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The effect of chronic administration of the dopamine reuptake inhibitor (DRI) bupriopion on 8-OH-DPAT-induced hypophagia in fasted rats The observation that the suppressant effect of the 5-HT1A receptor agonist 8-OH-DPAT on feeding in food-deprived rats or non-deprived rats given access to palatable food (see Ebenezer et al., 2003) is abolished following chronic treatment with antidepressants that selectively inhibit the reuptake of 5-HT, such as fluoxetine and sertraline, has suggested that this effect is due to desensitisation of central 5-HT1A receptors (Tite et al., 2003, Burki et al., 2005). The present study was undertaken to extend these observations and investigate the effect of chronic administration of the antidepressant drug bupriopion on 8-OH-DPAT-induced hypophagia in rat. While bupriopion is classically regarded as a dopamine reuptake inhibitor, recent studies have revealed that it is also a powerful reuptake inhibitor of noradrenaline but has no effect on the reuptake of 5-HT (see Ascher et al., 1995). Male Wistar rats (b.wt. 215 – 310 g; n = 16) were randomly divided into 2 equal groups and were deprived of food in their home cages for 22 h each day. Rats in Group 1 (Control Group) were injected i.p. once daily with physiological saline solution for 28 days, while rats in Group 2 (Treatment Group) were injected i.p. once daily with bupriopion (30 mg kg-1). On day 29 the animals in both groups were injected s.c. with 8-OH-DPAT (100 μg kg-1) and placed singly in experimental cages with free access to food and water (Ebenezer et al., 2003) and food intake measured. On day 28 a similar experimental protocol as described for day 29 was used except that the animals in both groups were injected with saline instead of 8-OH-DPAT in order to establish a control feeding baseline. The mean ± s.e.mean food intake per 100g body weight for the rats chronically treated with saline (Group 1) was 2.9 ± 0.2 g after saline and 1.9 ± 0.3 g (P<0.01) after 8-OH-DPAT. The mean ± s.e.mean food intake per 100 g body weight for the rats chronically treated with bupriopion (Group 2) was 2.6 ± 0.2 g after saline and 2.4 ± 0.2 g (ns) after 8-OH-DPAT. ANOVA revealed that there was a significant interaction between the two groups of rats and their responses to saline and 8-OH-DPAT (F(1,14) = 25.911, P<0.01), and indicate that chronic treatment with bupriopion reverses the hypophagic effect of 8-OH-DPAT in fasted rats. Although, bupriopion inhibits the reuptake of dopamine and noradrenaline but not 5-HT, there is evidence to suggest that chronic administration of the drug may act to desensitise 5-HT1A receptors by an indirect mechanism. El Mansari et al. (2008) have recently reported desensitisation of central 5-HT1A receptors in rat brain following chronic administration of bupriopion. It has been suggested the increase in extracellular level of central noradrenaline by chronic administration of bupriopion leads to desensitisation of α2-adrenergic hetroreceptors on 5-HT nerve terminals. As a result, the inhibitory control of noradrenaline on 5-HT neurones is abolished leading to increases in 5-HT release, which in turn, leads to desensitisation of central 5-HT receptors (see El Mansari et al., 2008). The results from this study therefore suggest that chronic treatment with bupriopion desensitises central 5-HT1A receptors resulting in the loss of the hypophagic effect of 8-OH-DPAT. These findings add further credence to the suggestion that the method described here may be useful as a novel in vivo test to assess psychoactive compounds for potential antidepressant activity (Tite et al., 2003, Burki et al., 2005).
Ascher, J.A. et al, (1995) J. Clin. Psychiatry. 56, 395 – 401.
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