Antiparkinsonian Agent Piribedil Displays Antagonist Properties at ...

886 Millan et al.
h� 2A- and h� 2C-ARs was comparable to that at D 2 receptors.
This suggests that at therapeutically relevant doses activating
D 2 receptors, piribedil also occupies � 2A- and � 2C-ARs.
Thus, � 2-AR blockade by piribedil likely contributes to its
functional actions, although the relative implication of � 2Aversus
� 2C-ARs remains to be clarified.
Second, certain other antiparkinsonian agents interact
with � 2-ARs (Montastruc et al., 1996). However, piribedil
behaves essentially as an antagonist, whereas several, such
as talipexole, are efficacious agonists (Meltzer et al., 1989;
Gessi et al., 1999). Moreover, apart from mild affinity at
5-HT 1A sites, piribedil is devoid of activity at multiple serotonergic
receptors. In contrast, other agents, such as bromocriptine,
pergolide, and cabergoline, are potent agonists at
5-HT 2A and 5-HT 2C receptors (DeMarinis and Hieble, 1989;
Seyfried and Boettcher, 1990; A. Newman-Tancredi, unpublished
observations).
Third, activation of postsynaptic � 2-ARs facilitates working
memory tasks integrated in FCX (Arnsten et al., 1998).
This mechanism has, thus, been advocated for management
of cognitive deficits in neuropsychiatric disorders. However,
the active dose range is narrow and � 2-AR agonists impair
performance in certain cognitive tasks in humans (Arnsten et
al., 1998; Jäkälä et al., 1999). Activation of postsynaptic
� 2-ARs also potentiated antiparkinsonian actions of a �-opioid
agonist in rats (Hill and Brotchie, 1999). However, the
“quality” of movement was “poor” and, in more conventional
models, � 2-AR agonists interfere with antiparkinsonian actions
of dopaminergic agonists in rats (Meltzer et al., 1989;
Mavridis et al., 1991a; Chopin et al., 1999) and primates
(Gomez-Mancilla and Bédard, 1993). Moreover, enhancement
of motor function via activation of postsynaptic � 2-ARs
is seen only following marked depletion of endogenous pools
of NE. In any event, the motor-depressant (and hypotensive),
autoreceptor-mediated actions of � 2-AR agonists are difficult
to reconcile with their potential utilization in parkinsonian
patients. Thus, � 2-AR (autoreceptor) antagonism, leading to
a reinforcement in (deficient) corticolimbic adrenergic transmission,
represents a more realistic hypothesis for improved
management of Parkinson’s disease. Even if postsynaptic
� 2-ARs are simultaneously antagonized, favorable actions
will be mediated via “functionally intact” and colocalized,
postsynaptic � 1- and �-ARs (Arnsten et al., 1998; Brefel-
Courbon et al., 1998; Millan et al., 2000a). Furthermore,
blockade of inhibitory � 2-ARs on dopaminergic and serotonergic
pathways should likewise be favorable (Millan et al.,
2000a).
Finally, � 2-ARs engage diverse intracellular cascades via
different subtypes of G protein (Bylund, 1995; Hieble et al.,
1995; Brink et al., 2000). The present study focused on their
principle mode of coupling via Gi. However, although Gi1� is
implicated in the fusion protein-mediated activation of
GTPase, the precise species of Gi transducing MAPK phosphorylation
and [ 35 S]GTP�S binding remains to be established.
Thus, the influence of piribedil upon specific subclasses
of Gi, and upon other G proteins (such as Gs) coupled
to � 2-ARs, would be of interest to evaluate further.
Summary and Conclusions. Although piribedil differs
structurally from imidazolines (such as idazoxan), from alkaloids
(such as yohimbine), and from other prototypical
antagonists, it shares their interaction with � 2-ARs (Hieble
et al., 1995). Importantly, further, piribedil shows similar
affinity for � 2-ARs and D 2 receptors. Together with agonist
actions at D 2 receptors, blockade of � 2-ARs may, thus, contribute
to its functional profile: notably, its influence upon
motor performance, mood, and cognitive function in Parkinson
patients. This issue is currently under clinical investigation.
In this regard, although piribedil shows only modest
affinity at h� 2B-ARs, the relative role of (cerebral) � 2A- compared
with � 2C-ARs in its actions requires elucidation. In
conclusion, piribedil provides a distinctive experimental and
clinical tool for evaluation of the significance of combined D 2
receptor activation and � 2-AR blockade in the management
of Parkinson’s disease.
Acknowledgments
We thank V. Pasteau, L. Verrielle, N. Fabry, L. Cistarelli, C.
Melon, and H. Gressier for technical assistance. We thank M.
Soubeyran for preparation of the manuscript.
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