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Alcohol and Alcoholism Advance Access published online on June 4, 2007
Alcohol and Alcoholism, doi:10.1093/alcalc/agm047
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The Author 2007. Published by Oxford University Press on behalf of the Medical Council on Alcohol.

Topiramate (Topamax) Reduces Conditioned Abstinence Behaviours and Handling-Induced Convulsions (HIC) after Chronic Administration of Alcohol in Swiss-Webster MICE

Justin M. Farook1,*, Dennis J. Morrell1, Ben Lewis1, John M. Littleton2 and Susan Barron1

1 Department of Psychology, Kastle Hall, University of Kentucky, Lexington, Kentucky-40506, USA
2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky-40536, USA

* Author to whom correspondence should be addressed at: Department of Psychology, Kastle Hall, University of Kentucky, Lexington, Kentucky-40506, USA. Tel: +1 859-257 6122; Fax: +1 859-323 1979; E-mail: justinfarook{at}uky.edu

Received 19 February 2007; first review notified 17 April 2007; in revised form 3 May 2007; accepted 11 May 2007


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials And Methods
 Results
 Discussion
 References
 
Topiramate has emerged as one of the promising drugs for the treatment of alcoholism and alcohol addiction. Recent studies have shown that topiramate reduces harmful drinking and initiates abstinence in humans, but little is known as to why this drug is effective. Aims: In the present study, we examined the effects of topiramate in reducing convulsions during alcohol withdrawal using a procedure called the handling-induced convulsion (HIC) test in male Swiss-Webster mice. In addition, we examined the ability of topiramate to reduce alcohol conditioned and anxiety related behaviours during conditioned abstinence using the elevated plus maze (EPM) test. Methods: HICs were examined 10 h after the 3rd daily alcohol (2.5 g/kg; 20% w/v) + 4 methylpyrazole (4MP) (9 mg/kg) intraperitoneal (i.p.) injection with topiramate (0, 10 or 20 mg/kg ip) administered 30 min before testing. In the EPM, alcohol (1.75 g/kg; 20%, i.p.) or saline was administered daily for 9 days and subjects were immediately placed on the maze. Anxiety related behaviours included the amount of time spent and number of entries in the open or closed arms and grooming bouts, and conditioned behaviours including the stretched-attend posture were examined 24 h after the last day of alcohol injection. Results: Topiramate (10 and 20 mg/kg) significantly reduced HIC scores (P < 0.05) compared to the alcohol/saline group. In the EPM, topiramate (20 mg/kg) reduced the stretched-attend postures (P < 0.001) compared to the alcohol/saline group. Conclusion: These findings suggest that topiramate reduces HICs during alcohol withdrawal and alcohol-conditioned behaviours during conditioned abstinence in Swiss-Webster mice.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials And Methods
 Results
 Discussion
 References
 
Naltrexone (Revia), acamprosate (Campral) and disulfiram (Antabuse) are the three drugs that are currently approved for anti-relapse treatment in alcohol dependence. While these drugs have been shown to be moderately effective, relapse is still common even when pharmacotherapy is combined with behavioural therapy. In consequence, it is essential that new treatments are developed. One possibility is topiramate, an anti-epileptic drug that has recently been shown (Johnson et al., 2003Go) to reduce drinking in alcohol-dependent patients. Using a double-blind, 12-week clinical trial, Johnson et al. showed that oral administration of topiramate decreased daily alcohol consumption and craving, decreased the number of heavy drinking days and increased the number of abstinence days. The mechanism of this action of topiramate is unkncite{(Shank et al., 2000Go), but the drug facilitates GABA activity (White et al., 1997Go; Kampman et al., 2004Go) and reduces glutamate activity (Shank et al., 1994Go, 2000Go; White et al., 1997Go), actions which are somewhat similar to those of acamprosate (Littleton and Zieglgansberger, 2003Go).

