haut de page

mise à jour du
24 septembre 2006
Pharmacol Biochem Behav
DSP-4 prevents dopamine receptor priming by quinpirole
Nowak P, Labus L, Kostrzewa RM, Brus R.
Department of Pharmacology, Medical University of Silesia, H., Zabrze, Poland
Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning. Serafine KM


Repeated treatments of rats with the dopamine (DA) D2 receptor agonist quinpirole, consistently produce long-lived DA D2 receptor supersensitization, by the process that has been termed priming. Rats so-primed in ontogeny behaviorally demonstrate adulthood enhancement of low-dose quinpirole-induced yawning. Because 1) dopaminergic neurons originate in midbrain nuclei (substantia nigra and ventral tegmental area), and 2) noradrenergic neurons originate in pontine (locus coeruleus) and medullary areas, it might be presumed that these two monoaminergic systems are independent, not interdependent. However, in the present study we demonstrate that there was an attenuation of quinpirole-enhanced yawning at 8 weeks in rats that were 1) primed by repeated neonatal quinpirole HCl treatments (50 microg/kg per day SC) during the first ten days of postnatal ontogeny, and 2) lesioned at 3 days after birth with DSP-4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride, 50 mg/kg SC). Dose-effect curves indicated a 23-45% reduction in yawning by DSP-4 treatment of quinpirole-primed rats, acutely treated as adults with quinpirole (25, 50, or 100 microg/kg). Effectiveness of DSP-4 is reflected by the 95% and 99% reductions in norepinephrine contents of frontal cortex and hippocampus, respectively (HPLC/ED method). The findings are supportive of a modulatory role of noradrenergic fibers on dopamine receptor priming (supersensitization) in rat brain.
1. Introduction
Low-dose dopamine (DA) receptor agonists are known to induce yawning in rats (Gower et al., 1984; Longoni et al., 1987; Serra et al., 1987; Stoessl et al., 1987; Yamada et al., 1990) possibly by actions at D2 and/or D3 receptors (Kostrzewa and Brus, 1991 a,b; Damsma et al., 1993). Through a series of studies started around 1990, we found that yawning responses to the dopamine D2 agonist, quinpirole, could be enhanced if rats were repeatedly treated neonatally with a daily dose of quinpirole, as low as 50 µg/kg per day; and for as little as 11 days (Kostrzewa et al., 1993b). This process is known as receptor priming (i.e., receptor supersensitization) (Kostrzewa, 1995), and it persists life-long even after a priming period as short as 11 days (Owiecimska et al., 2000). Rats primed in adulthood with high doses of quinpirole, display locomotor sensitization to acute
quinpirole treatments (Szechtman et al., 1998; Szumlinski et al., 2000). Moreover, repeated quinpirole injections have been used to model obsessive-compulsive disorder (Szechtman et al., 1998, 2001).
In another series of studies we found that serotonin (5-HT) systems in brain had a dramatic modulatory influence on DA systems, particularly in reference to DA D1 and D2 receptor sensitization. In rats that were lesioned as neonates with 6hydroxydopamine (6-OHDA) to largely destroy dopaminergic innervation and induce DA receptor supersensitization in striatum (Kostrzewa and Gong, 1991; Gong et al., 1993a), it was shown that 5-HT receptor supersensitization also developed (Gong and Kostrzewa, 1992). In addition, denervation with 5,7dihydroxytryptamine (5,7-DHT) (Brus et al., 1994) or with 5HT2 receptor antagonist treatments (Gong et al., 1992) were found to largely attenuate DA receptor behavioral sensitization (Gong et al., 1992, l993b, 1994; Kostrzewa et al., 1992, l993a, 1998; Plech et al., 1995). Further evidence of a 5-HT modulatory effect on DA receptor sensitization, relates to the fact that an enhanced quinpirole response was observed in rats lesioned with 5,7-DHT (Brus et al., 1995). An association between DA D1 receptors and yawning behavior has been reported (Diaz Romero et al., 2005).
The impetus for study of an interaction of 5-HT and DA systems relates to their coordinate innervation of much of the brain, particularly the striatum. Also, noradrenergic neurona influence on dopaminergic activity was first noted thirty years ago (Antelman and Caggiula, 1977; Kostowski et al., 1974 Ungerstedt, 1974), and recently, the selective NE reuptak inhibitor atomoxetine was shown to coordinately increase both NE and DA levels in prefrontal cortex (Bymaster et al., 2002) Atomoxetine (Strattera, Eli Lilly, Co.) was introduced as therapy of human hyperactivity a largely childhood disordet that had been treated primarily by dopaminomimetics, namely amphetamine and methyiphenidate. This series of developments serves as a rationale for the present investigation.
