Effects of serotonin 5-HT1/2 receptor agonists in a limited-access operant food intake paradigm in the rat

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Abstract

Hypophagic effects of serotonergic drugs have mostly been investigated in free-feeding paradigms and are generally ascribed to drug-induced acceleration of satiety, or to behavioral disruption. The present study investigated the hypophagic effects of various 5-HT1/2 receptor agonists in an operant paradigm. Because of its limited duration (10-min session) the procedure was considered to be relatively insensitive to satiety processes. The behavioral specificity of the hypophagic effect was assessed by additional testing of the compounds in a locomotor activity assay. Male Wistar rats, maintained at about 80% of their free-feeding weights, were trained to acquire stable operant responding in daily fixed ratio:10 food-reinforced sessions; after which they were tested once a week with a 5-HT receptor agonist. Each compound dose-dependently suppressed the number of earned pellets after i.p. administration: DOI (5-HT2A/2C receptor agonist; ED50: 0.36 mg/kg), TFMPP (5-HT1B/2C/2A; 0.37 mg/kg), m-CPP (5-HT2C/1B/2A; 0.54 mg/kg), ORG 37684 (5-HT2C/2A; 0.85 mg/kg), CP-94,253 (5-HT1B; 2.09 mg/kg), BW 723C86 (5-HT2B; 6.26 mg/kg) and ipsapirone (5-HT1A; 10.17 mg/kg). When tested at the dose equivalent to the ED50 value in the operant paradigm, only ORG 37684 and DOI weakly suppressed activity counts in a locomotor activity assay; suggesting that the inhibition of operant food intake obtained with the other compounds at these doses is not a direct consequence of unconditioned motor effects. It is suggested that the hypophagic effect induced by relatively low doses of CP-94,253, TFMPP and m-CPP, and by moderate doses of ipsapirone and BW 723C86, is partly due to a drug-induced suppression of appetite. Although the exact contribution of the diverse 5-HT1/2 receptor subtypes to appetite control remains to be studied in more detail, it is hypothesized that activation of 5-HT1B and/or 5-HT2C receptors attenuates appetite.

Introduction

Although it is now well established that serotonin (5-HT) receptor agonists with high affinity for the different subtypes of the 5-HT1 and 5-HT2 receptor families can affect ingestive behavior, the precise role of the diverse receptor subtypes (i.e., 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B and 5-HT2C) in the control of ingestive behavior, as well as the physiological, neuroanatomical and behavioral mechanisms underlying the hypophagic effect of these compounds are not yet fully understood (for reviews, see Blundell and Halford, 1998, Curzon, 1991, De Vry and Schreiber, 2000, Dourish, 1995, Samanin and Grignaschi, 1996, Simansky, 1996). Typically, the hypophagic effect of these compounds is investigated in free-feeding paradigms, using nondeprived or food-deprived animals, and has generally been ascribed to a drug-induced acceleration of satiety or satiation processes (Blundell, 1977, Blundell, 1984). Thus, by means of the so-called behavioral satiety sequence paradigm, or by using paradigms which analyse the macro- and microstructure of ingestive behavior, a number of research groups have suggested that 5-HT releasing agents, such as fenfluramine, and compounds which stimulate 5-HT2C and/or 5-HT1B receptors specifically enhance the state of satiety in rats (e.g., Clifton et al., 1993, Clifton et al., 2000, Halford et al., 1998, Kitchener and Dourish, 1994, Samanin and Grignaschi, 1996, Simansky and Vaidya, 1990). However, as discussed by Samanin and Grignaschi (1996), fenfluramine was also found to reduce appetite, in addition to its property to accelerate the process of satiety. Similarly, it was concluded by Halford and Blundell (2000) that the 5-HT system exerts an inhibitory effect over the pattern of food intake by modulating both satiety and appetite. It remains unclear to what extent the hypophagic effect of selective 5-HT1/2 receptor agonists can also be attributed to a drug-induced effect on appetite, and if so, what the exact contribution of the diverse 5-HT1/2 receptor subtypes to such process is. Although the majority of studies on the role of the 5-HT system in the control of food intake has been performed in rodents, Wolff and Leander (2000) recently investigated the effects of various 5-HT1/2 receptor agonists on food intake in pigeons and concluded that hypophagia induced by 5-HT2C receptor activation may be related to decreased appetite; whereas hypophagia induced by 5-HT2A receptor activation may be related to emesis.

