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.
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