Topiramate moderately reduces the motivation to consume alcohol and has a marked antidepressant effect in rats.
BACKGROUND
In recent human studies, the anticonvulsant drug topiramate (TPM) has shown efficacy in treating alcohol craving and mood disorders. However, preclinical evidence supporting such effects is surprisingly sparse. Three experiments were conducted here to assess possible anticraving and antidepressant effects of TPM using animal models.


METHODS
In Experiment 1, rats were given 23 weeks ad libitum access to food, water, and either beer (4.44% ethanol v/v) or "near-beer" (a calorie-matched nonalcoholic beer, 0.44% ethanol) in their home cages. They were then restricted to daily 1 hour operant sessions in which they licked for water and either beer or near-beer under a progressive ratio schedule of reinforcement in a lickometer apparatus. The acute effects of TPM on the motivation to consume beer or near-beer were then assessed. The effects of naloxone were also assessed (as a positive control) after TPM testing. In Experiment 2, rats were given 11 weeks of ad libitum home-cage access to food, water, and beer. They then received repeated daily injections of TPM and effects on beer consumption under ad libitum home cage access conditions were monitored. In Experiment 3, the effects of TPM were assessed in the modified Porsolt forced swim test, emergence test, and elevated plus-maze (EPM) using alcohol naïve rats.


RESULTS
Topiramate (10, 20, and 40 mg/kg) significantly reduced the motivation to lick for beer, although the maximal effect was moderate in comparison with naloxone (10 mg/kg). However, naloxone, unlike TPM, also reduced responding for near-beer suggesting an alcohol-specific effect of TPM. In Experiment 2, TPM (40 and 80 mg/kg) tended to transiently reduce alcohol consumption in the home cage under ad libitum access but this effect disappeared with repeated administration of the drug. TPM (10 to 80 mg/kg, given twice over 4 hours before test) produced a robust dose-dependent decrease in immobility and increase in active coping strategies in the forced swim test similar to that seen with desipramine (2 x 20 mg/kg). There were modest anxiolytic effects of TPM on the EPM and emergence tests.


CONCLUSIONS
With acute administration, TPM is moderately effective and relatively selective in reducing the drive to consume alcohol in Wistar rats. This anti-alcohol effect is modest in comparison with naloxone and appears to dissipate under conditions of chronic treatment and ad libitum alcohol access. A marked antidepressant-like effect in the forced swim test and partial anxiolytic effects in other animal models suggests that TPM may be a beneficial treatment for affective disorders. These preliminary results suggest further research is warranted to resolve the mechanisms involved in TPM modulation of both mood and alcohol consumption.
Hargreaves
Garth A
GA
School of Psychology, University of Sydney, Sydney, New South Wales, Australia.
McGregor
Iain S
IS
D000428:Alcohol Drinking / Q000188:drug therapy / Q000503:physiopathology*; D000437:Alcoholism / Q000188:drug therapy; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003863:Depression / Q000188:drug therapy; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009042:Motivation; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013550:Swimming / Q000502:physiology; D000077236:Topiramate
D000928:Antidepressive Agents; D009292:Narcotic Antagonists; D000077236:Topiramate; D005632:Fructose; D009270:Naloxone