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One of the crucial questions in the study of schizophrenia is, whether the diagnosis of the disease represents one entity or a group of disorders ("Gruppe der Schizophrenien"). Nancy Andreasen suggests the term "lathomenology" for a bottleneck on the pathogenetic way from various possible etiological factors to diverse phenomenological expressions (symptoms) (Arch Gen Psych 1999;56:781-787). In the background of this common denominator, there is an anatomical and functional disruption in neuronal connectivity and communication, which can be a consequence of incomplete or erroneous neuron formation, migration, synaptogenesis or pruning during ontogenesis. Also apoptosis and activity dependent changes might play a role in this development. This all can happen from conception to early adulthood and can lead to the impairment in fundamental cognitive functions. This leads to the development of clinical symptoms, either positive or negative. Schizophrenia can be regarded as a "disconnection" or "information processing disorder". There are many neural circuits, where the clinical impact of the disconnection or misconnection is worthy of study. One of them is the fronto-thalamo-cerebellar 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 (inşammatory 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-3ß phosphorylation and thus apoptosis etc.