[The involvement of 5-HT1a serotonin receptors in the pathophysiology and pharmacotherapy of schizophrenia].
Many studies of schizophrenic brains indicate the dysfunction of dopamine and glutamate systems in the prefrontal and frontal cortex. It seems that better understanding of mechanisms regulating functions of these neuronal cortical systems could contribute to creation of new drugs acting in the cortex selectively. This might be profitable in cognition of dysfunction and negative symptoms in schizophrenia. This article presents preclinical data concerning the role of 5-HT1A serotonin receptors in the modulation of cortical dopamine system and in psychotomimetic effects of non-competitive NMDA receptor antagonists. Neurochemical studies have shown that 5-HT1A receptor agonists increase dopamine release in the rat prefrontal cortex on the one hand, and they inhibit the augmentation of dopamine release induced by stress or amphetamine, on the other. However, the increase of dopamine release induced by non-competitive NMDA receptor antagonists is blocked by 5-HT1A receptor antagonists. Blockade of 5-HT1A receptors seems to be important also in reduction of most psychotomimetic effects induced by non-competitive NMDA antagonists both involving (locomotor hyperactivity, working memory impair) and not involving (sensorimotor gating deficits) dopamine mechanism. Thus, binding with 5-HT1A receptors can be an important site for the regulation of cortical dopamine system, both in physiological conditions and in disregulation of the system induced by stress, psychostimulants or psychotomimetics. On the other hand, 5-HT1A receptors modulate most of psychotomimetic effects of non-competitive NMDA receptor antagonists. The above results of preclinical investigations indicate that 5-HT1A receptor can be involved in the pathology of schizophrenia, what is partly confirmed by clinical postmortem studies of schizophrenic brains. These studies showed the increase of 5-HT1A receptor density in prefrontal and frontal cortex in schizophrenic brains. It also seems that 5-HT1A receptors might be a good target for the antipsychotic drugs. Although the clinical studies have demonstrated controversial data, maybe further studies using substances with selectivity to 5-HT1A receptors would help to determine more precisely the role of these receptors in pathology and pharmacotherapy of schizophrenia.
Maćkowiak
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Zakładu Farmakologii Instytutu Farmakologii PAN w Krakowie.
Czyrak
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Wedzony
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D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005625:Frontal Lobe / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D016202:N-Methylaspartate / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology*
D014150:Antipsychotic Agents; D011985:Receptors, Serotonin; D016202:N-Methylaspartate