mystery of yawning
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Fetal yawning assessed by 3D and 4D sonography
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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Pharmacol Biochem Behav
1995;50(3):389-397
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.

Chat-logomini

 
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.