Antiparkinsonian Agent Piribedil Displays Antagonist Properties at ...

Fig. 10. Antagonism by piribedil of the depletion of [ 3 H]PI evoked by NE at cloned h� 1A-ARs transfected into CHO cells. Data are representative of
three independent experiments, each performed in triplicate.
Fig. 11. Influence of piribedil upon the electrical activity of adrenergic
neurons in the locus ceruleus (LC). Top, representative neuron that
illustrates the dose-dependent increase in firing rate elicited by piribedil.
Bottom, dose-response relationship for activation of adrenergic neurons is
shown. Data are means � S.E.M, N � 5. ANOVA as follows. F(4,24) � 8.4,
P � 0.01. *P � 0.05 to vehicle (VEH) values in Newman-Keuls test.
lular levels of NE (Millan et al., 2000a), piribedil showed
negligible affinity for these sites.
Influence upon � 2-AR-Mediated Sedation. Engagement
of � 2-AR autoreceptors elicits sedation (Hayashi and
Maze, 1993; Millan et al., 1994, 2000b; Kable et al., 2000)
and, in analogy to other � 2-AR antagonists, piribedil suppressed
induction of LRR by xylazine. In distinction, � 1-AR
antagonists enhance sedative actions of � 2-AR agonists (Hayashi
and Maze, 1993; Millan et al., 2000b). Correspondingly,
these data emphasize that � 2-AR antagonist properties of
piribedil outweigh its weak blockade of � 1-ARs. Activation of
D 2/D 3 receptors is unlikely to be involved since dopaminergic
agonists only variably and submaximally attenuate hypnotic
sedative actions of xylazine (M. Brocco, unpublished observations).
� 2-Adrenoceptors and Parkinson’s Disease 885
Fig. 12. Influence of piribedil upon extracellular levels of norepinephrine
in the frontal cortex and dorsal hippocampus of freely moving rats. Top,
frontal cortex. Bottom, dorsal hippocampus. Data are means � S.E.M.s of
NE levels expressed relative to basal, pretreatment values (defined as
100%). These were 1.25 � 0.09 and 0.92 � 0.09 pg/20 �l of dialysate for
frontal cortex and dorsal hippocampus, respectively. N � 5/value.
ANOVA as follows. Frontal cortex: 2.5, F(1,12) � 0.1, P � 0.05; 5.0,
F(1,15) � 5.3, P � 0.05; 10.0, F(1,14) � 19.9, P � 0.01; and 40.0, F(1,12) �
75.5, P � 0.01. Dorsal hippocampus: 2.5, F(1,14) � 0.1, P � 0.05; 10.0,
F(1,14) � 10.7, P � 0.01; and 40.0, F(1,13) � 82.9, P � 0.01. Asterisks
indicate significance of drug-treated groups versus vehicle-treated group.
*P � 0.05.
General Discussion. Several general points emerge from
these studies.
First, although piribedil is not a potent agent, its affinity at
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