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mise à jour du
27 novembre 2005
Pharmacol Biochem Behav
7-OH-DPAT, unlike quinpirole, does not prime
a yawning response in rats
Oswiecimska J, Brus R, Szkilnik R, Nowak P, Kostrzewa RM
Department of Pharmacology, Silesian Medical University, Zabrze, Poland
Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning. Serafine KM


Repeated treatment in ontogeny with the dopamine (DA) D(2)/D(3) receptor agonist quinpirole is associated with enhanced quinpirole-induced yawning and other behaviors such as vacuous chewing, vertical jumping, and antinociception. To determine if the reputedly DA D(3) agonist (+/-)-2-(dipropylamino)-7-hydroxy-1,2,3, 4-tetrahydronaphthalene (7-OH-DPAT) would prime for yawning in a manner analogous to that for quinpirole, rats were treated for the first 11 days after birth with an equimolar dose of either quinpirole or 7-OH-DPAT (195.4 nmol/kg/day) and tested for agonist-induced yawning in adulthood. While enhanced quinpirole-induced and 7-OH-DPAT-induced yawning was observed in quinpirole-primed rats, acute treatments with quinpirole and 7-OH-DPAT did not produce an enhanced yawing response in 7-OH-DPAT-"primed" rats. Our findings indicate that 7-OH-DPAT, unlike quinpirole, does not prime for quinpirole- or 7-OH-DPAT-induced yawning in rats.
Quinpirole induces characteristic behaviors in rats, most notably oral activity and yawning. Oral activity is the type behavior described by Waddington [24] as spontaneous chewing movements that are not directed onto physical material (i.e., vacuous chewing). Quinpirole is thought to induce vacuous chewing via stimulation of the dopamine (DA) D2 receptor class (i.e., D2, D3, and D4 receptors), because its effect is blocked by spiperone. However, some interaction with receptors is evident, as the D1 receptor antagonist R(+) -7- chloro -8 -hydroxy 3-methyl - 1 -phenyl- 2,3,4,5 - tetrahydro - 1H-3 -benzazepine (SCH 23390) similarly attenuates the quinpirole effect [3]. A number of other behaviors are induced by DA D2 agonists, including eating, vertical jumping, rearing, paw treading, and antinociception. Each of these behaviors has been shown to be enhanced by ontogenetic quinpirole priming [13-17]. Until now, there have been no published data concerning the ability of (± ) -2- (dipropylamino) -7 -hydroxy -1,2,3,4 - tetrahydronaphthalene (7OH - DPAT) to prime receptors for subsequent enhanced effects by agonists.
Both quinpirole and 7-OH - DPAT reportedly induce yawning behavior in rats via stimulation of the DA D2 receptor class [7,12,13,19]. In a series of studies involving the induction of DA receptor supersensitization, we found that ontogenetic treatments with quinpirole would produce long-lived sensitization of receptors mediating quinpirole-induced yawing response in adult rats [13]. In addition, it is evident that these DA receptors can be permanently sensitized by extraordinarily low doses of quinpirole, administered once a day for the first 11 days after birth [15].
The current study was conducted to determine if quinpirole and 7-OH - DPAT, applied in equimolar doses, would be equi-effective in inducing yawning in rats. Moreover, we sought to determine if repeated low equimolar doses of quinpirole and 7-OH - DPAT, administered during postnatal ontogeny, would sensitize receptors for both quipirole and 7OH-DPAT induced yawning later un life.
In accordance with previous findings, repeated quinpiroie treatments of rats in early postnatal ontogeny produced long-term enhancement of quinpirole-induced yawning in adulthood [4,13,15]. Other long-lived D2 agonist-enhanced behaviors occurring in these rats include locomotor activity with rearing [5,6,17], age-related jumping with paw treading [16], eating [16], and antinociception [14]. The induction of long-lived sensitization of DA receptors, produced by repeated agonist treatments during ontogenetic development, is readily achieved in rats that are largely DA denervated [2], and this phenomenon has been designated as a "priming" process.
