Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al




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14 avril 2005
2005; 56; 2; 69-73
Enhanced binding of dopamine D(1) receptors in caudate-putamen subregions in High-Yawning Sprague-Dawley rats
Diaz-Romero M, JA Arias-Montano, JR Eguibar, G Flores
Instituto de Fisiolog§a , Benemerita Universidad Autonoma de Puebla, Mexico
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


In our laboratory we obtained two inbred sublines of Sprague-Dawley rats that differ in their spontaneous yawning frequency (Urba´-Holmgren et al., 1990). The High-Yawning (HY) subline has a mean of 20 yawns per hour, and the Low-Yawning (LY) subline has an average of 2 yawns/hour (Urba-Holmgren et al., 1990; Eguibar et al., 2003).
A yawn is a phylogenetically old, stereotypic event that occurs alone or associated with other behavior such as grooming or penile erection and in different environmental conditions (Anias et al., 1984; Baenninger and Greco, 1991;Holmgren et al., 1991; Argiolas and Melis, 1998; Eguibar et al., 2004).
The physiological function of yawning is still unknown; however, it is clear that several neurotransmitters participate in its regulation. Among them, the best known are dopamine (DA), acetylcholine, and several neuropeptides such as ACTH1Ð24, a-MSH, endorphin, oxytocin, and prolactin (for a review, see Argiolas and Melis, 1998).
Some studies examined the participation of the nigrostriatal or mesolimbic dopaminergic systems (Dourish and Hutson, 1985; Stoessl et al., 1987; Stahle and Ungersted, 1990). DA receptors are classified into two broad families, the D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors (Gingrich and Caron, 1993; Niznik and VanTol, 1992; Sibley and Monsma, 1992). Both the D1 and the D2 receptors are abundantly expressed and widely distributed throughout striatal and limbic dopamine fields, including the nucleus accumbens, caudate-putamen, and the olfactory tubercle (Flores et al., 1996).
It is well known that the activation of the D2 receptors by apomorphine, (Ð)-3-PPP (3- (3-hydroxyphenyl)-N-propylpiperidine hydrochloride), and quinpirole induce yawning (Mogilnicka and Klimek, 1977; Holmgren et al., 1980; Yamada and Furukawa, 1980, Stahle, 1992; Eguibar et al., 2003). Lesions with 6-OH-DA in the nigrostriatal pathway abolished dopaminergic yawning (Dourish and Hutson, 1985; Yamada et al., 1986; Stoessl et al., 1987; Stahle and Ungersted, 1990). In addition, yawning induced by apomorphine can be blocked by the D1 antagonist SCH 23390 (Code and Tang, 1991).
The DA D1 agonist SKF 38393 decreases yawning but increases grooming in HY rats compared to LY rats, but quinpirole produced a higher yawning frequency in HY than in LY rats (Eguibar et al., 2003). HY rats have a higher score of grooming bouts in a novel environment and after wetting the fur (Eguibar and Moyaho, 1997; Moyaho et al., 1995).
Therefore, both DA receptors have been proposed to participate in the control of yawning and grooming behavior. Our pharmacological reports strongly suggest differences in the effects of dopaminergic induced behaviors in HY compared to LY rats. Taking into account such differences, in the present study we compared the regional distribution of the DA receptor subtypes, D1-like and D2-like, and the DA transporter in the caudate-putamen and mesolimbic areas between adult male HY and LY rats using autoradiography.
In the present study we found that HY rats have higher levels of DA D1-like receptors in some subregions of the caudate-putamen, such as the dorsomedial, ventral, and fundus compared to LY rats, whereas the DA D2-like receptor and DA transporter levels were not significantly different between either subline in any subregion measured.
Previous findings indicated that DA D1-like receptors are implicated in yawning and grooming behaviors (Ferrari and Mangiafico, 1988; Berridge and Aldrich, 2000a,b). Pharmacological data from our laboratory and our recent report suggest that HY and LY rats have an altered DA function at the level of the nigrostriatal DA system compared with outbred Sprague-Dawley rats (Urba-Holmgren et al., 1993; Eguibar et al., 2003).
