Differential
effects of quinelorane and pergolide on
behaviour, blood pressure, and body temperature
of spontaneously hypertensive rats and
Wistar-Kyoto rats
van den Buuse M.
Marion Merrell Dow Research
Institute, Strasbourg, France.
Abstract
The systemic administration of the dopamine
agonists quinelorane or pergolide to
Wistar-Kyoto rats (WKY) induced a significant
increase of locomotor activity at higher doses.
In spontaneously hypertensive rats, these
compounds induced a significant hypoactivity at
low doses, but only a modest, and late, increase
in locomotor activity at higher doses.
Quinelorane was more potent than pergolide on
locomotor activity. In WKY and SHR, which had
unilateral lesions of the nigrostriatal dopamine
system, quinelorane and pergolide induced
similar dose-dependent contralateral turning
that, in the case of pergolide, was
significantly greater in SHR than in WKY. Both
quinelorane and pergolide induced yawning
similarly in WKY and SHR, and quinelorane was
more potent than pergolide. The intravenous
administration of quinelorane induced an
immediate and dose-dependent increase in blood
pressure in WKY and SHR, which could be
completely prevented by pretreating the rats
with the dopamine antagonist haloperidol.
Pergolide similarly caused a rise in blood
pressure in WKY and SHR, but its effect could
only partially be blocked by haloperidol. The
subcutaneous injection of quinelorane or
pergolide induced similar dose-dependent
hypothermia in WKY. Pergolide also caused a
decrease of body temperature in SHR, but
quinelorane had little effect in this strain.
These results show differences in the effects of
quinelorane and pergolide between various
experimental test situations and between WKY and
SHR. These differences may be related to the
involvement of dopamine receptor subtypes and to
the previously described changes in central
dopaminergic activity in SHR.
SPONTANEOUSLY hypertensive rats (SHR) show
an agerelated rise in blood pressure and
behavioural hyperreactivity (18,22,23). A number
of reports have described differential changes
in central dopaininergic regulation in SHR when
compared to normotensive controls [reviewed
in (27)1. For example, although in Wistar-Kyoto
rats (WKY) the dopamine D2 receptor antagonist
sulpiride induced an inhibition of exploratory
locomotor activity, in SHR this compound had
little effect (26,29). In contrast, sulpiride
induced a normal increase in central dopamine
turnover and an exaggerated rise of plasma
prolactin concentrations in SHR (29). The
dopamine D2 receptor agonist quinpirole induced
an inhibition of loco-
motor activity at low doses in both SHR and
WKY, but the marked hyperactivity induced in WKY
by high doses of quinpirol was completely absent
in SHR (11,24). The centrally mediated increase
in blood pressure in response to intravenous
(IV) injection of quinpirole was normal or
enhanced in SHR (24).
The significance of changes in central
dopaminergic activity in SHR is illustrated by
the inhibition of the development of
hypertension in these animals after depletion of
central dopainine (31,32). Thus, central
injection of the catecholamine neurotoxin
6-hydroxydopamine (6-OHDA) in young,
prehypertensive SHR caused an attenuation and
retardation of the rise in blood pressure and
depletion of central noradrenaime and dopamine
(12,28). The effect of 6-OHDA on the development
of hypertension could be inhibited by
pretreatment with the dopamine uptake inhibitor
GBR-l2909, which prevented the depletion of
central dopamine (32), but not by pretreatment
with the noradrenaline uptake inhibitor
desipramine, which prevented the depletion of
noradrenaline (31). Moreover, discrete lesions
in the substantia nigra of young SHR caused an
attenuation of the development of hypertension
and depletion of central dopamine (30,32). Thus,
alterations in central dopaminergic function
play a role in the development of spontaneous
hypertension and depletion of central dopamine
interfered with this mechanism.
Doparninergic drugs may induce centrally
mediated effects on blood pressure (5,6,16,17).
Electrical stimulation of ventral midbrain
dopaminergic cell groups caused pressor
responses in anesthetized, normotensive rats and
cats (7,20) and baroreceptor denervation caused
changes in dopamine release in the striatum (1),
suggesting a link between forebrain dopamine
systems and cardiovascular regulation. Studies
on central dopamine receptor levels or dopamine
concentrations and turnover in SIIR have failed
to provide a clear neurochemicai basis for any
changes in this interaction in SHR, however
[reviewed in (27)],
Pergolide is a dopamine agonist with
affinity for both dopamine D1 and D2 receptors.
