The results of this investigation support the hypothesis that zonisamide may reduce ethanol consumption in rodents. In both mice and rats, significant reductions in ethanol consumption were observed after administration of the 50-mg/kg dose, but not after the 25-mg/kg dose. Following the discontinuation of zonisamide administration, both rats and mice resumed consumption of ethanol solutions at levels that were equivalent to baseline intake levels, suggesting that the effects on drinking of this anticonvulsant were readily reversible. While the 50-mg/kg dose of zonisamide reduced ethanol intake, it did not alter daily weight in the rats over the treatment period, and produced only modest weight loss in mice. This suggests that the effects of this drug on ethanol consumption are not associated with a marked influence on the neuronal systems that are involved in the regulation of food consumption.
The oral administration of topiramate to rats resulted in a moderate reduction in the consumption of an ethanol-sucrose solution. The overall treatment effect was significant for the 50-mg/kg dose of topiramate. However, while ethanol consumption tended to be lower for the topiramate than for the lactose group when the 50-mg/kg dose of this drug was administered, between group comparisons for individual treatment days indicated a significant group difference for the last treatment day only. Other investigators have shown that the administration of topiramate will decrease alcohol consumption in C57BL/B6J mice (Gabriel and Cunningham, 2005
; Nguyen et al., 2007
). It is of interest to note that topiramate administration has not been found to alter ethanol-induced place preference in C57Bl/6J mice (Gremel et al., 2006
Drugs were administered to rats in marshmallows during the first four treatment days to minimize the stresses associated with forced oral administration. The consumption of marshmallows two-hours before drinking sessions, however, tended to reduce the amount of ethanol/sucrose solution consumed, although this effect only approached significance for the rats treated with lactose. Consequently, drugs were administered in suspension form during the last 6 days of treatment.
The reduction in the intake of ethanol-sucrose solutions seen after the consumption of marshmallow suggests that the presence of sugar may have been a major factor in motivating rats to drink these solutions, because the motivation for consuming sucrose may have been satiated by the marshmallows. The presence of sugars was clearly not a factor, however, in motivating mice to drink ethanol-water solutions in the second experiment. This leaves open the question as to whether zonisamide altered ethanol consumption by mice and rats through similar mechanisms involving a selective action on the motivation to consume alcohol, or if its influence on the consumption of sugars was a major factor for rats and not mice. In recent work in a collaborating laboratory, a 50 mg/kg IP dose of zonisamide was found to reduce the consumption of an ethanol/water solution in one group of Long Evans rats, but not that of a sucrose solution in a second group of animals (Leite-Morris and Ciraulo, 2007
). Thus, zonisamide administration may have a selective inhibitory effect on ethanol intake while not influencing sucrose consumption. The lack of effect of zonisamide administration on sucrose solution intake also suggests that this drug does not have a non-specific suppressant effect on liquid consumption.
In mice, the administration of topiramate, at doses that reduced ethanol consumption in C57BL/6 mice, did not significantly alter motor activity (Nguyen et al., 2007
). Locomotor activity is not significantly decreased by the IP administration of topiramate at doses ranging between 30 and 50-mg/kg in rats (Ciraulo et al., 2006
; Shannon et al., 2005
). Performance on the rotorod is not impaired by the administration of doses of topiramate at a dose of 200-mg/kg IP to mice (Tutka et al., 2005
). These results suggest that topiramate-induced reductions in ethanol consumption observed in the present study also are unrelated to effects of this agent on motor activity.
When used clinically, anticonvulsant doses are increased gradually to enhance the extent to which they are tolerated. An attempt was made to parallel this practice in the present study with the dose of topiramate and zonisamide being raised to the 50-mg/kg level only after five days of administration of the 25-mg/kg dose. This approach should have reduced the likelihood that non-specific drug effects such as sedation had an influence on the consumption of ethanol by the experimental animals when the 50-mg/kg dose was administered.
The doses of zonisamide tested in animals in the present study were comparable to those found to be effective in the prevention or suppression seizure activity in mice (Borowicz et al., 2006
; Masuda et al., 1979
; Masuda et al., 1980
; Nakamura et al., 1994
) and rats (Hamada et al., 2001
; Kitano et al., 2005
; Masuda et al., 1979
; Nakamura et al., 1994
). These doses are markedly lower than those of zonisamide reported to produce motor impairing or sedative/hypnotic effects in most studies. The ratio for plasma concentrations of anti-seizure to motor impairing (as assessed by the rotorod test) effects of zonisamide have been reported to be 7.6 and 8.8 for STD-ddy strain mice and Wistar HLA strain rats, respectively (Masuda et al., 1979
). In Sprague-Dawley rats, locomotor activity was significantly suppressed by a minimum effective dose of 300-mg/kg (IP) of zonisamide (Shannon et al., 2005
). Oral doses of zonisamide below 300-mg/kg (PO) did not alter the spontaneous movement of mice or rats (Masuda et al., 1980
). The ED50
for impairment of Wistar rats on the rotorod for zonisamide has been reported to be 160 mg/kg (PO) (Kitano et al., 2005
). Impairment of performance of mice on the rotorod test has been produced by zonisamide with ED50
's ranging between 100-292 mg/kg (PO) (Kitano et al., 2005
; Masuda et al., 1980
; Uno et al., 1979
). A 50 mg/kg dose of zonisamide when administered IP did not significantly alter latency for escape by Long Evans rats from the water in a Morris Water Maze (Ciraulo et al., 2006
). The ED50
for the hypnotic effects of zonisamide in mice was found to be 934-mg/kg (PO) (Masuda et al., 1980
). These findings suggest that zonisamide, at the doses used in the present study, may not have hypnotic or motor impairing effects in either mice or rats.
Higher concentrations of zonisamide may be attained in the plasma after IP injection of this drug than if this drug was administered orally when the same mg/kg dose of the drug is administered (Masuda et al., 1979
; Nagatomo et al., 1996
). This may be one explanation as to why the effects of zonisamide on ethanol intake were greater in mice treated IP with this anticonvulsant than they were in rats who received zonisamide orally. This may also explain why zonisamide had an effect on weight loss in the present study in mice, but not in rats. Finally, the possibility needs to be considered that non-specific effects of zonisamide resulting in reduced ethanol consumption would be more likely to occur in the present experiment in mice after IP injection of this agent than it would in rats following the oral administration of this drug.
The limited access model of drinking used in the present study fails to incorporate many features of drinking seen in the clinical manifestations of alcohol dependence. For example, mice or rats, when given limited access to ethanol, do not typically consume sufficient quantities of ethanol over a long enough period of time to produce the sustained high blood alcohol concentrations needed to produce physical dependence such as is seen in severe alcoholism. Ethanol consumption by animals in the experiments described here can be characterized as being modest. This level of consumption would not be expected to produce elevations in brain or blood alcohol concentrations that exceed those observed in previously reported limited access model studies of alcohol consumption (Finn et al., 2004
; Nurmi et al., 1999
; O'Callaghan et al., 2002
). Despite the limitations associated with the use of limited access models, drugs such as naltrexone (Kim et al., 2004
; Stromberg et al., 1998
; Stromberg et al., 2002
), that have reduced ethanol consumption in limited access sessions, have been found to be effective medications for the treatment of alcoholism. Therefore, the finding in the present study that zonisamide decreases ethanol intake in both rats and mice may indicate that zonisamide, like topiramate, will reduce alcohol consumption in humans.