Different effects of Bifeprunox, Aripiprazole, and Haloperidol on body weight gain, food and water intake, and locomotor activity in rats

Abstract

Following on the success of Aripiprazole with its high clinical efficacy and minimal side effects, further antipsychotic drugs (such as Bifeprunox) have been developed based on the same dopamine D2 partial agonist pharmacological profile as Aripiprazole. However clinical trials of Bifeprunox have found differing results to that of its predecessor, without the same significant clinical efficacy. This study has therefore investigated the different effects of 10 week treatment with Aripiprazole (0.75 mg/kg, 3 times per day), Bifeprunox (0.8 mg/kg, 3 times per day) and Haloperidol (0.1mg/kg, 3 times per day) on body weight gain, food and water intake, white fat mass, and 8 week treatment on locomotor activity. Treatment with Bifeprunox was found to significantly reduce all of the measured parameters except white fat mass compared to the control group. However, Aripiprazole and Haloperidol treatment reduced water intake compared to the control, without any significant effects on the other measured parameters. These findings further demonstrate the potential pharmacological differences between Aripiprazole and Bifeprunox, and identify potential weight loss side effects and increased anxiety behaviour with Bifeprunox treatment.

Atypical antipsychotics and effects on feeding: from mice to men

“…Conversely, 1 or 12 weeks of ARI (2.25 mg/kg divided into three daily doses) administered to female Sprague Dawley rats did not alter food intake, body weight, or fat mass (Han et al 2008). A similar result was also found in male Sprague Dawley rats administered ARI (0.75 mg/kg three times daily) with no noted change in food intake or body weight (De Santis et al 2014). However, to date, there is a relative paucity of studies examining ARI effects on food consumption in rodents.…”

“…In an experiment using male rats, Minet-Ringuet et al (2006b) examined 1 mg/kg/day of HAL mixed with food and failed to find changes in weight or food intake. De Santis et al (2014) found similar results with no change in body weight or food intake of male rats when HAL was administered three times daily at a dose of 0.7 mg/kg. Interestingly, in the context of lack of changes in food intake or absolute weight gain, HAL has been noted to variably increase adiposity, with one study in male rats reporting increases in fat mass (Minet-Ringuet et al 2006a) and at least one study failing to find increases in adiposity in female rats (Han et al 2008).…”

“…The other rodent studies looked at changes in locomotion. The majority found decreases in locomotor activity with OLA, ZIP, or RIS treatment (Arjona et al 2004, Hartfield et al 2006, Fell et al 2007, Snigdha et al 2008, Weston-Green et al 2011, although other studies have reported no change (Kirk et al 2004;Baptista et al 2004;Coccurello et al 2006;De Santis et al 2014). AAPs beyond those noted have not been evaluated.…”

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

“…It was reported that aripiprazole and bifeprunox, at these dosages, had over 90% D 2 receptor occupancy in rat brains (Wadenberg, 2007), while haloperidol reached approximately 70% D 2 R occupancy , Naiker et al, 2006, Natesan et al, 2006. Furthermore, the dosages used in this study have been shown to be physiologically and behaviourally effective in rodents (Assie et al, 2006, De Santis et al, 2014, Han et al, 2009, Kesby et al, 2006, Wadenberg, 2007, whilst not causing EPS side-effects (Natesan et al, 2006, Wadenberg, 2007. After 1-week administration, all rats were sacrificed between 10:00 AM and 12:00 PM to minimise possible circadian-induced variation of protein expression.…”

“…These dosages were equivalent to the recommended dosage in the clinic, and they were translated based on body surface area according to the FDA guidelines for clinical trials (FDA, 2005, Reagan-Shaw et al, 2008. This drug administration method has been well established in our laboratory (De Santis et al, 2014. A 0.75 mg/kg aripiprazole dosage in rats is equivalent to ~7.5 mg in humans (60 kg body weight), while 0.8 mg/kg bifeprunox and 0.1 mg/kg haloperidol is equivalent to ~8 mg and ~1 mg respectively, all of which are within the used/recommended clinical dosages (Casey et al, 2008, Emsley, 2009, Mace and Taylor, 2009.…”