Alcohol dependence may be due to either (or both) the positive and the negative reinforcing effects of alcohol. The positive reinforcing effects are due to the rewarding properties of alcohol, whereas the negatively reinforcing effects increase drinking behaviour to stop, or avoid negative consequences associated with drinking such as withdrawal signs or craving (Koob et al., 1998Go; Littleton, 2000Go). Naltrexone, the opiate antagonist, acts primarily by reducing or blocking the positive reinforcing effects of alcohol (Cole et al., 2000Go) whereas acamprosate may act on both the positive and negative reinforcing effects of alcohol via its actions on glutamatergic and/or dopaminergic (DA) activity (Cole et al., 2000Go). Acamprosate inhibits the mild seizure activity associated with withdrawal (Zeise et al., 1994Go) and reduces the alcohol-conditioned anxiety in the elevated plus maze (EPM) whereas naltrexone does neither of these (Cole et al., 2000Go). Rodent models such as the conditioned place preference (CPP) or self administration (SA) procedure have been valuable to study the positive reinforcing effects of alcohol, and the data show that naltrexone or other opiate antagonists can clearly affect CPP and alcohol SA (Cowen et al., 2005Go). Acamprosate also can reduce SA although acamprosate's effects on CPP and SA are complicated (Cowen et al., 2005Go). The negative reinforcing effects of alcohol have not been studied as much although the EPM has been used to assess the anxiolytic actions of pharmacotherapeutic agents to examine how these agents can reduce cue-induced adaptations to repeated alcohol exposure (Cole et al., 1999Go, 2000Go). Using the EPM, acamprosate reduced conditioned behaviours associated with alcohol withdrawal on the maze (the stretch-attend posture) while naltrexone did not (Cole et al., 2000Go). Therefore, the overall objective of this experiment was to test topiramate in tests that distinguish between acamprosate and naltrexone.

To date, there have been very few studies that have examined the underlying mechanisms of the action of topiramate using animal models of alcohol consumption. Topiramate had no effect on alcohol's rewarding effects as measured in a CPP procedure (Gremel et al., 2006Go) although higher doses of topiramate did reduce alcohol consumption in C57Bl/6 J mice (Gabriel and Cunningham, 2005Go; Nguyen et al., 2007Go). Thus, the findings are somewhat mixed on whether topiramate has actions on the positively rewarding effects of alcohol. It is suggested that topiramate works by reducing alcohol withdrawal's conditioned negative reinforcing effects (Gremel et al., 2006Go). This concept is shared by Cagetti et al. (2004Go) that showed topiramate to be an effective drug in reducing alcohol induced withdrawal and anxiety behaviours in the EPM such as time spent in open arms, number of entries in open arms, and total number of entries in all arms following chronic intermittent ethanol (CIE) exposure. The current study was designed to further assess the effects of topiramate for its ability to reduce the negative reinforcing effects of alcohol, in particular, susceptibility to seizures during withdrawal and conditioned responses to cues following chronic alcohol in the EPM.


   Materials And Methods
TOP
 ABSTRACT
 Introduction
 Materials And Methods
Results
 Discussion
 References
 
Animals
Male Swiss–Webster mice (N = 5&ndash;6/group) weighing 26– 32 g were obtained from Harlan Laboratories, IN. The mice were housed 3/cage in a room maintained on a 16/8 light/dark cycle (lights on at 06:00 AM and off at 09:00 PM) and kept at a constant temperature. Food and water were available ad libitum. All research was conducted in accordance with National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23) revised 1996 and approved by the University of Kentucky Institutional Animal Use and Care Committee.