The affinity values for these receptors vary
between studies, but pergolide appeared to have
a 20-50-fold selectivity for D2 receptors over
D1 receptors [reviewed in (10)].
However, recent studies by Wong and colleagues
(34) have indicated a K, of pergolide against
[3H]spiperone binding of 75 nM (D2
receptors) and against L3H]SCH 23390 of
128-158 nM (D1 receptors), indicating virtually
similar affinities for both receptor subtypes.
Sokoloff and coworkers (19) found a I( of 19 nM
for dopamine D2 receptors and an even higher
affinity of 2 nM for the recently cloned
dopamine D3 receptors, indicating that at least
some of the effects of pergolide could be
mediated by this latter receptor subtype.
Administration of pergolide to rats induced a
range of neurochemical effects, including a rise
in striatal levels of acetylcholine, depletion
of hypothalamic adrenaline, and reduction of
striatal dopamine turnover (10,11,34).
Furthermore, several behavioural effects of
pergolide have been described, such as changes
in locomotor activity in intact rats or the
induction of turning behaviour in rats with
unilateral lesions of the nigrostriatal bundle
(10,13). Pergolide also induced a fall in body
temperature in rats (13).
Quinelorane is a dopamine agonist with a
structure related to that of pergolide. Agonist
affinity of quinelorane at dopamine D1 receptors
has been studied by few authors, although the
compound failed to induce an increase in
striatai adenylate cyclase activity, an
indicator of D1 agonist activity (4). In vitro
binding tests with quinelorane showed a K1 of
340 nM for dopamine D2 receptors and 4 nM for D3
receptors (19). Similar to pergolide,
quinelorane caused an increase in striatal
acetylcholine levels and a reduction of
adrenaline levels and dopamine turnover (4,8,9).
Quinelorane induced dose-dependent hypo- and
hyperactivity and turning behaviour in rats (9).
In these tests, quinelorane displayed higher
potency than quinpiroie, but comparable potency
to pergolide.
In the present study, SHR and WKY were
treated with pergolide or quinelorane and were
tested in a number of experimental protocols in
vivo, some of which have not been extensively
studied before in these strains (27). The
results extend our earlier knowledge, which was
obtained largely with quinpirole (24) and
sulpiride (29), and shed more light on central
dopaniinergic function in these strains.
DISCUSSION
This study shows a number of effects of the
potent dopamine agonists quinelorane and
pergolide in WKY and SHR.
The main findings were that SHR differed in
their responses from WKY in that they lacked the
hyperactivity induced by higher doses of
quinelorane or pergolide, and showed more
intense turning behaviour after treatment with
pergolide, but less hypothermia after treatment
with quinelorane. Quinelorane differed from
pergolide in that it was more potent on
locomotor activity in intact WKY and SHR, to
induce turning and hypothermia in WKY, and to
induce yawning in both WKY and SHR. In
addition, whereas the quinelorane-induced
pressor response could be antagonized completely
by pretreatment with haloperidol, the effect of
pergolide was only partially prevented.
In normotensive rats, dogs, or man,
quinelorane and pergolide have been shown to
cause several endocrine, behavioural, and
neurochenucal effects. Endocrine effects of both
compounds include a reduction of plasma
prolactin concentrations and an increase of
plasma corticosterone concentrations (9,10).
Behavioural effects include dose-dependent
changes in locomotor activity in intact animals
and contralateral turning in rats with
unilateral nigrostriatal lesions (3,13).
Neurochemical effects include a decrease in
central dopamine turnover and release
(4,8,9,13). Furthermore, pergolide and
quinelorane may cause changes in body
temperature and influence cardiovascular
regulation E(5,6,9,1O), and references
therein]. Recently, it was shown that, in
addition to being potent agonists at dopamine D2
receptors, quinelorane and pergolide showed high
affinity for dopamine D3 receptors (19).
