G.D. Kotzalidis, A. Facchi, L. Tarsitani, P. Pancheri - Vol. 8, June 2002, Issue 2
Testo Immagini Bibliografia Summary Indice
Effetti della somministrazione di
antipsicotici sull’espressione regionale cerebrale di geni immediati precoci
(IEG)
Effects of the administration of antipsychotic
drugs on the regional brain expression of immediate early genes (IEGs)
Antipsychotics were found to induce immediate early genes (IEGs) in selected brain regions. There is a net splitting between the effects of classical neuroleptics and the newer antipsychotics in their effects on IEG expression, in that the former induce them in the most motor portion of the striatum, whereas the latter are less potent in this area. Almost all antipsychotics induce IEGs in the nucleus accumbens septi, with a difference accumbens minus striatum which is greater for atypical antipsychotics. Standard areas of IEG measurement after antipsychotics include the striatum, both its dorsolateral (motor) and ventromedial (limbic or «emotional») portions, the nucleus accumbens and the major island of Calleja, and the medial prefrontal cortex, whereas other important areas, such as the amygdala, the thalamus, the hippocampus, and the lateral septum are less investigated. Atypical antipsychotics tend to induce IEGs in the prefrontal cortex whereas classical neuroleptics tend to be inactive at this respect. The most frequently investigated IEG is c-fos, but c-jun or other Fos and Jun proteins were also extensively investigated, but not for all antipsychotics. These IEGs are acutely, but transiently induced by these drugs; less investigations were carried-out on the induction of more persistent forms of oncogenes and their results are usually at odds with what was found for acute IEG induction, specially for the older neuroleptics, which tend to be more similar to the atypicals at this regard. IEG induction pattern and antipsychotic or extrapyramidal side effect induction profile usually correlate, with some notable exception. Discrepancies between IEG induction and antipsychotic potential should induce to evaluate new drugs with other experimental paradigms as well, to avoid that potentially useful drugs are rejected only on the grounds that they do not induce IEGs as desired. Most drugs were investigated in only a few studies, with most studies testing the effects of major class representatives, such as haloperidol, clozapine, and sulpiride, and entire classes, such as thioxanthenes, lacking from the list. Regarding the mechanisms of IEG induction, D2 blockade appears to be one the most important mechanisms in most areas, but other mechanisms may participate as well. 5-HT2A blockade, which is a mechanism commonly advocated for atypical antipsychotic action, should actually bring about a reduction in c-fos expression, therefore, it should not be considered as being directly responsible for c-fos induction. D3 mechanisms should not be important for the action of atypicals on c-fos. Indirect mechanisms could involve NMDA activation. Other, transiently expressed genes, such as those involved in the wingless pathway, despite their reported involvement in schizophrenia, have not been investigated as related to antipsychotics. IEG expression is an adequate and useful test to predict antipsychotic action and/or extrapyramidal side effect induction only if its results are combined with those of other screening tests and its results should not be considered as a constraint.