Furthermore, differences in the receptor levels would imply differences in genetic elements regulating receptor expression, which therefore explains the different expression of behavior in the mediated limbic or nigrostriatal pathways, and so could beinvolved in quantitative differences in yawning and grooming in HY and LY rats. The HY rats exhibit higher spontaneous yawning frequency (Urba-Holmgren et al., 1990) and also show higher incidences of yawning after systemic administration of DA D2 agonists (Urba-Holmgren et al., 1993; Eguibar et al., 2003).
However, HY rats also have a higher incidence of grooming bouts after systemic injection of SKF 38393, a DA D1 agonist. However, quinpirole, a DA D2 agonist, coadministered with SKF-38393, a DA D1 agonist, did not potentiate the yawning-induced by quinpirole (Eguibar et al., 2003), whereas the activation of just the DA D1 receptors by SKF 38393 produced a decrease in the yawning behavior more markedly in HY than in LY rats (Eguibar et al., 2003). However, some reports proposed that the coactivation of dopamine D1 and D2 receptors is necessary to induce yawning (for review, see Beninger et al., 1991). Yawning is a typical dopaminergic autoreceptor-mediated response (Stahle and Ungersted, 1986).
The activation of the DA D3 receptor is quite effective in eliciting yawning (Kostrzewa and Brus, 1991; Damsma et al., 1993). We have preliminary results that suggest a major participation of the DA D3 receptors in the yawning behavior of the HY compared to LY rats (M. D§´az-Romero and J.R. Eguibar, unpubl. data).
The caudate-putamen is the main nucleus of the basal ganglia with the highest level of DA D1-like and D2-like receptors (Flores et al., 1996, 2002). Moreover, the caudate-putamen nucleus is a key element in the generation and maintenance of the grooming syntactic chain (Berridge et al., 2000a). The multiunit recording of single neurons, from the dorsolateral part of the caudate- putamen nucleus, shows an increase of their activity during the initial phase of the syntactic grooming chain (SGC), but not in other related areas, indicating the importance of the caudate-putamen in initiating sequential behaviors (Berridge and Fentress, 1987). Bilateral lesions in the rostral dorsolateral part of the caudate-putamen produced impairment of SGC in the rat (Cromwell and Berridge, 1996).
However, bilateral lesions in the dorsomedial, ventromedial, or ventrolateral part of the caudate-putamen did not impair organization of the syntactic grooming chain (Berridge and Whishaw, 1992). In fact, the systemic or intraventricular administration of SKF 38393, a D1 agonist, increased the ability to initiate SGC but not to complete it (Berridge and Aldrich, 2000a,b). In addition, the intraventricular administration of SKF 82958, a full D1 agonist, increased the total of grooming behavior; however, it was not changed by SKF 38393, indicating a complex participation of postsynaptic dopaminergic receptors in the regulation of grooming (Berridge and Aldrich, 2000b).
These results also demonstrate that dopaminergic neurotransmission in the nigrostriatal pathway is a key element in the expression of SGC. The higher expression of grooming behavior of HY compared to LY rats under different conditions could be caused by, at least in part, a higher number of DA D1-like receptors in the caudate-putamen, as shown in this report. Systemic D1 agonists induced a greater number of grooming bouts in HY compared to LY rats (Eguibar et al., 2003). Grooming bouts are also more numerous in HY rats after water immersion.
These bouts are disorganized and have a low mean duration but higher frequency, indicating greater perseverance in cleaning behavior in HY than in LY rats (Moyaho et al., 1995; Eguibar and Moyaho, 1997). The perseverance in the cleaning behavior is suggestive, in some ways, of an obsessive-compulsive disorder (OCD), because OCD patients frequently show perseverance in cleaning activities, have alterations in the caudate nucleus (Rapoport, 1989), and are treated with dopaminergic antagonists, supporting the participation of the dopaminergic system in this illness. Further experiments will help to elucidate the specific role of dopaminergic receptors in OCD and in grooming behavior in HY rats.
In summary, our findings provide additional evidence that an increase in the DA transmission via DA D1-like receptors in the caudate-putamen in HYrats may be in part be related to the increase in the grooming behavior exhibited by this inbred Sprague- Dawley subline of rats.