SYMPOSIA

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org
Abstracts of the Invited Speakers
neural circuits, where the clinical impact of the disconnection or misconnection is worthy of study. One of them is the fronto-thalamocerebellar
circuit with the special role of the cerebellum not only in the synchronization of motor processes, but also in the coordination
of motor-cognitive sequences. The disconnection of these circuits leads to “cognitive dysmetria”. Mezo-cortical pathways also represent
a crucial pathogenetic point. Dopaminergic fibers from the ventral tegmental area to the pre-frontal cortex are under serotonergic
inhibition via 5-HT2 receptors. This configuration can help in the understanding of the dual mode of action of novel antipsychotic agents,
which are effective in both positive (hyperdopaminergic state in mezo-limbic areas) and negative (hypodopaminergic state in prefrontal
cortex) symptoms. Disconnection can play a role also in circuits involved in executive functions (fronto-parieto-temporo-cingulate).
On the neurochemical level, many imbalances in information processing can be explained by the framework of Carlsson’s scheme of
psychotogenic pathways. The crucial mechanism involves striato-thalamic GABA-ergic control of gating, which is under glutamatergic
control from cortex. The scheme can also explain the amphetamine model of psychosis, the dopamine hypothesis of schizophrenia, the
glutamatergic model of schizophrenia and the psychotogenic effects of hallucinogens (LSD), atropine, phencyclidine etc. Our own study
on the role of serotonin regulation of psychotogenic pathways will be reported (Bubeníková et al., The effect of tryptophan depletion on
the action of haloperidol in MK-801 treated rats. Eur J Pharmacol, 2004; 502, 1-2:109-116).
The background of disconnection may involve gene-environment interaction including early neuroinfection (inflammatory process).
The classical antipsychotic drugs exert primarily antidopaminergic properties, which are responsible also for their side-effects such
as hyperprolactinemia and extrapyramidal syndrome. Nevertheless, psychotogenic pathways in the brain involve several different
mechanisms, which could serve as targets of antipsychotic modalities, e.g., facilitation of glutamatergic neurotransmission, blockade of
serotonin 5-HT2A receptors, expression of BDNF and bcl2, inhibition of GSK-3β phosphorylation and thus apoptosis etc.
Key words: Schizophrenia, glutamate, dopamine, serotonin, information processing disorder, gating
Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S48-9
The ins and outs of the human model of schizophrenia
Jiri Horacek 1 , Vera Bubenikova Valesova 1 , Tomas Palenicek 1 , Filip Spaniel 2 , Cyril Höschl 1
1Prague Psychiatric Center, Prague, Czech Rep.
2 rd 3 Medical Faculty of Charles University, Prague, Czech Rep.
E-mail: horacek@pcp.lf3.cuni.cz
The experimental models of schizophrenia are based on morphological, biochemical and genetic findings in the clinical population. These
models serve as an important tool for the research of etiology and pathophysiology, and for testing novel potential treatment methods.
The experimental models of schizophrenia are divided into neurodevelopmental, pharmacological and genetic. Only the pharmacological
model is useful in humans.
An important role of the glutamatergic neurotransmitter system in the pathogenesis of schizophrenia has been supported by findings
on various levels from molecular interactions up to the structural layout of the neuronal network in the human brain. The research of
the glutamatergic system in schizophrenia has advanced with the use of non-competitive antagonists of glutamate NMDA receptors
(phencyclidine, ketamine, and dizocilpine). These compounds change both human and animal behavior and induce schizophrenia-like
manifestations in the field of different neurobiological modalities and markers.
The models based on both acute and chronic administration of non-competitive antagonists of glutamate NMDA receptors in humans
and rats show phenomenological validity and are suitable for searching for new substances with antipsychotic effects. In particular, the
human model of schizophrenia based on infusion of ketamine exerts high face validity in term of induction both positive and negative
symptoms, and characteristic cognitive, electrophysiological (qEEG) and metabolic (PET) changes.
Nevertheless, the pathophysiology of schizophrenia remains unexplained. In the light of the neurodevelopmental model of schizophrenia
based on the early administration of NMDA receptor antagonists, it seems that increased cellular destruction by apoptosis or changes
in function of glutamatergic NMDA receptors in the early development of the central nervous system are decisive for subsequent
development of psychosis, which often does not manifest itself until adulthood. Chronic administration of NMDA (not applicable
in humans) antagonists initializes a number of adaptation mechanisms, which correlate with findings obtained in patients with
schizophrenia; therefore, this animal model is necessary for research into the pathophysiology of this disease.
This work was supported by project 1M0517 from the MEYS Czech Republic
Key words: Schizophrenia, models, NMDA receptors, ketamine, glutamate, neurodevelopment
Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S49
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