Szechtman et al. [211 have demonstrated that the number of injections of DA agonist, rather than the dosing interval between injections, is the predominant factor regulating development of long-lived quinpirole sensitization in rats. The dose of quinpirole within a defined range has additional impact on sensitization to later quinpirole enhancement of behaviors in these rodents with primed DA receptors. For example, Szechtman's group reported that repeated treatments of rats with a quinpirole dose of 0.025 mg/kg did not induce enhanced quinpirole effects, even after 10 consecutive daily treatments. However, higher doses (0.25 and 2.5 mg/kg) did sensitize this receptor complex. This same group further found that long-term intermittent treatments with quinpirole (0.5 mg/kg) induced pronounced sensitization to quinpirole - induced locomotor response (i.e., sixfold increase) [10].
As previously stated, 7-OH -DPAT was approximately equi - effective with quinpirole in inducing yawing episodes in male rats. It should be noted that quinpirole-induced yawning has been associated with reduced microdialysate levels of DA, presumably by action at DA D3 receptors [7]. In addition, quinpirole and 7-OH -DPAT have similar affinities for DA D3 receptors [18]. Therefore, it is not surprising that quinpirole and 7-OH -DPAT had similar effects on yawning number in "saline-primed" rats in the current study.
Presumed long-lived sensitization of DA "D2 complex" receptors was observed as enhanced yawning responses to both quinpirole and 7-OH-DPAT in male rats; and as enhanced quinpirole responses in female rats. However, unlike quinpirole, ontogenetic treatments with 7-OH-DPAT did not appear to prime receptors. In rats in which there was attempted ontogenetic priming with 7OH -DPAT, there was no later enhancement of yawning by acute quinpirole treatment or 7-OHDPAT treatment. Others have shown that repeated 7-OH - DPAT treatments (0.01 to 1.0 mg/kg) do not result in cross -sensitization to apomorphine- or cocaine-induced locomotor activity in rats [20]. Conversely, the 10-day treatment with a high dose of 7-OH-DPAT (1000 p.g/kg) produced progressive increases in locomotor activity, demonstrating that 7-OH DPAT is inherently capable of inducing behavioral sensitization [20]. In the current study, failure of 7-OH -DPAT to induce sensitivity to a later challenge dose of 7-OH DPAT is therefore likely to be related to the purposeful low dose of 7-OH-DPAT that was used for priming. It is noteworthy, that quinpirole at an equimolar dose, did prime receptors to later challenges with quinpirole.
There is a question of whether quinpirole acts preferentially at a population of DA D2 or D3 receptors, different from those activated by 7-OH-DPAT; or whether each of these D2/D3 agonists acts with different efficacy on the same receptor population. Currently, this problem is not easily addressed. One might approach this, using the preferential DA D3 agonist (+) - trans - 3,4,4a, lOb -tetrahydro 4- propyl - 2H,SH- (1 )benzopyrano(4,3b) - 1,4- oxasin -9- ol [PD 128907], which has been used in a behavioral model of D3 receptor activation, namely hypothermia and prepulse inhibition [23], and failure to lower serum prolactin levels [9]. However, more recent findings clearly demonstrate, nonetheless, that PD128907 is also a partial agonist at DA D3 receptors [22]. In addition, even the locomotor and hypothermic actions of reputed D3 agonists now has been ascribed to DA D2 receptor effects [1,8]. Therefore, even when more-selective D3 agonists are developed, it will remain difficult to definitively ascribe DA receptor populations to the observed priming (behavioral) responses of quinpirole and 7-OH-DPAT.
From these behavioral experiments, we can conclude that 7-OH-DPAT is unable to prime receptors in the same way as a low equimolar dose of quinpirole, but that quinpiroleprimed rats display greater responses to both quinpirole and 7-OH - DPAT. Differences between quinpirole and 7-OH DPAT in effectively priming DA receptors, conceivably could be related to their respective effects on other neurochemical systems (see Ref. [11]), but this has not been systematically studied.
In summary, there is a major difference in the abilities of quinpirole and 7-OH-DPAT to prime rats for yawning responses to low doses of these respective DA agonists. It is premature to preferentially assign either specific D2 or D3 receptors to this effect, but the findings bring into question the generally assumed categorization of D3 receptors with DA agonist-induced yawning.
Mogilnicka E, Klimek V Drugs affecting dopamine neurons and yawning behavior. Pharmacol Biochem Behav 1977; 7; 303-305
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
Nowak P, Labus L, Kostrzewa RM, Brus R. DSP-4 prevents dopamine receptor priming by quinpirole Pharmacol Biochem Behav. 2006;84(1):3-7