Experiment 1: the effects of topiramate on convulsions using the HIC test
A reliable method to assess seizure susceptibility during alcohol withdrawal involves picking up an alcohol-dependent mouse by the tail during withdrawal and assessing for seizure susceptibility (Wilson and Little, 1998Go). Topiramate (2,3:4,5-bis-O-(1 methylethylidene)- ß-D-fructopyranose sulfamate; C12H21NO8S) was obtained from Sigma-Aldrich, USA. 4 methylpyrazole (4MP) (Sigma-Aldrich, USA) blocks alcohol dehydrogenase and thus slows down the breakdown of alcohol (Paez et al., 2004). 4MP (9 mg/kg) was weighed separately, mixed with alcohol (2.5 g/kg, 20% w/v) and administered intraperitoneally (i.p.) (injection volume 10 ml/kg) on three consecutive days between 12:30 PM and 02:00 PM. On day 3, 10 h after the animals received their last injections, the mice received topiramate i.p. (dissolved in 0.9% saline) at doses of 10, 20 mg/kg or saline and 30 min later were subjected to the HIC test. The test began by lifting the mouse from its cage by the tail and scoring its behaviour according to signs/symptoms as described in Table 1. If no convulsions were observed, the mouse was spun clockwise and then counterclockwise (360°) for a period of 5 s. All mice were scored by an experimenter who was blind to the treatment condition.


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  		Table 1 (Modified after Wilson and Little, 1998Go)

 
Experiment 2: the effects of topiramate on alcohol conditioned and anxiety behaviours during conditioned abstinence using the elevated plus maze (EPM) test
Elevated plus maze test The EPM consisted of a maze with four arms (in the shape of a ‘plus’ sign) with two of the arms enclosed by Plexiglas walls (30x17x6 cm) and two of the arms having a floor but no walls (30x6 cm). The maze was elevated 44.5 cm above the floor.

Treatment Male Swiss–Webster mice were divided into 6 groups (N=5/group) in which 3 groups received saline while the remaining 3 groups received i.p. alcohol injections (1.75 g/kg) daily for 9 days between 12:00 PM and 01:00 PM. Ten min after they received injections, they were placed on the centre of the plus maze test apparatus for a 5 min conditioning session (Wilson and Little, 1998Go). On day 10, all subjects received 0, 10 or 20 mg/kg topiramate and 30 min later they were then placed in the centre of the maze.

Testing On day 10, behaviour on the maze was recorded for a 5 min test session. The dependent variables included: cumulative time spent in the open and closed arms; the total number of visits to the open and closed arms; the number of stretch-attend postures (defined as when the subject stretches forward with its forepaws without actually moving its hind paws) (Cole et al., 1999Go, 2000Go); and grooming bouts. Stretch-attend posture and grooming bouts are considered conditioned responses since they are produced only in the presence of a conditioned stimulus (in this case, the environment). There are no known reports of the actions of topiramate as an anxiolytic on conditioned responses. An arm visit was defined as all four paws on one arm. Behavioural experiments were conducted between 09:00 AM and 05:00 PM and were analyzed and scored by an individual who was blind to the treatment conditions.

Statistics All data were analyzed using SPSS for Windows (v. 12). The multiple dose determination studies for the various doses of topiramate were analyzed using two-way analysis of variance (ANOVA) with dose (0, 10 and 20 mg/kg) and group (saline or alcohol) as factors. Interactions were examined via one-way ANOVA. Post-hoc comparisons were conducted using Tukey HSD multiple range tests.


   Results
TOP
 ABSTRACT
 Introduction
 Materials And Methods
 Results
Discussion
 References
 
HIC scores
Prior studies conducted in our laboratory showed that alcohol in combination with 4MP (alcohol + 4MP) showed a significant increase in convulsions compared to the alcohol alone; 4MP alone or saline. One-way ANOVA using SPSS for windows (v. 12): F (3, 19) = 7.829, P < 0.05 (Fig. 1). Topiramate significantly reduced seizure susceptibility at both the 10 and 20 mg/kg dose compared to the alcohol control (alcohol + 4 MP) group (Ps < 0.001); One-way ANOVA: F (2, 14) = 18.296, P < 0.001 (Fig. 2).


Figure 1
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  		Effects of intraperitoneal (i.p.) administration of saline, alcohol (2.5 g/kg), 4MP (9 mg/kg), alcohol + 4MP in Swiss–Webster mice (N = 5/group) in HIC test. Values are expressed as ± S.E.M. **P < 0.001 by post-hoc Tukey against the saline group.

