Alternative method of oral dosing for rats

Abstract

Oral administration of drugs to laboratory rodents typically is achieved by using the gavage technique. Although highly effective, this method occasionally can cause esophageal injury as well as restraint-associated distress, particularly with repeated use. The aim of this study was to assess an alternative oral dosing method that could reduce the distress and morbidity associated with standard gavage techniques. The palatability and pharmacokinetic profile of 2 medicines approved for the treatment of Alzheimer disease, donepezil and galantamine, were investigated in male Lister hooded rats by using a syringe-feeding method and compared with results from traditional gavage administration. In addition, the stimulant nicotine was tested by using the syringe-feeding method in a separate series of experiments. Animals reliably learned to drink voluntarily from the syringe, and latency to drink decreased rapidly. The addition of donepezil, galantamine, or nicotine to sucrose had no apparent effect on the palatability of the solution, although nicotine produced aversive effects that inhibited subsequent voluntary intake. Oral bioavailability was improved by using syringe feeding with donepezil but not galantamine. Both drugs improved cognitive performance in the novel object recognition test, with similar behavioral profiles between the 2 methods of administration. Our results suggest that the syringe-feeding technique is an effective alternative oral dosing method in rats.

Figure 1.

Rats readily drinking galantamine (0.5 mg/kg) by the novel syringe-dosing method on day 3 of training.

Figure 2.

Latency to drinking for (A) donepezil (0.5 mg/kg; syringe-dosed) and (B) galantamine (0.5 mg/kg; syringe-dosed). Total drinking latency did not differ between vehicle only (10% sucrose), donepezil, and galantamine over the 5-d training period. Data are expressed as mean ± SEM (n = 5).

Figure 3.

Drinking latency of nicotine (0.5 mg/kg; syringe-dosed). No differences in total drinking latencies between the vehicle (10% sucrose solution) and nicotine were present during the first training day (day1). However by day 2, total drinking latency differed significantly (+, P < 0.001) between vehicle- and nicotine-treated rats. All animals subsequently failed to drink the nicotine solution over the remaining training days. Data are expressed as mean ± SEM (n = 6).

Figure 4.

(A, C) Blood and (B, D) brain concentrations of (A, B) galantamine and (C, D) donepezil in syringe- and gavage-dosed rats. Donepezil syringe-dosed animals showed 5.4-fold (+, P < 0.001) increases in donepezil concentration in blood and brain compared with gavage-dosed animals. Data are expressed as mean ± SEM (n = 3).

Figure 5.

Blood pharmacokinetics profiles of (A) donepezil and (B) galantamine. Blood samples were collected over an 8-h period after administration of a single dose (0.5 mg/kg). Whereas blood concentrations of galantamine did not differ over time between syringe and gavage-dosed rats, donepezil syringe-dosed animals showed significantly (+, P < 0.05) higher blood concentrations at 30 and 60 min after dosage. Data are expressed as mean ± SEM (n = 6).

Figure 6.

Effect of donepezil (0.5 mg/kg) administered 30 min prior to testing on (A) total object exploration, (B) novel versus familiar object exploration, and (C) the recognition index (Exploration of novel object [s] – exploration of familiar object [s] / total exploration [s]). Donepezil enhanced recognition memory, as evident by a significant (+, P < 0.001) increase in novel versus familiar exploration, which translated to a significant (*, P < 0.01, +, P < 0.001) increase in the recognition index in both syringe- and gavaged-dosed animals. Overall recognition memory did not differ between syringe and gavaged-dosed animals. Data are expressed as mean ± SEM (n = 8).

Figure 7.

Effect of galantamine (0.5 mg/kg) administered 30 min prior to testing on (A) total object exploration, (B) novel versus familiar object exploration, and (C) the recognition index (Exploration of novel object [s] – exploration of familiar object [s] / total exploration [s]). Galantamine enhanced recognition memory, as evident by a significant (P < 0.001) increase in novel versus familiar exploration, which translated to a significant (P < 0.001) increase in the recognition index in both syringe- and gavaged-dosed animals. Overall recognition memory did not differ between syringe- and gavaged-dosed animals. Data are expressed as mean ± SEM (n = 8).