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Repeated DOI and SR 46349B treatments do not affect elevated plus-maze anxiety despite opposite effects on cortical 5-HT2A receptors

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Abstract

We report the consequences of a 4-day treatment (b.i.d) with the 5-HT2A,2B,2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1.5 mg/kg) or the selective 5-HT2A receptor antagonist trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3-(2-fluorophenyl)propen-1-yl]phenol hemifumarate (SR 46349B, 7.5 mg/kg) on (i) anxiety-related behaviour in an elevated plus-maze, and (ii) specific [3H]ketanserin binding at central 5-HT2A receptors, in Roman rats. Neither DOI nor SR 46349B pretreatment affected the behaviour in the open arms of the elevated plus-maze; however, DOI pretreatment promoted discrete changes in the closed arm entries. The Bmax value of [3H]ketanserin binding at cortical 5-HT2A receptors was decreased by repeated DOI pretreatment. Conversely, Bmax, but also KD, values were increased by SR 46349B pretreatment. Thus, changes at central 5-HT2A receptors may occur without there being changes in anxiety-related behaviour in the elevated plus-maze.

Introduction

The lack of availability of selective ligands for numerous 5-HT receptor types has hampered the recognition of their respective roles, if any, in the aetiology of anxiety. Among these receptors, the 5-HT2A receptor is of interest as early clinical data have suggested that its blockade could lead to anxiolysis (Ceulemans et al., 1985). However, this suggestion emerged from studies involving ritanserin, a 5-HT2A,2B,2C receptor antagonist (Baxter et al., 1995). In keeping with the acute anxiolytic effect of 5-HT2B,2C receptor blockade in animals (Kennett et al., 1996), the hypothesis that 5-HT2A receptors do not mediate the clinical effects of ritanserin is noteworthy. This hypothesis is reinforced when one considers the results of animal studies aimed at analysing the role of 5-HT2A receptors in anxiety. Actually, acute administration of the widely used 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has been reported to exert anxiolytic, anxiogenic, or no effects at all (see Griebel, 1995). However, the interpretation of DOI-related studies is complicated by the finding that DOI also binds to 5-HT2B,2C receptors (Baxter et al., 1995), the acute stimulation of which leads to anxiety (Kennett et al., 1989). Moreover, acute administration of the preferential 5-HT2A receptor antagonists ketanserin and RP 62203 (Kennett, 1993) decreases or does not affect anxiety-related behaviours (see Griebel, 1995). This uncertainty concerning the acute role of 5-HT2A receptors on anxiety extends to repeated/chronic manipulations of this receptor. The behavioural effects of repeated treatments with selective 5-HT2A receptor antagonists in animal models of anxiety have not yet been reported. Acute pretreatment (48 h beforehand) with the 5-HT2A,2B,2C receptor antagonist mianserin or repeated pretreatment (last pretreatment 24 h beforehand) with the 5-HT2A,2B,2C receptor antagonist ritanserin has been shown to elicit anxiolysis in the elevated plus-maze (Benjamin et al., 1992; Wright et al., 1992), an effect associated with 5-HT2A receptor down-regulation (Leysen et al., 1986; Benjamin et al., 1992). However, knock-out mice lacking 5-HT2C receptors display decreased anxiety in the elevated zero-maze (Tecott, 1996), thus questioning again the role of 5-HT2A receptors in the behavioural effects of ritanserin and mianserin.

The aim of this work was thus to investigate the effects of repeated treatment with the selective 5-HT2A receptor antagonist trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3-(2-fluorophenyl)propen-1-yl]phenol hemifumarate (SR 46349B; Rinaldi-Carmona et al., 1992, Rinaldi-Carmona et al., 1993a, Rinaldi-Carmona et al., 1993b) in the elevated plus-maze test of anxiety. In addition, because the effects of repeated stimulation of 5-HT2A,2B,2C receptors on anxiety are not yet known, the effects of SR 46349B were compared with those of DOI. To verify that these treatments were endowed with opposite effects on 5-HT2A receptors (McKenna et al., 1989; Chaouloff et al., 1993; Rinaldi-Carmona et al., 1993a, Rinaldi-Carmona et al., 1993b), [3H]ketanserin binding to cortical 5-HT2A receptors was also studied. Lastly, to investigate whether the effects of DOI and SR 46349B on elevated plus-maze behaviours (if any) and 5-HT2A receptors depend on the baseline levels of these variables, we performed our experiments with Roman high- (RHA) and low-avoidance (RLA) rats. Thus, using Roman rats (Bordeaux sublines), we recently reported that RHA and RLA rats displayed high and low cortical [3H]ketanserin binding and high and low anxiety scores in the elevated plus-maze, respectively (Kulikov et al., 1995). However, because of the high number of animals required for the present study, we used RHA and RLA rats of the original subline (RHA/Verh and RLA/Verh).

Section snippets

Animals and housing conditions

The animals used in the present study have been bred for one generation from rats of the RHA/Verh and RLA/Verh lines, kindly provided by Dr P. Driscoll (Swiss Federal Institute of Technology, Zürich, Switzerland). Animals were weaned at 3 weeks and randomly housed, four per cage, by line and sex. All cages were placed in a room with constant temperature (22±1°C) and a 12 h:12 h cycle of illumination (lights on: 07.00 h).

Experimental procedure

When 10–12 weeks old, 36 males of each line were weighed and injected i.p.

Effects of DOI and SR 46349B pretreatments on body weight in RHA and RLA rats

Analyses of the respective effects of the 4-day pretreatments on body weight revealed no strain effect, but a significant decrease in DOI-pretreated rats (0.6±0.3% and 0.75±0.81% decreases in RHA and RLA rats, respectively) and, to a lesser extent, in SR 46349B-pretreated rats (1.47±0.39% and 1.47±0.47% increases in RHA and RLA rats), compared with vehicle-pretreated rats (4.18±0.53% and 3.44±0.3% increases in RHA and RLA rats, respectively; P<0.01 for the differences with DOI and SR 46349B in

Discussion

We have previously reported that RLA rats (i) entered more often, and spent more time, on the open arms of an elevated plus-maze, and (ii) displayed decreased [3H]ketanserin binding at cortical 5-HT2A receptors, compared with RHA rats (Kulikov et al., 1995). In this study, the percent time spent on the open arms of the plus-maze was the sole variable that displayed a significant strain-dependent profile. This discrepancy may be related to the rats' origin, as the present study used rats bred

Acknowledgements

We thank Dr. P. Driscoll (Zürich, Switzerland) and Sanofi Recherche (Montpellier, France) for the kind gift of Roman breeders and SR 46349B, respectively.

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