 


Figure 2
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  		Effects of intraperitoneal administration (i.p.) of topiramate (0, 10 and 20 mg/kg) in Swiss–Webster mice (N = 5/group) in HIC test. Values are expressed as ± S.E.M. **P < 0.001 by post-hoc Tukey HSD against the control (alcohol + 4mp) group.

 
Elevated plus maze
Anxiolytic/anxiogenic measures The highest dose of topiramate produced an anxiolytic effect in saline controls (Sal/20 mg/kg) as measured by more entries in the open arms and reduced time in the closed arms relative to saline controls (Sal/Sal, P < 0.001) (Fig. 3(a) and (b)). A very different pattern was observed for the alcohol-exposed subjects. While the Alc/Sal group showed a similar pattern of behaviour with reduced time spent in the closed arms and increased entries in the open arms relative to the Sal/Sal controls, the alcohol-exposed offspring that received topiramate did not show this pattern but instead resembled Sal/Sal controls. The ANOVA, for time spent in closed arms, revealed a significant group x dose interaction, F (2, 29) = 11.856 (P < 0.001). For the number of entries into the open arms, the ANOVA revealed a significant group x dose interaction F (2, 29) = 12.291 (P < 0.001) as well as a main effect of dose, F (2, 29) = 5.029, (P < 0.05).


Figure 3
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  		The effects of nine prior exposures to the plus maze with saline or ethanol injections followed by plus maze performance on day 10 after either Topiramate, (10 or 20 mg/kg) or saline treatment, on time spent on the closed arms (a), number of entries in open arms (b), number of postures (c). Data are expressed as mean ±SEM. *P < 0.05, **P < 0.01 by post-hoc Tukey HSD compared with Sal/Sal for 9 days and topiramate (10 or 20 mg/kg) on day 10. ## P < 0.01 by post-hoc Tukey HSD compared with Alc/Sal for 9 days and topiramate (10 or 20 mg/kg) on day 10.

 
Grooming bouts There were no differences in the number of grooming bouts across any of the treatment groups or drug conditions.

Conditioned behaviours
Stretched-attend postures As predicted, the group that received alcohol across 9 days and then received saline on the 10th day in the EPM displayed more stretched-attend responses than the saline controls. Both doses of topiramate eliminated this effect. The Alc/T20 and Alc/T10 both showed statistically fewer stretch-attend postures than the Alc/Sal group (Ps < 0.01) although they did not differ from each other (Fig. 3(c)). In contrast, there were no differences in the number of stretched-attend postures across the saline-treated groups. Two-way ANOVA for stretched-attend posture: dose, F (2, 29) = 21.553, (P < 0.001); group, F (1, 29) = 1.609, (P=0.217) and interaction, F (2, 29) = 45.285 (P < 0.001).


   Discussion
TOP
 ABSTRACT
 Introduction
 Materials And Methods
 Results
 Discussion
References
 
In the present study, potential mechanisms by which topiramate exerts its actions on alcohol relapse prevention using a mouse model were examined. The results from this study indicated that topiramate reduced convulsions during alcohol withdrawal in male mice at both the 10 and 20 mg/kg doses of topiramate. In the EPM paradigm, topiramate at the highest dose (20 mg/kg) produced anxiolytic effects in controls as measured by increased entries into the open arms of the plus maze. This pattern was not shown in alcohol-exposed subjects and in fact, topiramate tended to ‘normalize’ behaviours relative to controls. Of particular interest, topiramate significantly reduced the stretch-attend response in the alcohol-exposed groups at both doses relative to the Alc/Sal group.

As stated in the introduction, it has been suggested that both positive and negative reinforcement contribute to alcohol and other drug use/abuse. The positively reinforcing actions of alcohol are mediated, in part, via the projection of DA neurons of the ventral tegmental area into the nucleus accumbens and cortex (Weiss and Porrino, 2002Go) and topiramate may exert its effects on alcohol reward via actions on these neurotransmitters (glutamate, GABA and DA) (Kohl et al., 1998Go) although at least one study suggests that this may not be the main action of topiramate (Gremel et al., 2006Go).

