Comparative effects of continuous infusion of mCPP, Ro 60‐0175 and d‐fenfluramine on food intake, water intake, body weight and locomotor activity in rats

Abstract

1 The aim of the study was to compare the e ects of 14 day subcutaneous infusion of the 5-HT 2C receptor agonists, m-chlorophenylpiperazine (mCPP, 12 mg kg 71 day 71 ) and Ro 60-0175 (36 mg kg 71 day 71 ) and the 5-HT releasing agent and re-uptake inhibitor, d-fen¯uramine (6 mg kg 71 day 71 ), on food and water intake, body weight gain and locomotion in lean male Lister hooded rats. 2 Chronic infusion of all three drugs signi®cantly reduced food intake and attenuated body weight gain. In contrast, drug infusion did not lead to signi®cant reductions in locomotor activity in animals assessed 2 and 13 days after pump implantation. 3 In a subsequent 14 day study that was designed to identify possible tolerance during days 7 ± 14, animals were given a subcutaneous infusion of mCPP (12 mg kg 71 day 71 ) or d-fen¯uramine (6 mg kg 71 day 71 ) for either 7 or 14 days. During the ®rst 7 days both drugs signi®cantly reduced body weight gain compared to saline-infused controls; however, from day 7 onwards animals withdrawn from drug treatment exhibited an increase in body weight such that by day 14 they were signi®cantly heavier than their 14-day drug-treated counterparts. 4 Both mCPP and d-fen¯uramine reduced daily food intake throughout the infusion periods. For 14-day treated animals this hypophagia was marked during the initial week of the study but only minor during the second week. In light of the sustained drug e ect on body weight, the data suggest that weight loss by 5-HT 2C receptor stimulation may be only partly dependent on changes in food consumption and that 5-HT 2C receptor agonists may have e ects on thermogenesis. 5 These data suggest tolerance does not develop to the e ects of d-fen¯uramine, mCPP and Ro 60-0175 on rat body weight gain.

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

“…This demonstrates that any 5-HT 2C receptor desensitization that might be induced by Ro60-0175 is not sufficient to produce tolerance to the effect of Ro60-0175 to reduce responding for cocaine. These results are in agreement with other reports showing a lack of tolerance to the anorectic actions of Ro60-0175 (Hayashi et al, 2005;Vickers et al, 2000). However, there are reports of rapid tolerance, developing within 7 days, to the anorectic effects of the 5-HT 2C receptor agonists m-CPP and YM 438 (Hayashi et al, 2005).…”

WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Anorectic Activity

“…These enhanced properties would suggest that WAY-163909 will have a low propensity for 5-HT 2A/B receptor-mediated side effects. From the early pharmacological studies demonstrating anorectic effects of mCPP in multiple species (Samanin et al, 1979;Curzon, 1988: Kennett andCurzon, 1991;Walsh et al, 1994;Cowen et al, 1995;Sargent et al, 1997) to more recent data with novel 5-HT 2C agonists that demonstrate effects on both food intake and body weight (Martin et al, 1998;Rosenzweig-Lipson et al, 2000;Welmaker et al, 2000;Vickers et al, 2000Vickers et al, , 2003Hayashi et al, 2004;Sabb et al, 2004), the pharmacological data supporting a role for 5-HT 2C agonists in obesity is compelling. The pharmacological data are supported by studies in mice lacking the 5-HT 2C receptor.…”

“…Studies using 5-HT antagonists that differ in selectivity among the 5-HT receptor subtypes have provided evidence supporting a role for the 5-HT 2C receptor in the regulation of this mCPP response Curzon, 1988, 1991). More recently described 5-HT 2C agonists such as Ro 60-0175, WAY-161503, VER-3323, PNU-22394, YM348, and WAY-629 have been reported to reduce food intake and body weight in animal models (Martin et al, 1998;Rosenzweig-Lipson et al, 2000;Vickers et al, 2000Vickers et al, , 2003Welmaker et al, 2000;McCall et al, 2001;Bickerdike, 2003;Hayashi et al, 2004;Kimura et al, 2004;Sabb et al, 2004). Conversely, pharmacological agents exhibiting 5-HT 2C antagonist activity such as antipsychotics increase food intake in rodents and cause weight gain in humans (Kennett and Curzon, 1988;Allison et al, 1999;Masand, 2000;Whitaker, 2000).…”

Olanzapine Reduces Physical Activity in Rats Exposed to Activity-Based Anorexia: Possible Implications for Treatment of Anorexia Nervosa?

“…It has been widely described that 5-HT pathways play an important role in energy balance. Increased levels of 5-HT or direct activation 5-HT 2A/2C receptors reduces food intake (Clifton et al 2000;Vickers et al 2000), whereas blockade of 5-HT 2A/2C receptors increases food intake and body weight gain (Currie et al 1996). Anorectic effects of d-fenfluramine (a 5-HT releaser and uptake inhibitor) are reduced in (obese) 5-HT 2C receptor deficient mice (Vickers et al 1999).…”