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.
