1-(2-methoxyphenyl)-4-(4-succinimidobutyl) piperazine (MM-77) is a putative 5-HT_1A antagonist with apparent specificity for post-synaptic 5HT1A receptors (Mokrosz et al., 1994). The present study was undertaken to characterise the effects of MM-77 on food intake in rats.

In all these experiments, groups of male Wistar rats (n=32, b. wt: 250 - 350g) were housed in groups of 4 and had free access to water at all times. In some experiments the rats had free access to food in their home cages and in others they were fasted for 22h each day. Food intake measurements were carried out in experimental cages where the animals were presented with food and water, as described previously (Arkle et al., 2000). Cumulative food consumption was measured at intervals over a 2h period. Experiment 1. Free feeding rats (n=8) and fasted rats (n=8) were injected s.c. with either vehicle (DMSO in saline, 75% w/v; veh) or MM-77 (1, 2, or 4 mg kg^-1) and placed singly in separate experimental cages immediately after drug administration. Experiment 2. Free feeding rats (n=8) and fasted rats (n=8) received the following treatments: Saline or WAY 100635 (0.3 mg kg^-1; WAY) followed 15 min later by either veh or MM-77 (2 mg kg^-1). Both injections were given by the s.c. route. The animals were placed singly in separate experimental cages immediately after the second injection and food intake measured. In all experiments, a repeated measures design was used with each rat receiving all treatments for the particular experiment; 3 - 4 days separated successive trials. The data was analysed by ANOVA with post hoc Dunnett's test.

MM-77 produced a dose-related increase in cumulative food intake in free-feeding rats at 60 and 120 min (Fig.1). By contrast, MM-77 caused a suppression in cumulative food intake in food-deprived rats at 30 and 60 min (Fig. 2). The findings are similar to those reported for 5HT_1A agonists in non-deprived and fasted rats (see Arkle et al., 2000 for details). Moreover, these effects on food consumption were totally abolished with WAY, a selective antagonist at both 5HT_1A pre-synaptic and post-synaptic receptors (see Arkle et al., 2000). The results obtained in Experiment 2 show that WAY abolished the hyperphagic effect of MM-77 at 60 min. Thus, MM-77 increased food intake from a control value (mean ± s.e. mean) of 4.1 ± 0.5g to 5.9 ± 0.3g (P<0.05) and pre-treatment with WAY reduced the hyperphagic effect of MM-77 to near control values of 4.4 ± 0.7g. However, WAY did not abolish the hypophagic effect of MM-77 in fasted rats. Thus, at 30 min, mean food intake ± s.e. mean were as follows: sal-veh: 10.1 ± 1.1g; sal-MM-77: 19.0 ± 1.4, P<0.05; WAY - MM-77: 18.6 ± 1.9g, P<0.05. These findings suggest that MM-77 displays some of the characteristics of a 5HT_1A agonist, but it is likely that other effects on feeding may be mediated by an action at other non-5HT receptors. It was noted that MM-77 produced ptosis in the rats, which is indicative of antagonism at central adrenoceptors or dopamine receptors.

Fig.1. Effects of MM-77 on food intake in non-deprived rats

Fig.2. Effects of MM-77 on food intake in food-deprived rats.

Arkle, M. et al., (2000) Eur. J. Pharmacol., 408, 273 - 276.
Mokrosz, J.J. et al. (1994) J. Med. Chem., 37, 2754 - 2760.