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Vol. 286, Issue 3, 1341-1355, September 1998
Institut de Recherches Servier, Centre de Recherches de Croissy,
Psychopharmacology Department, 125, Chemin de Ronde, 78290 S 16924 showed a pattern of interaction at multiple (>20)
native, rodent and cloned, human (h) monoaminergic receptors similar to
that of clozapine and different to that of haloperidol. Notably, like
clozapine, the affinity of S 16924 for hD2 and
hD3 receptors was modest, and it showed 5-fold higher
affinity for hD4 receptors. At each of these sites, using a
[35S]GTP
Croissy-sur-Seine, Paris, France
S binding procedure, S 16924, clozapine and
haloperidol behaved as antagonists. In distinction to haloperidol, S
16924 shared the marked affinity of clozapine for h5-HT2A
and h5-HT2C receptors. However, an important difference to
clozapine (and haloperidol) was the high affinity of S 16924 for
h5-HT1A receptors. At these sites, using a
[35S]GTPS binding model, both S 16924 and clozapine
behaved as partial agonists, whereas haloperidol was inactive. In
vivo, the agonist properties of S 16924 at 5-HT1A
autoreceptors were revealed by its ability to potently inhibit the
firing of raphe-localized serotoninergic neurones, an action reversed
by the selective 5-HT1A receptor antagonist, WAY 100,635. In contrast, clozapine and haloperidol only weakly inhibited raphe
firing, and their actions were resistant to WAY 100,635. Similarly, S
16924 more potently inhibited striatal turnover of 5-HT than either
clozapine or haloperidol. Reflecting its modest affinity for
D2 (and D3) autoreceptors, S 16924 only weakly
blocked the inhibitory influence of the dopaminergic agonist, apomorphine, upon the firing rate of ventrotegmental area-localized dopaminergic neurones. Further, S 16924 only weakly increased striatal,
mesolimbic and mesocortical turnover of dopamine (DA). Clozapine was,
similarly, weakly active in these models, whereas haloperidol, in line
with its higher affinity at D2 (and D3)
receptors, was potently active. In the frontal cortex (FCX) of freely
moving rats, S 16924 dose-dependently reduced dialysate levels of 5-HT, whereas those of DA and NAD were dose-dependently increased in the same
samples. In contrast, although S 16924 also suppressed 5-HT levels in
the striatum and nucleus accumbens, DA levels therein were unaffected.
Clozapine mimicked this selective increase in DA levels in the FCX as
compared to striatum and accumbens. In contrast, haloperidol modestly
increased DA levels in the FCX, striatum and accumbens to the same
extent. In distinction to S 16924, clozapine and haloperidol exerted
little influence upon 5-HT levels. Finally, the influence of S 16924 upon FCX levels of 5-HT, DA (and NAD) was attenuated by WAY 100,635. In
conclusion, S 16924 possesses a profile of interaction at multiple
monoaminergic receptors comparable to that of clozapine and distinct to
that of haloperidol. In addition, S 16924 is a potent, partial agonist at 5-HT1A receptors. Correspondingly, acute administration
of S 16924 decreases cerebral serotoninergic transmission and
selectively reinforces frontocortical as compared to subcortical
dopaminergic transmission. In line with these actions, S 16924 shows a
distinctive profile of activity in functional (behavioral) models of
potential antipsychotic activity (companion paper).
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