death in the USA. While single-agent pharmacotherapies have variable efficacy, medication combinations may produce additive effects by modulating multiple neural pathways. Objectives Here, we examined in animal models of ethanol consumption and relapse the combined effects of ondansetron (a serotonin-3 antagonist) and topiramate (a GABA/ glutamate modulator), two medications with demonstrated efficacy for treating alcohol dependence, hypothesizing that their combination would produce a more efficacious response. Methods The effects of acutely administered ondansetron (0–0.01 mg/kg) and topiramate (0–10 mg/kg) alone and in combination on ethanol consumption were examined in alcohol preferring (P) rats (N=20) and in rats from their background strain (Wistars, N=20) using a 24-h access free-choice paradigm. Next, we examined their ability to prevent an increase in ethanol consumption following a deprivation period (i.e., an animal model of relapse). Results Whether administered alone or combined with ondansetron, topiramate produced a similar modest but persistent reduction in ethanol consumption. However, an analysis of efficacy by drinking level revealed that the combination was superior to topiramate alone in heavy-drinking P rats, but was without effect in lighter-drinking P rats and Wistar rats. Both topiramate alone and the combination blocked the alcohol deprivation effect in both Wistar and P rats with the combination tending to produce a greater decrease than topiramate alone. Conclusions The combination of ondansetron and topiramate may be a promising treatment for preventing relapse and for treating alcohol dependence in heavy-, but not lighter-drinkers.

Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment

“…All compounds were dissolved in 0.9% sodium chloride and sterile water. Doses of naltrexone (1 mg/kg) and topiramate (10, 20 g/kg) were chosen based on previous studies demonstrating the ability of these doses to reduce ethanol consumption/reinforcement in male P rats (Lynch et al 2011; Moore et al 2014). …”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…And, GABA A and GABA B receptors mediate some of the rewarding, reinforcing, and motivational effects of alcohol consumption and alcohol binge drinking (Eiler & June, 2007; Nowak, McBride, Lumeng, Li, & Murphy, 1998; Tanchuck, Yoneyama, Ford, Fretwell, & Finn, 2011; also see Agabio & Colombo, 2014). Systemically, the GABA A agonist topiramate (Breslin, Johnson, & Lynch, 2010; Lynch, Bond, Breslin, & Johnson, 2011) and GABA B agonist baclofen (Liang et al, 2006; Maccioni et al, 2012) and GABA B positive modulators GHB (June et al, 1995), CGP7930 (Liang et al, 2006) and GS39783 (Maccioni et al, 2012) all reduced ethanol drinking and/or self-administration by P rats. Similarly, negative modulators of the benzodiazepine-site Ro 15-4513 (McBride, Murphy, Lumeng, & Li, 1988), Ro 19-4603 (June et al, 1996; June, Murphy, Mellor-Burke, Lumeng, & Li, 1994; June, Torres, et al, 1998), Ru 34000 (June, Eggers, et al, 1998), Ro 15-1788 (June et al, 1994; June, Torres, et al, 1998), CGS 8216 and ZK 93426 (June, Devaraju, et al, 1998; June, Zuccarelli, et al, 1998) all reduced ethanol intake and/or self-administration by P rats.…”

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).…”