Behavioural
evidence that different neurochemical mechanisms
underly
stretching-yawning and penile erection
induced
in male
rats by SND 919,
a new
selective D2 dopamine receptor
agonist
F. Ferrari, F. Pelloni, D. Giuliani
Institute of Pharmacology,
University of Modena, ltaly
Abstract.
The behaviourat effects induced in male
Wistar rats by SND 9t9, a new drug reputed to
have selective agonistic activity at D2 dopamine
(DA) receptors, were studied. The following
aspects of behaviour were considered: motor
activity, stretching-yawning (SY), penile
erection (PE) and stereotyped behaviour (SB).
Intraperitoneal injection (IP) of the drug
(0.01-20 mg/kg) induced an SY syndrome in the
form of a bell-shaped doseresponse curve, the
effect being maximal at the dose of 0.1 mg/kg
and disappearing completely at 10 mg/kg. SND 919
also potently elicited PE; this latter effect,
however, was not coincident with SY induction,
being maximal at 1 mg/kg and persisting at 10
and 20 mg/kg. SND 919- induced SY was potently
antagonized by pretreatment not only with the D2
antagonist, L-sutpiride (20 mg/kg), but also
with the ~2 antagonist, yohimbine (1, 3 mg/kg),
and the more selective ~2 antagonist, idazoxan
(1, 2 and 5mg/kg). While sulpiride also
decreased SND 919- induced PE, idazoxan at all
doses and yohimbine at 1 mg/kg did not affect
this behaviour. Inhibition of motor activity was
induced by the D2 agonist at low doses (0.05,
0.1 mg/kg), while at high doses (1, 10 and 20
mg/kg), it was actually replaced by a form of SB
characterized by downward sniffing and licking.
When, for comparison, the D 2 agonist, RU 24213
(0.1-20 mg/kg IP), was tested for PE, SY, motor
activity and SB, it displayed a behavioural
pattern very similar to that obtained with SND
9t9. Idazoxan (2mg/kg), administered before RU
24213 (10mg/kg), significantly antagonized the
drug-induced SY, but not PE. The discussion
centres on the specific neurochemical mechanisms
presumably underlying the various forms of SND
919-induced behaviour and, in particular, PE and
SY, which seem to differ, at least with respect
to alpha2 involvement.
The recently synthesized drug, SND 919, is
expected to have selective stimulant activity at
D2 dopamine (DA) receptors and low agonistic
activity at :~ adrenoceptors (personal
communication, MH Jennewein, Boehringer
lngelheim, Germany). Behavioural studies in rats
support the hypothesis that SND 919 is active on
D a receptors, since 1) it potently elicits a
stretching-yawning (SY) syndrome which is
antagonized by the D 2 receptor antagonists,
spiperone and YM-09151-2, (Matsumoto et al.
1989) and 2) it is accepted that the SY syndrome
reflects an agonistic effect on D 2 receptors
(Mogilnicka and Klimek t977; Baggio and Ferrari
1983; Gower et al. 1984; Stahle and Ungerstedt
1984; Ferrari 1985; Yamada et at. t986; Melis et
al. 1987; Timmerman et al. 1989; Ferrari and
Claudi 1991).
Repeated episodes of penile erection (PE),
in addition to SY, are also typically produced
by all D2 agonists and by DI-D 2 agonists when
administered to male rats at doses incapable of
eliciting a marked degree of stereotyped
behaviour (SB) (Baraldi and Benassi Benelti
1977; Benassi Benelli and Ferrari 1978; Baggio
and Ferrari 1983; Gower et al. 1984; Ferrari
1985; Melis et al. 1987; Ferrari and Claudi
1991). The observation that the selective D2
antagonist sulpiride (Corsini et al. 1979; Stool
and Kebabian 1984)antagonizes PE would suggest
that in this case too, D 2 receptor mechanisms
are primarily involved (Baggio and Ferrari 1983;
Gower et at. 1984); thus contemporaneous PE and
SY evaluation would represent a simple method
for the detection of agonistic activity on D2
receptors (Ferrari and Claudi 1991).
The present study examines the behavioural
effects induced in rats by SND 919, with
particular reference to PE, which has not yet
been investigated. For comparison, some
behavioural experiments were performed with the
D 2 agonist RU 24213 (Euvrard et al. 1980).
Discussion
The results obtained in this study show
that, as expected of a DAD 2 agonist, SND 919
potently increased SY and PE; moreover, it
produced other distinct behavioural effects
according to the dose. At low doses, it appeared
to sedate the animals, judging by their
behaviour, and inhibited their motor activity,
while at high doses it elicited SB. It is
therefore likely that the behavioural profile of
SND 919 at varying doses may depend on the
different specific neurochemical mechanisms
involved.
