Clozapine chronically suppresses alcohol drinking in Syrian golden hamsters

Abstract

Alcohol use disorder is common in patients with schizophrenia and is associated with poor clinical outcomes. Preliminary reports from our group and others suggest that the atypical antipsychotic clozapine may decrease alcohol use in these patients. We have previously shown that clozapine suppresses alcohol consumption for 9 days in Syrian golden hamsters. Here, we assessed the effects of clozapine on alcohol consumption in hamsters over a 27-day period, using a continuous access, 2-bottle (15% alcohol vs. water) protocol. Clozapine (4, 8, or 12 mg/kg/day, injected subcutaneously [s.c.]) dose-dependently suppressed alcohol drinking, while increasing food and water intake. There was no tolerance within individual groups to the effect of clozapine on alcohol drinking over time. In a separate experiment, the effects of clozapine on sucrose and water drinking and food intake over a 9-day period were assessed. Clozapine (4, 8, or 12 mg/kg/day s.c.) failed to suppress sucrose (0.09 M), food, or water consumption at any time-point tested. In a related study, assessment of blood alcohol levels in hamsters indicated that blood alcohol levels were maintained within a narrow and moderate range (7-13 mg/dL), levels noted by others to produce physiologic effects in rodents. The ability of clozapine to suppress alcohol drinking in the hamster over an extended period of time without suppressing sucrose, water, or food consumption is consistent with preliminary reports indicating that clozapine limits frequent alcohol use, even producing abstinence in many patients with schizophrenia.

Fig. 1

Effects of clozapine treatment on alcohol drinking in hamsters. Prior to randomization into treatment groups, all animals had 24 days of free-choice access to alcohol and water in 2 separate bottles. Baseline alcohol intake was taken as the 4 days (Days −3, −2, −1, and 0) immediately prior to the initiation of treatment. During the Treatment Phase, clozapine (4, 8, or 12 mg/kg) was injected once daily over 27 days (Days 1–27). All doses of clozapine (CLOZ) but not vehicle (VEH) decreased alcohol drinking below baseline. The changes were dose-dependent and relatively stable over time.

Fig. 2

Effects of clozapine treatment on food and water. All doses of clozapine (CLOZ), but not vehicle (VEH), increased food intake (top) and water intake (bottom), while they decreased alcohol drinking. Clozapine did not alter total daily caloric intake (data not shown). Empty bars: averaged rates during the baseline period. Solid bars: average rates during the treatment period.

Fig. 3

Effect of clozapine treatment on sucrose preference. Although sucrose preference decreased over time, there was no effect of clozapine treatment on sucrose preference.

Fig. 4

Effects of clozapine treatment on food and water intake. Clozapine failed to alter food intake (top) or water intake (bottom). Clozapine did not alter total daily caloric intake (data not shown). Empty bars: averaged rates during the baseline period. Solid bars: average rates during the treatment period.