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mise à jour du 17 avril 2003
 Braz J Med Biol Res
Effects of a single administration of buspirone on catalepsy, yawning and stereotypy in rats
Conceicao IM, Frussa-Filho R
Departemento de farmacologica, Escola Paulista de Medicina Sao Paulo, Brasil


In recent years, nonbenzodiazepine anxiolytics have joined benzodiazepines on the anxiolytic market. One such agent is buspirone, a member of a group of heterocyclic compounds, the azospirodecanediones, which are structurally unrelated to the benzodiazepines. In fact, buspirone has no affinity for benzodiazepine-GABA receptor complex but shows high affinity for dopaminergic and serotoninergic binding sites.

Several lines of pharmacological evidence have indicated that the dopaminergicactivity of buspirone cannot be considered to be that of atypical neuroleptic, although buspirone shares some biochemical effects with these drugs. Indeed, as is the case for classical neuroleptics, acute buspirone administration raises striatal levels of the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid. On the other hand, in contrast to typical neuroleptics the drug does not modify the levels of 3-methoxytyramine, the extraneuronal metabolite of dopamine and decreases dopamine concentration in striatal tissue.

The aim of the present study was to determine the effects of a single buspirone administration on three dopamine-related behaviors in rats: haloperidol induced catalepsy, apomorphine-induced yawning and stereotyped behavior.

Three experiments were performed using young male Wistar rats. In the first, rats were randomly and equally divided into five groups: one control and four experimental groups of 8 animals each. Animals in the experimental groups were injected subcutaneously (sc) with 0.1, 0.3, 1.0 and 3.0 mg/kg buspirone, respectively, and the control group received the same volume of 0.9% NaCl by the same route. Fifteen min after buspirone administration, all rats received 2.0 mg/kg haloperidol intraperitoneally (ip) and were observed for catalepsy behavior 15 min later.

Catalepsy was measured by means of the bar test, as modified from Ferre et al.. Rats were grasped gently and the front paws placed over a horizontal bar 10 cm high; the animal was timed from then until both forepaws touched the floor or until reaching the maximum time allowed in our experiment (60 min). A determination of catalepsy was performed every 20 min for three consecutive periods (15-35, 35-55 and 55-75 min after haloperidol administration). Between determinations, animals were introduced into homecages. The sum of durations (in seconds) of catalepsy in each period was transformed to logarithmic values (In) in order to achieve a nonnalization of the data, as proposed by Ferre et al.

In the second experiment, rats were also divided at random into one control and four experimental groups of 10 animals each. The control group received 0.9% NaCl sc and the experimental groups 0.1, 0.3, 1.0 and 3.0 mg/kg buspirone sc, respectively. Twenty min after treatment, all animals were injected sc with 0.06 mg/kg apomorphine and 10 min later the total number of yawns was counted for 30 min.

In the third experiment, rats were divided into one control and four experimental groups of 7 animalseach. The control group received O.9% NaCl sc and the experimental rats were injected sc with 0. 1, 0.3, 1.0 and 3.0 mg/kg buspirone, respectively. Thirty mn later all animals were injected sc with 1.0mg/kg apomorphine and stereotyped behavior was quantified every 10 min for 100 min after apomorphine treatment, using the scoring system proposed by Setler et al. The sum of stereotyped scores was used to perform statistical analysis.

Catalepsy data were analyzed statistically by analysis of variance (ANOVA) followed by Duncan's test. Yawning responses and stereotypy scores were analyzed by Kruskal-Wallis one-way analysis of variance followed by the two-tailed MannWhitney U-test, as proposed by Yamada et al.

A single dose of buspirone was able to decrease the three observed behaviors in a dosedependent way (F(4,35) - 4.02, P<0.05, for catalepsy; H = 34.06, P< 0. 05, for yawning; H = 24.66, P<0.05 for stereotypy).

The observation that buspirone inhibits apomorphine-induced stereotypy confirms the data of Stanley et al. However, to our knowledge, the present study demonstrates for the first time that buspirone antagonizes in a dose-dependent way both haloperidol induced catalepsy and apomorphine-induced yawning. It is also the first to show agonist and antagonist dopaminergic effects of this drug on different dopamine related behaviors.

The present results indicate that buspirone presents unique pharmacological effects not only in biochemical but also in behavioral terms involving dopaminergic transmission. In fact, while the reduction of apomorphine-induced yawning and stereotyped behavior indicates a doparninergic antagonist activity of buspirone, the antagonism of haloperidol-induced catalepsy suggests that this drug also has dopamine agonist properties.

Some considerations are relevant to the possible mechanisms that may underlie these peculiar effects of buspirone on dopamine-related behaviors. First, a pharmacokinetic interaction between buspirone and haloperidol or apomorphine cannot be ruled out. In addition, buspirone has high affinity for the 5HT 1A subtype of central 5HT receptors and differences in the influence of serotoninergic transmission on the three behaviors studied here may account for these paradoxical effects of buspirone. Finally, buspirone might act as a dopaminergic partial agonist, thereby reducing the effects of full agonists and antagonists on yawning-related high-sensitivity dopamine receptors and on stereotypy/catalepsy-related low-sensitivity dopamine receptors. With respect to yawning-related dopamine receptors, it was first hypothesized that this behavior may be mediated by a reduction of synaptic dopamine levels which, in turn, is mediated by stimulation of autoreceptors. However, the autoreceptor hypothesis has been recently questioned by several research groups who have proposed that yawning is mediated by a population of postsynaptic dopamine receptors which are more sensitive to dopamine agonists and antagonists than other postsynaptic receptor populations such as the receptors that mediate stereotyped and catalepsy behavior.

These considerations of the mechanism by which acute buspirone administration might reduce apomorphine-induced yawning as well as stereotypy and haloperidol-induced catalepsy are speculative and further work is needed to clarify and define them. However, the peculiar effect of buspirone on dopamine-related behaviors is a provocative finding that should stimulate further study of this phenomenon.