For negative reinforcement, environmental cues that are repeatedly paired with alcohol can initiate a series of events that may increase the risk for relapse (Cole et al., 1999Go, 2000Go). An underlying component of the conditioned negative reinforcement hypothesis suggests that relapse can occur in response to cues that have previously been associated with alcohol consumption (Koob, 2000Go; Littleton, 1998Go). The conditioned cues come to produce an adaptive response that opposes alcohol's effects and may actually appear as early physiological signs of alcohol withdrawal. Since topiramate reduces these conditioned responses (at least the stretch-attend response), this may be important for our understanding of how topiramate works in reducing relapse to drinking. These results imply that topiramate may be exerting at least some of its effects as an anti-relapse drug via its effects on conditioned negative reinforcement and to the best of our knowledge, this is the first study to show that topiramate acts on alcohol-conditioned abstinence behaviours. It is interesting to note that acamprosate produced similar effects on the stretch-attend response as the results obtained in this study although naltrexone did not (Cole et al., 2000Go).

Topiramate also reduced seizure susceptibility during alcohol withdrawal in our HIC paradigm. Since topiramate is currently used as an anticonvulsant, these findings were not particularly surprising although the only existing study (to the best of our knowledge) that examined the ability of topiramate to reduce seizure susceptibility during alcohol withdrawal used a protracted 60-day chronic alcohol treatment regimen and a challenge with the convulsant drug pentylenetetrazol (Cagetti et al., 2004Go). The findings from the current study showed that using an abbreviated screening procedure developed in our laboratory, topiramate reduced seizure susceptibility during alcohol withdrawal following only 3 days of alcohol treatment with the addition of 4MP. Since topiramate is currently being tested clinically, the results obtained here validate these paradigms as possible screening methods. Pre-clinical screens with predictive validity based on currently approved therapeutic drugs such as naltrexone, acamprosate, and now topiramate, may be very beneficial in aiding our understanding of how these drugs work, and in future, work in the field of medication development.

Topiramate did have an anxiolytic effect in the EPM at the higher dose (20 mg/kg) in the control animals although there was little evidence for this following chronic alcohol exposure. This dose had been used previously by Cagetti et al. (2004Go) and an anxiolytic effect on the plus maze was observed following alcohol exposure. These conflicting results are currently difficult to reconcile although species differences (rats vs mice) could possibly explain this discrepancy. There is also some clinical evidence that at considerably higher doses, topiramate has anxiolytic properties (Van Ameringen et al., 2004Go; Barbee, 2003Go) although this data also is mixed and requires further study.

Alcohol withdrawal and relapse are complicated behaviours mediated by a variety of brain regions and neurotransmitter systems. Compensatory changes as a consequence of chronic alcohol exposure include reductions in GABAergic sensitivity and glutamate super sensitivity, and these play important roles in alcohol withdrawal-induced seizures (Kalluri and Ticku, 2002Go; Hoffman and Tabakoff, 1994Go) and possible relapse (White et al., 1997Go; Gibbs et al., 2000Go), and as stated in the introduction, activities of both these neurotransmitters are altered by topiramate.

In conclusion, the findings from this study reveal some of the underlying mechanisms by which topiramate alters response to alcohol and alcohol associated cues in male Swiss–Webster mice. With the limited number of effective agents available for treating alcoholism and alcohol abuse disorders, further examination and testing of topiramate to gain further understanding of its actions is critical. Topiramate's ability to target a number of neurotransmitters that have been implicated in alcohol dependence, withdrawal and relapse, and the recent interest in topiramate's ability in treating a variety of other psychiatric disorders makes the future of topiramate potentially exciting indeed.


   ACKNOWLEDGEMENTS
 
This work was supported in part by a Petite Grant awarded to J.M.F from the Center on Drug and Alcohol Research, University of Kentucky, AA Grants to S.B (# 014032) and J.M.L (# 12600). We thank Adam Farnsworth, Amber Estes and Erin Bowling for their valuable contributions towards this study.


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