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Vol. 295, Issue 3, 853-861, December 2000
Psychopharmacology Department, Institut de Recherches Servier,
Centre de Recherches de Croissy, Croissy/Seine, Paris, France
Although antagonism of mesolimbic dopamine D2
receptors by neuroleptics such as haloperidol attenuates positive
symptoms of schizophrenia, a significant population of "resistant"
patients fails to respond while negative and cognitive symptoms are
little modified. Furthermore, concomitant blockade of striatal
D2 receptors is associated with extrapyramidal motor side
effects. The superior "atypical" antipsychotic profile of clozapine
appears to reside in its broad pattern of interaction with
D2 receptors and a diversity of other monoaminergic sites.
In this regard, serotonergic mechanisms are of particular relevance
both in view of their modulation of dopaminergic transmission and their
key role in the control of mood, cognition, and motor behavior. While
most attention has focused on potential advantages of preferential
5-HT2A versus D2 receptor blockade,
5-HT1A receptors likewise represent a valid target for
improved antipsychotic agents. In this regard, rather than selective
agents, ligands interacting with both 5-HT1A
and D2 receptors appear of interest. A
modest level of efficacy appears optimal, that is, sufficient to engage
highly sensitive 5-HT1A autoreceptors while blocking their
low-sensitivity postsynaptic counterparts. Such a profile may counter
negative and cognitive symptoms, improve mood, diminish extrapyramidal
5-HT1A motor side effects, and, perhaps, enhance efficacy
in refractory patients. Notably, "partial agonist" properties of
clozapine at 5-HT1A receptors may contribute to its
distinctive functional profile. However, notwithstanding this
compelling body of experimental data, clinical studies of
antipsychotics interacting with 5-HT1A receptors are required to establish their genuine pertinence to the
hopefully improvedtreatment of schizophrenia.
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