The effect of chronic administration of diazepam on 24h food intake and body weight gain in non-deprived rats

Sunit M Patel, Ivor S Ebenezer. University of Portsmouth, Portsmouth, Hampshire, United Kingdom.

We have previously reported that chronic i.p. administration of diazepam (4 mg kg-1) increases short-term food intake in non-deprived rats without the induction of tolerance to the drug-induced hyperphagia, but decreases body weight gain (Patel et al., 2004). The present study was therefore undertaken to investigate the effects of chronic administration of diazepam on 24 h food intake and body weight in rats to determine whether the reduction in weight gain was due to effects on long term food intake. Adult male Wister rats (n = 12; starting body weights: 300 – 360 g) were divided into 2 equal groups and injected i.p. with either saline (Group 1) or diazepam (2 mg kg-1; Group 2) on a daily basis for 29 days. Following the 1st, 10th and 29th injection of saline or diazepam, the rats were placed separately into experimental cages with free access to food and water and cumulative food intake measured at 30 min intervals for 24h. Daily body weight for each rat was also recorded and expressed as the percentage change relative to body weight on treatment Day 1. Diazepam produced a general increase in short-term cumulative food intake during the 3 measurement days which was mainly apparent during the first 400 min following injection. Thus, at 120 min the cumulative food intake (g) ± s.e. mean was as follows: Day 1: 3.4 ± 0.5 for Group 1(saline) and 5.4 ± 0.5 for Group 2 (diazepam; P<0.01), Day 10: 3.1 ± 0.3 for Group 1 and 7.6 ± 0.5 for Group 2 (P<0.01), Day 29: 4.0 ± 0.9 for Group 1 and 7.4 ± 0.6 for Group 2 (P<0.01). Statistical analysis (ANOVA and post-hoc t-test) showed that tolerance did not occur to the early stimulation of feeding induced by diazepam. However, analysis of the 24 h feeding data revealed that there was no significant differences in food consumption between the control and diazepam treated groups during the experiment. For example, after the 1st and 29th injections, the 24 h cumulative food intake ± s.e. mean was as follows: 1st injection: 32.0 ± 1.5 for Group 1 and 34.6 ± 1.7 for Group 2 (n.s.), 29th injection: 31.0 ± 2.4 for Group 1 and 33.0 ± 2.8 for Group 2 (n.s.). In agreement with previous results (Patel et al., 2004), the rats treated with the 2 mg kg-1 dose of diazepam displayed significant decreases in weight gain relative to controls for the duration of the experiment. Thus for example, the percentage changes in body weights ± s.e. mean on treatment Day 4, 10 and 29 were as follows: Treatment Day 4: saline 2.9 ± 0.6, diazepam 0.8 ± 0.6 (P<0.05); Treatment Day 10: saline 12.3 ± 0.6, diazepam 7.3 ± 0.6 (P<0.01); Treatment Day 29: saline 28.1 ± 1.6, diazepam 20.6 ± 0.8 (P<0.01).These observations suggest that while chronic administration diazepam (2 mg kg-1) increases short-term food intake in rats without the occurrence of tolerance, it has no effect on long term (24 h) food consumption. Hence, the inhibitory action of diazepam (2 mg kg-1) on body weight gain is not related to long-term suppression of food intake. It is therefore likely that the effects of diazepam on feeding and body weight may be mediated by different mechanisms. While there is evidence to support a role for central benzodiazepine receptors in the stimulant effects of diazepam on short-term feeding (Cooper, 1980), it is possible that the effect on body weight gain may be secondary to changes in metabolic rate mediated by an action of diazepam at peripheral benzodiazepine receptors located on mitochondria (see Casellas et al., 2002).

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Patel, S.M. et al. (2004) Proc Brit Pharmacol. Soc at http://www.pa2online.org/Vol1Issue4abst128P.html