The present experiments were performed to investigate the effect of a number of compounds which activate different receptor subtypes of the 5-HT1 and 5-HT2 receptor families on food intake in a limited-access, fixed ratio:10 operant paradigm. Because of its limited duration (10-min sessions) the procedure was considered to be relatively unsensitive to satiety processes. In order to maximize the contribution of appetitive processes to the paradigm, the animals were maintained at about 80% of their free-feeding weights by restricting their daily food supply to about 13–15 g (offered immediately after the daily session, in which they typically consumed 3–4 g of pellets). In a first experiment (“repeated testing experiment”), it was tested to what extent repeated exposure of the animals to five consecutive 10-min operant sessions (performed within 6 h) affected operant food intake. As it was found that about the same amount of food pellets was consumed during the first two sessions (spaced 20 min apart), it was concluded that the paradigm used for pharmacological testing was mainly controlled by appetite, and that satiety (development) was hardly present during the first session. Pharmacological testing was performed with the following 5-HT receptor agonists: ipsapirone (5-HT1A; Traber et al., 1984), CP-94,253 (5-HT1B; Koe et al., 1992), TFMPP (5-HT1B/2C/2A; Fuller et al., 1981b), m-CPP (5-HT2C/1B/2A; Fuller et al., 1981a), ORG 37864 (5-HT2C/2A; Leysen and Kelder, 1998); BW 723C86 (5-HT2B; Kennett et al., 1997) and DOI (5-HT2A/2C; Shannon et al., 1984). These compounds were selected on the basis of their 5-HT receptor subtype selectivity and/or their well-described effects in free-feeding paradigms, both in nondeprived and food-deprived rats (Aulakh et al., 1992, Aulakh et al., 1995, Bovetto and Richard, 1995, Fletcher and Davies, 1990, Gilbert and Dourish, 1987, Halford and Blundell, 1996, Kennett et al., 1997, Lee and Simansky, 1997, Samanin et al., 1979, Schechter and Simansky, 1988, Schreiber et al., 2000, Wong and Reid, 1987). In order to assess the possible contribution of unconditioned drug effects on general activity, the effect of these compounds (administered at a dose which was equivalent to the ED50 value in the operant paradigm) on locomotor activity was tested during a similar 10-min session in rats habituated to the test environment. A preliminary report of the present data has been published previously (De Vry and Schreiber, 2000).

Section snippets

Animals

Male Wistar rats were purchased from Harlan-Winkelmann (Hsd/cpb: WU, Borchen, Germany). Body weight upon arrival at the laboratory was around 200 g, which gradually increased to 350–530 g during the course of the studies. Rats were individually housed in Macrolon® type 3 cages under a normal 12-h light/dark period (light on at 7:00 a.m.). Room temperature was maintained at 22–23 °C. Throughout the studies, tap water was supplied ad libitum in the home cages, but the animals were (after 1 week of

Results

In the “repeated testing experiment”, exposure to five consecutive 10-min test sessions within 6 h resulted in a progressive decrease in operant responding (Fig. 1). Thus, as compared with the first test session, retesting 20, 80, 200 and 320 min after the end of the first session reduced operant performance by 11, 21, 24 and 30%, respectively [F(1,30)=10.05, P=0.003; significance levels of the pair-wise comparisons with the first session are indicated in Fig. 1].

Throughout the pharmacological

Discussion

The serotonergic system is thought to be intimately involved in the control of ingestive behavior (Blundell, 1977, Blundell, 1984). Among the lines of evidence leading to this hypothesis is the fact that a variety of serotonergic compounds (particular 5-HT receptor agonists and 5-HT releasing compounds) induce a reduction of ingestive behavior (for references, see Introduction). Typically, hypophagic effects of these compounds have been investigated in free-feeding paradigms, using nondeprived

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