We previously pointed out that all D 2
agonists share the ability to increase
simultaneously both PE and SY, which are
generally incompatible with a high degree of SB
(Baraldi and Benassi-Benelli 1977;
Benassi-Benelli and Ferrari 1978; Baggio and
Ferrari 1983). Our present work demonstrates
that for SND 919 and RU 24213 there is a clear
disjunction between the mechanisms underlying PE
and SY; however, the discussion in neurochemical
terms of the specific receptors involved will
obviously be largely speculative, for our
studies are concerned with behavioural phenomena
whose interpretation is based on a putative
selectivity of action of drugs, and experience
teaches us that any such selectivity is often
contradicted by subsequent knowledge (Scatton et
al. i980; Horn et al. 1982).
PE and SY are both stimulated by DA
agonists; however, while SY has been widely
investigated and is claimed by many researchers,
but by no means all (Stahle and Ungerstedt
1989), to be the behavioural expression of
reduced dopamine release following stimulation
of D e autoreceptors (Yamada and Furukawa 1980;
Baggio and Ferrari 1983; Gower et al. 1984;
Ferrari 1985; Bourson et al. 1989; Timmerman et
al. 1989), PE has attracted less attention.
Certainly, some fundamental common mechanism
between PE and SY must exist since the two
phenomena almost always appear in association
(Gower et al. 1984; Holmgren et al. 1985).
However, their possible disjunction may be
inferred from results obtained in previous
studies. In the case of lisuride, an ergot
derivative which acts on DA as well as
5-hydroxytryptamine (5-HT)-receptors, PE and SY
stimulation does not coincide; moreover, PE but
not SY is also prevented by the 5-HT antagonist,
methysergide (Baggio and Ferrari 1983). More
recently, apomorphine- induced SY and PE have
been described as being differently affected by
the calcium channel blocker, nifedipine, and the
activator, Bay K 8644 (Bourson et al. 1989);
again, physostigmine and pilocarpine also induce
yawning but not PE (Gower 1987).
In our experiments, SND 919 at 10 and 20
mg/kg no longer induced SY but still potently
increased PE, which was apparent in association
with SB, thus indicating that the mechanisms
underlying PE and SY are distinct and not always
capable of being contemporaneously activated or
abolished; yet the fact that PE and SY have
different dose-response curves may simply be
explained by behaviour competition between SB
and SY, but not between SB and PE. However,
while SY was antagonized not only by the D2
antagonist sulpiride (Corsini et al. 1979), as
expected, but also by the c~ 2 selective
antagonist idazoxan (Dabire 1986) and by
yohimbine, which at 1 mg/kg is reputed to be
rather selective for c~ 2 blockade (Goldberg and
Robertson 1983), PE was not significantly
modified by the two c~ 2 antagonists. The
phenomenon, first observed with SND 919, was
confirmed using idazoxan in the case of the D 2
agonist RU 24213 (Euvrard et al. 1980) and the
dose-response curves tor PE and SY did not
coincide with either drug.
It has already been reported that yohimbine
antagonizes B-HT 920-induced SY (Ferrari 1985)
and, in the same experiments, yohimbine was also
able to antagonize B-HT 920-induced PE. It is
always difficult to compare drug effects from
one study to another employing different
manipulative agents. However we would point
out:
a) B-HT 920 is a D 2 agonist (Jennewein et
al. 1986) considered specific for D 2
autoreceptors (Anden et al. 1982; Cichini et at.
1987; Pifl et at. 1988) but is also active on ~2
adrenoceptors (Grabowska and Anden 1984);
b) As D 2 agonists, B-HT 920 and SND 919 act
quite differently on DA receptors, judging by
our behavioural experiments. While the first
never elicits SB in normosensitive rats (Hjorth
and Carlsson 1987) but always leads to sedation
(Anden et al. 1982; Ferrari 1985), the second
displays a biphasic effect, inducing
hypomotility at 0.05 and 0.1 mg/kg and SB after
1 mg/kg. SND 919 therefore does not seem to be a
specific stimulant of those receptors which
mediate hypomotility (D2 autoreceptors?) (Di
Chiara et al. 1976) but also exerts an agonistic
effect at the D 2 postsynaptic receptors which
cooperate with D I receptors for SB (Braun and
Chase 1986; Mashurano and Waddington 1986;
Longoni et al. 1987; Gandolfi et al. 1988;
Murray and Waddington 1989). Moreover, unlike
B-HT 920, SND 919 increased PE over a wide dose
range and the phenomenon was also observed in
association with marked SB;
c) Finally, it is known that yohimbine is
less selective than idazoxan for c~ 2 receptors
(Dgbire 1986) and has been reported to increase
DA turnover in the striatum of rats, which is
indicative of a blockade of D 2 receptors
(Scatton et al. 1980). This could be the reason
why yohimbine at 3 mg/kg also antagonized SND
919-induced PE.
To conclude, in the light of the present
results, a possible hypothesis is that while
agonistic activity at D2 receptors is crucial
for both PE and SY, a certain ~2 adrenoceptor
stimulation is involved in SY but negatively
interferes with D 2 receptors for PE expression.
This would be in line with known inhibitory role
of brain c~ 2 adrenoceptors in male sexual
behaviour (Clark et al. 1985; Smith et al. 1987)
and would also explain why, in the case of SND
919, the lack of strong c~ 2 agonism might
responsible for the persistent induction of
PE.