Previously, we (24) and others (11) have
shown that the administration of moderately high
doses of quinpirole, an ergoline derivative
closely related to quinelorane, induced only an
inhibition of locomotor activity in SHR, whereas
in WKY it induced marked hyperactivity. When a
longer observation period was used, a slight,
and late, quinpirole-induced increase in
locomotor activity became apparent in SHR, an
effect that was marginal compared to that in WKY
(Van den Buuse, unpublished observations). The
present results show that quinelorane and
pergolide share this effect with quinpirole,
inasmuch as only a slight, and late, increase in
behavioural activity was observed in SHR, in
contrast to the marked hyperactivity observed in
WKY. Thus, intact SHR show a reduced sensitivity
to the locomotor stimulant effects of dopamine
D2 receptor agonists. Surprisingly, in SHR and
WKY with unilateral 6-OHDA-induced lesions of
the nigrostriatal system, quinelorane induced
similar contralateral turning behaviour, whereas
pergolide had greater effects in SHR than in
WKY. This finding raises two questions-about the
difference between the response of intact and
lesioned rats, and about the differential
effects of quinelorane and pergolide. The
microinjection of 6-OHDA in the nigrostriatal
bundle is likely to have caused a significant
depletion of dopamine in terminal regions such
as the caudate nucleus and nucleus accumbens. It
is possible that this depletion altered the
responsiveness of dopamine D (or D3) receptors,
which rendered the SHR equisensitive or more
sensitive to the effect of agonists than WKY. It
is well known that unilateral lesions in central
dopamine systems cause postsynaptic dopamine
receptor supersensitivity and an uncoupling of
the otherwise obligatory "permissive" role of D1
receptor activation in 1)2 receptor-mediated
effects (2,33). Lesions in brain dopamine
systems caused an inhibition of the development
of hypertension (31,32) and it is tempting to
speculate that this inhibition and the
"normalizing" effect of 6-OHDA lessions on
locomotor activity in the present study
represent similar mechanisms. However, this does
not explain the differential effect of the
lesions for quine- lorane and pergolide. It is
possible that the mixed D1/D2 agonist activity
of pergolide renders it more effective than the
"pure" D2 agonist quinelorane to induce turning,
but further experiments with combined treatment
with D1 and D2 agonists will be needed to test
this hypothesis. Indeed, the contribution of
stimulation of dopamine D1 receptors in the
effects of pergolide has been questioned in some
studies [for a review, see (10)].
The normal yawning reponse of SHR
after treatment with quinelorane or pergolide
suggests that dopamine receptors involved in
this response are normal in this strain. Some
authors have suggested that yawning is
induced after activation of presynaptic dopamine
D2 receptors, but this was disputed by others
and it was suggested that, instead, a population
of postsynaptic D2 receptors with high
sensitivity for agonists may be involved
[reviewed in (21)]. Presynaptic
D2-mediated inhibition of dopamine release was
greater in SHR in vivo and in vitro (14,15), but
in this study no evidence for â strain
difference in yawning was observed.
The immediate pressor response to injection
of quinelorane and pergolide is in line with
results obtained with quinpirole and other
dopamine agonists (17,24). The relatively
shortlasting effect of these compounds may be
explained by a rapid desensitization of the
dopamine receptors involved or by systemic
compensatory mechanisms, such as changes in
vasopressor or vasodepressor hormone levels,
which bring blood pressure back to baseline
(24). The complete antagonistic effect of
pretreatment with haloperidol suggests that,
similar to quinpirole (24), quinelorane acts
primarily on dopamine D2 receptors to mediate
its effect on blood pressure. In contrast,
pergolide appears to have an additional effect
on receptors that
were not blocked by haloperidol. Although
this could represent the action of pergolide on
dopamine D1 receptors, a further pharmacological
analysis of the central effect of pergolide is
needed to prove this. In any case, there was
little difference between WKY and SHR with
regard to their overall cardiovascular response
to injection of either quinelorane or pergolide.
Similar to quinpirole (24), at high doses of
quinelorane SHR tended to have a greater pressor
response than WKY, but this was at least partly
because the response in WKY tended to become
smaller at further increasing the dose. Although
at such doses WKY showed hyperactivity and
stereotypy, SHR showed few behavioural effects,
and this difference in behavioural response may
influence the cardiovascular effects (24).
The hypothermia induced by treatment with
apomorphine or L-DOPA was greater in SHR than in
WKY (for references, see (27)]. In the
present study, pergolide induced similar
hypothermia in these strains, whereas
quinelorane had less effect in SHR than in WKY.
The explanation for this difference is unclear,
but again could be related to the different
receptor selectivity of these compounds (i.e., a
significant contribution of dopamine D1
receptors in the action of pergolide).
In conclusion, in the present study, central
dopamine function in WKY and SHR was
investigated by using two wellcharacterized
dopamine receptor agonists. The differences in
the effects of these compounds between the two
strains suggests selective alterations of
dopamine receptor subtype density or coupling
mechanisms in the SHR, which could play a role
in the development of hypertension in these
rats. Further analysis of the changes in central
dopamine systems in SHR with selective
antagonists for dopamine D1 or D2 receptors
could provide more details on these
alterations.
