Abstract
Although antagonism of mesolimbic dopamine D2receptors 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-HT1Aand 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 improved—treatment of schizophrenia.
Footnotes
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Send reprint requests to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, chemin de Ronde, 78290 Croissy/Seine, France. E-mail:mark.millan{at}fr.netgrs.com
- Abbreviations:
- 5-HT
- serotonin
- AR
- adrenoceptor
- DA
- dopamine
- DRN
- dorsal raphe nucleus
- FCX
- frontal cortex
- GABA
- γ-aminobutyric acid
- MRN
- median raphe nucleus
- NA
- noradrenaline
- NMDA
- N-methyl-d-aspartate
- PET
- positron emission tomography
- Received July 6, 2000.
- Accepted August 3, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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