To approach the relatively selective destruction of noradrenergic innervation of brain, the neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromo-benzylamine] was selected. Ross et al. (1973), Ross (1976), and Ross and Renyi (1976) had shown that DSP-4 crosses the blood-brain barrier to alkylate the norepinephrine (NE) transporter and ultimately destroy noradrenergic neurons. Accordingly, DSP-4 was administered to rats shortly after birth to destroy noradrenergic nerves, while rats were tested in adulthood for responses to the DA agonist quinpirole. In essence, the study was performed in a manner analogous to others performed by us, in which an association was found between 5HT systems and their role in modulating DA receptor sensitization status.
5. Discussion
The present findings confirm our earlier studies showing that the complex of DA D2/D3 receptors can be sensitized during postnatal ontogeny by repeated daily treatments with low dose quinpirole (Kostrzewa and Brus, 1991b, 1993b). The quinpirole dose used in this study, 60-times lower than that used in our first study (Kostrzewa and Brus, 1991b), is consistent with other studies in which this low dose was used to prime D2 receptors (Owicimska et al., 2000; Kostrzewa et al., 2004; Nowak et al., 2004). This also is in accord with the suggestion that the yawning response may be a partially dopamine D3 receptor-mediated event (Kostrzewa and Brus, 1991a) because quinpirole has an affinity 113-times higher for the D3 vs. D2 receptor (Sokoloff et al., 1990). Not all DA-induced behaviors are enhanced by quinpirole priming (Kostrzewa et al., 1990; Brus et al., 2003).
DSP-4 is a relatively selective neurotoxin for both central and peripheral noradrenergic neurons (Jaim-Ethceverry and Zieher, 1980; Jaim-Etcheverry, 1998; Brus et al., 2004). The mechanism through which DSP-4 produces the above effect is not well understood. However, it is recognized that DSP-4 has selective affinity for the NE transporter to which it is bound, and then spontaneously cyclizes to an aziridinium derivative which alkylates the transporter (Ross et al., 1973). Because swollen noradrenergic fibers (i.e., tyrosine hydroxylase immunofluorescent axons) were seen in the hippocampus in the absence of electron microscopic changes and in the absence of silver degeneration staining of DSP-4-treated rats, it has been proposed that DSP-4 may produce a dysfunctional but not destructive effect on noradrenergic neurons (Booze et al., 1988). However, swollen axonal preterminals enriched in tyrosine hydroxylase or norepinephrine are a hallmark of nerve terminal degeneration (Jacobowitz and Kostrzewa, 1971), and there is newer evidence indicating that DSP-4 is neuronally destructive (Zhang et al., 1995). It appears that there are two phases in the response of noradrenergic axons to DSP-4 administration: an acute phase characterized by the precipitous loss of transmitter, and a neurodegenerative phase in which dopamine-hydroxylase is lost with accompanying structural damage (Fritschy et al., 1990). It must be added that DSP-4 in the central noradrenergic system induces permanent neurodestructive loss of NE-containing neurons (Jaim-Etcheverry, 1998; Brus et al., 2004).
DSP-4 injected in newborn rodents produces long term biochemical and morphological changes in the central noradrenergic system (Jaim-Etcheverry, 1998). In our laboratory we confirmed the above results on noradrenergic neurons following DSP-4 treatment (50 µg/kg SC per day) on the 1st and 3rd days of postnatal life (Brus et al., 2004). As shown in the present study, DSP-4 alters noradrenergic input to hippocampus and frontal cortex, without impairing dopaminergic and serotoninergic inputs into these regions or in the striatum.
Despite evidence of relatively selective effects of DSP-4 on the noradrenergic system in brain, the present findings indicate that an enhanced quinpirole behavioral response to quinpirole in primed rats was attenuated by ontogenetic DSP-4 treatment as our preliminary findings had indicated (Brus et al., 2004; Labus et al., 2004; Nowak et al., 2004). In summary, because intact central noradrenergic innervation is important for expression of a priming response, it appears that noradrenergic systems are important regulators of dopaminergic systems in brain. The effectiveness of atomoxetine, a selective norepinephrine reuptake-inhibitor for treatment of hyperactivity, may be dependent, at least in part, on such a noradrenergic-dopaminergic modulatory interaction.
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