- Abstract. Lisuride increased the
incidence of stretching and yawning (SY) as well
as of penile erection (PE) and elicited
stereotyped behavior (SB), aggressive behavior
and mounting in male rats, depending on the dose
used. SY was prevented by two dopaminergic
antagonists, haloperidol and sulpiride, but not
by methysergide, a serotoninergic antagonist,
while PE was antagonized by all three drugs.
With regard to SB, aggressive behavior and
mounting, all three were suppressed by
haloperidol; sulpiride, while partially
antagonizing aggressiveness, failed to affect SB
and mounting; mcl hysergide did not
significantly influence any of the three. This
suggests that lisuride principally affects the
dopaminergic system. Although further detailed
studies are required to elucidate which type of
the complex population of DA-receptors is
involved in each kind of behavior, we suggest
that SY at least is due to the activation by
lisuride of presynaptic DAreceptors.
-
- Biochemical and behavioral evidence suggests
that lisuride, a semi-synthetic ergot derivative
used mainly as a prophylactic agent in migraine,
acts on 5-hydroxytryptamine (5-HT) and dopamine
(DA) receptors (Votáva and
Lamplová 1961; Horowski and Wachtel 1976;
Pieri et al. 1977: Kehr 1977).
-
- A central dopaminergic action has also been
proposed for the other ergot derivatives
(Corrodi et al. 1973: Johnson et al. 1973;
Woodruff et al. 1974; Kehr 1977). Moreover,
2-bromo--ergocryptine is reported to induce
stereotyped behavior (SB) (Johnson et al. 1974)
and bromocriptine to induce repeated episodes of
penile erection (PE) and stretching and yawning
(SY) in rats (Bertolini et al. 1979). These
modes of behavior are considered to be specific
expressions of the stimulation of brain
dopaminergic systems (Randrup and Munkvad 1968;
Benassi-Benelli et al. 1979). The aim of our
investigation was to assess whether lisuride
also acted on DAreceptors, the stimulation of
which evokes SY and increases PE, besides the
other modes of behavior previously described,
namely, SB (Horowski and Wachtel 1976; Horowski
1978), aggressive behavior (Podvalová and
Dlabaé 1970) and mounting (Da Prada et
al. 1977).
-
- Discussion
-
- Our results show that lisuride elicits in
male rats a number of different responses,
according to the dose, and suggest that mainly
DA-receptors are involved in these effects.
Previous experiments with other well-known
dopamine agonists, such as APO and NPA, have
supported the hypothesis that SY. PE and SB are
signs of activation of DA-receptors in the CNS
(Menon et al. 1978: Benassi-Benelli and Ferrari
1979; Benassi-Benellj et al. 1979). Induction of
SB by lisuride has already been reported
(Horowski and Wachtel 1976; Horowski 1978), but
the increase in SY and PE at very low doses to
our knowledge has not. For SY, lisuride was as
potent as NPA, and more so than APO
(Benassi-Benelli and Ferrari 1979), but although
these DA-agonists were also potent
dose-dependent inducers of PE, the increase in
sexual behavior caused by lisuride was small.
Only the percentage of animals responding was
significantly influenced, and not the mean
number of PE per animal responding.
-
- An effect of lisuride on male sexual
behavior has already been described for the
mating pattern in rats and 5HT involvement has
been suggested to underlie the phenomenon
(Ahienius et al. 1980). On the other hand,
several similarities between lisuride and APO,
such as the antagonism of reserpine-induced
motor depression, hypothermia (Horowski and
Wachtel 1976), aggressive behavior
(Podvalovâ and Dlaba 1970), decrease in
serum prolactin (Horowski et al 1975) and emesis
in dogs, would support the concept that lisuride
has mainly central DA-activity, as suggested by
Horowski and Wachtel (1976). PE elicited by
lisuride in rats was antagonized by both DA and
5-HT antagonists, rendering a simple
interpretation difficult.
-
- The antagonism might be non-specific and not
exerted at the same receptor site, especially
given the above mentioned, mild activation of PE
by lisuride, in comparison with that obtained
with other typical dopaminomimetics. On the
other hand, the supposed dopaminergic nature of
SY was confirmed by the clear antagonism
obtained with haloperidol and sulpiride and by
the failure of methysergide. Haloperidol,
classically considered a dopamine antagonist
drug, exerts its activity on pre- and
post-synaptic DA-receptors (Long et al. 1975;
Lokhandwala and Buckley 1977). Sulpiride seems
also to be a specific DA-receptor antagonist
with particular affinity for presynaptically
located DA-receptors involved in the inhibition
of DA-synthesis and release, the so-called
autoinhibitor-receptors (Kehr et al. 1972;
Carlsson 1975; Bunney and Aghajanian 1975; Di
Chiara et al. 1976; Corsini et al. 1979; Spano
et al. 1979). Although detailed studies must
obviously be undertaken on the biochemical
changes in neurotransmission correlated with SY,
our data suggest that this behavior might be an
expression of a preferential
DAautoreceptor-stimulation. It must be stressed
that we observed that the low doses of lisuride
which elicitSYsimultaneously induced sedation
(that is, a considerable reduction in
spontaneous locomotor activity-data not
reported). This is in agreement with the
behavioral effects of low doses of typical
DA-stimulants such as APO and N PA, which elicit
SY (Benassi-Benelli and Ferrari 1979;
Benassi-Benelli et al. 1979) and sedation both
in animals and in man (Di Chiara et al. 1976;
Corsini et al. 1977a, b; Spano et al. 1979),
simultaneously inhibiting dopaminergic firing
and DA-synthesis in the caudate nucleus and
nucleus accumbens, presumably through
preferential activation of presynaptic
receptors, as assessed by changes in DOPAC
levels (Serra et al. 1981). Moreover, lisuride
is also reported to reduce DA turnover and
synthesis at low doses (Kehr 1977).
-
- In conclusion, our behavioural
findings strongly support an effect of lisuride
on dopaminergic mechanisms. At low doses it
probably has a preferential affinity for
presynaptic inhibitor receptors, the activation
of which leads to SY and, probably, to PE
enhancement. At higher doses it would appear to
have chiefly an agonistic effect on the
postsynaptic DA-receptors, thereby eliciting SB.
1f this hypothesis is confirmed by biochemical
studies, induction of SY in addition to sedation
could be used as a simple and sensitive
behavioral model for testing drugs acting on
presynaptic autoinhibitory DA-receptors.
Whatever the type of receptor involved, we
should like to stress that SY, specifically
stimulated by dopamine agonists, would seem to
be a parameter worthy of attention in studying
animal behavior.
-
-
|