Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
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7 avril 2005
1989; 98; 567-568
SKF 38393 potentiates yawning induced by LY 171555: further evidence against the autoreceptor hypothesis of yawning
L Spina, R Longoni, A Mulas, G di Chiara
Institute of experimental pharmacology and toxicology, Univesity of Cagliari, Italy


Dopamine (DA) receptor agonists active on D-2 receptors share the property of eliciting yawning in rats (Protais et al. 1983; Gower et al. 1984; Longoni et al. 1987a). The receptors mediating this effect have been initially identified as "autoreceptors" on the basis of the observation that this behaviour is elicited by DA-agonists devoid of behavioural stimulant effects and is blocked by DA receptor antagonists active at D-2 receptors (Gower et al. 1984; Stahle and Ungerstedt 1984; Ferrari 1985). As supporting evidence for the latter view has been regarded the fact that DA-agonists also elicit yawning in the low-dose range, i.e. at doses superimposable to those eliciting typical autoreceptor effects such as hypomotility and sedation (Gower et al. 1984; Stahie and Ungerstedt 1984; Serra et al. 1986).
In contrast with this hypothesis, we first suggested that yawning is due to stimulation of D-2 receptors located on structures post-synaptic to the dopaminergic ones (Morelli et al. 1986); this suggestion was based on the observation that yawning induced by the D-1 D-2 agonist apomorphine was reduced by blockade of D-1 receptors with the specific D-1 antagonist SCH 23390 and potentiated by a 12 h reserpine pretreatment (Morelli et al. 1986). From these results it appeared that agonist-induced yawning responds to certain pharmacological treatments in much the same way as a typical post-synaptic D-2 response such as hypermotility and stereotypy, which is also blocked by SCH 23390 (Longoni et al. 1987 b) and shows supersensitivity after a subacute reserpine pretreatment (Di Chiara and Gessa 1975).
If this hypothesis is correct, yawning in response to specific D-2 agonists should be under permissive control by endogenous DA acting on D-1 receptors (Longoni et al. 1987b). In aggreement with this possibility, the D-1 antagonist SCH 23390 also reduces the yawning elicited by D-2 agonists such as LY 171555 and BHT-920 (Longoni et al. 1987a). It remains to be established, however, if yawning, like typical post-synaptic D-2 responses, is potentiated by concurrent administration of a D-1 receptor agonist (Mashurano and Waddington 1986; Longoni et al. 1987 b). Here we report the results of such investigation.
Materials and methods
Male Sprague-Dawley rats (Charles River, Calco, Como, Italy) weighing 180-200 g were housed six per cage and kept in a temperature and humidity controlled room under a 12 h light/dark cycle (6 a.m.-6 p.m.) with food (rat chow) and water ad lib. After reception from the supplier the rats were allowed about 1 week to recover before the experiment. Experiments were performed between 4 p.m. and 6 p.m.
The day before the experiment the rats were transferred to individual wire mesh cages (40x25 x 15 cm high) for adaptation. Yawning was measured blindly by direct observation by two independent observers as number of yawns in a 60-min period.
The following drugs were used: LY 171555 (Eli Lilly Co., USA), SCH 23390 (Essex-Schering, Italy). SKF 38393 (Smith, Kline and French, USA) dissolved in saline (0.1 mg/ 100 g) and administered SC.
Analysis of variance (ANOVA) followed by student's t-test for individual comparison or Dunnett's t-test for multiple comparisons was applied to evaluate the significance of the results obtained.
Results and conclusions
Figure 1 shows the dose-response curve for LY 171555-induced yawning in control rats and in rats pretreated with SKF 38393 (2.5 mg/kg SC 15 min before LY 171555); clearly, pretreatment with SKF 38393 increased the incidence of yawning over the whole range of the LY 171555 dose-response curve with a resulting shift to the left.
SKF 38393 by itself failed to elicit yawning at any of the doses tested (2.5, 5.0 and 10.0 mg/kg SC). The potentiating effect of SKF 38393 (2.5 mg/kg SC) on yawning was abolished by low doses of SCH 23390 (0.012 mg/kg SC 10 min before LY 171555) which in turn failed to affect yawning elicited by LY 171555 (0.025 mg/kg SC) alone (LY 171555: 3.8±0.5; SKF 38393+LY 171555: 9.6±1.3; SCH 23390+SKF 38393+LY 171555: 3.2±0.5*; SCH 23390+LY 171555: 4.2±0.6; mean±SEM of yawns recorded in five rats during 1 h after SKF 38393; *p<ØQ5 as compared to SKF 38393+LY 171555).
The main finding of the present study is that administration of low doses of the D-1 agonist SKF 38393, while failing to elicit yawning by itself, facilitated the expression of yawning as a result of stimulation of D-2 receptors by the D-2 agonist LY 171555. That the effect of SKF 38393 was due to stimulation of D-1 receptors is demonstrated by the observation that it was abolished by low doses of the D-1 antagonist SCH 23390 which failed to affect yawning by LY 171555 alone. These results show that stimulation of D-1 receptors exerts a facilitatory influence on the expression of yawning in much the same way as observed for the expression of typical post-synaptic responses such as hypermoility and stereotypy (Longoni et al. 1987b).
Therefore, these results support the contention that yawning, rather than an autoreceptor-mediated response, is a post-synaptic response.
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Spina, R Longoni, A Mulas, G di Chiara SKF 38393 potentiates yawning induced by LY 171555: further evidence against the autoreceptor hypothesis of yawning Psychopharmacology 1989; 98; 567-568
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