mise à jour du
3 juillet 2006
Pharmacol Biochem Behav
Ontogenic homologous supersensitization of
quinpirole-induced yawning in rats
Kostrzewa RM, Brus R. 
Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, USA
Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning. Serafine KM


Yawning in male rats is a behavior that may be induced by a group of dopamine receptors when low doses of dopamine-receptor agonists are administered. To determine whether agonist treatments during postnatal development could produce a long-lived supersensitization of these dopamine receptors, rats were treated daily for the first 28 days from birth with quinpirole HCl (3.0 mg/kg/day, IP), an agonist that acts at D2 and D3 receptors. At 8 to 10 weeks from birth the dose-effect curve for quinpirole-induced yawning demonstrated that a supersensitization of dopamine receptors for yawning behavior had occurred. Yawning at the optimal dose of quinpirole HCl (100 microgram/kg, IP) was increased 2-fold. The Bmax and Kd for D2 receptor binding in rat striatum were unaltered in this group of rats. These findings indicate that dopamine receptors can be ontogenically "primed" or supersensitized, and that the phenomenon apparently is not related to changes in striatal D2 receptor binding characteristics.
YAWNING is a behavior that can be induced by a variety of substances, including dopamine D2 receptor agonists and mixed DIM agonists. Generally, as the dose of agonist increases, yawning response rate decreases so that a bell-shaped dose-effect curve for the yawning response is typically observed. At least part of the explanation for this effect is that higher doses of agonists induce competing behaviors, including the stereotyped actions that are commonly associated with such agonists. Since there are few competing behaviors with low doses of dopamine receptor agoists, yawning represents a behavior that offers advantages over others when studying the phenomenon of receptor supersensitization.
In rats with lesions of brain dopamine-containing neurons, prolonged dopamine receptor supersensitization can result (2,19). However, other treatments and procedures are associated with temporary changes in dopamine receptor sensitization.
Because of the finding that neonatal treatments with dopamine Dl and D2 receptor antagonists produced an impaired development of striatal Dl and D2 receptors respectively (8,15), it was expected that postnatal treatments with a dopamine receptor agonist would increase receptor number and/or alter the sensitivity of the receptor. Also, such an effect was expected to be long-lived, as per those after Dl and D2 antagonist treatments. Yawning was the candidate behavior for demonstrating this effect, because of the reasons described above.
This paper describes the production of a long-lived supersensitization of dopamine receptors that mediate yawning behavior. Although the exact class of dopamine receptor involved with the behavioral event is not known with certainty, it is shown that the binding characteristics of dopamine D2 receptors in the striatum are not altered by these treatments.
In 8- to 10-week-old male rats that were treated with quinpirole HCI for the first 28 days from birth, the number of yawns was not different from that of the vehicle group during the 60min interval after an injection of saline. Each group had a mean incidence of yawning in this instance of less than 1. A challenge dose of quinpirole increased yawning behavior in both groups of rats. The maximal incidence of yawning in both groups occurred at a dose of quinpirole HCl of 100 g/kg. However, quinpirole-induced yawning was increased to a much greater extent in the group of rats that was ontogenically primed (p<O.OS). For this group yawning was greater at each different challenge dose of quinpirole HCI (25 to 200 µg/kg, IP), vs. the vehicle group (p<O.OS, Fig. 1). The 200 µg/kg dose of quinpirole HCI produced less yawning than the 100 µg/kg dose, indicating the bell-shaped curve previously noted by others for quinpirole-induced yawning in control rats. The total number of yawns induced by the optimal dose of quinpirole (100 µg/kg) in the quinpirole-primed rats (this report) is greater than that observed previously after dopamine agonist treatment of rats. In the present study, as in the above cited reports, more than 90% of yawns occurred during the first 30 min after agonist treatment (data not shown). These findings demonstrate that the absolute maximal score for yawning behavior can be enhanced in a specified time frame, thereby providing further evidence for supersensitization of those dopamine receptors that mediate the yawning response.
Despite the increased sensitivity of ontogenically primed rats for quinpirole induction of yawning, there was no change in either the Bmax or Kd for binding to the D2 receptor in rat striatum. Therefore, sensitization appears to be a phenomenon not related to the number or affinity of D2 receptors. It is likely that mechanisms associated with generation of second messengers are more relevant in mediating the supersensitive phenomenon. However, it is possible that a different class of receptors, namely the D3 subgroup, may be involved in mediating yawning behavior per se, and the supersensitization of this behavior. This view is supported by the fact that quinpirole is 100 times more selective for D3 than D2 receptors. Specific agonists and antagonists for the D3 receptor are not yet available to resolve this hypothesis.
In summary, we have produced a rat model with a long-lived supersensitization of dopamine receptors that is associated with yawning behavior. This model may be of value in the study of both behavioral and biochemical processes related to supersensitization of receptors.
Drugs affecting dopamine neurons ans yawning behavior Mogilnicka E, Klimek V
R Brus , R Szkilnik, RM Kostrzewa Nitric oxide (NO) and central dopamine (DA) D3 receptor reactivity to quinpirole in rats Act Neurobiol Exp 1996; 56; 15-19
Kostrzewa RM and R Brus Is dopamine-agonist induced yawning behavior a D3 mediated event? Life Sci 1991; 48; 26; 129
-Kostrzewa RM, Brus R. Ontogenic homologous supersensitization of quinpirole-induced yawning in rats. Pharmacol Biochem Behav. 1991;39(2):517-519.
-Kostrzewa RM, Brus R, Rykaczewska M, Plech A. Low-dose quinpirole ontogenically sensitizes to quinpirole-induced yawning in rats. Pharmacol Biochem Behav. 1993;44(2):487-489.
Eguibar JR et al Behavioral differences between selectively bred rats: D1 versus D2 receptors in yawning and grooming Pharmacology; Biochemistry and Behavior 2003; 74; 827-832
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
Oswiecimska J, Brus R, Szkilnik R, Nowak P, Kostrzewa RM 7-OH-DPAT, unlike quinpirole, does not prime a yawning response in rats Pharmacol Biochem Behav. 2000; 67; 11-15