A. DE BARTOLOMEIS, C. TOMASETTI - Vol. 9, December 2003, Issue 4
Testo Bibliografia Summary Indice
Schizofrenia e disregolazione dopaminergica
cortico-sottocorticale: basi molecolari
e correlati clinici dell’agonismo parziale dopaminergico come strategia terapeutica
Schizophrenia and dopamine cortico-subcortical dysregulation: molecolar
implication for dopomine partial agonism therapy
Dopamine release dysregulation has been demonstrated in vivo
in schizophrenic patients by means of PET and fMRI dynamic imaging.
Both hyper- and hypo-dopaminergia have been suggested to be crucial in schizophrenia
pathophysiology even if the molecular mechanism responsible of dopamine aberrant
release is still elusive. First generation antipsychotics (APS) have provided
a meaningful therapy against productive symptomatology mainly. However, dopamine
D2 receptor blockade, considered the crucial mechanism of the typical antipsychotics
efficacy, is responsible of EPS scorge as well as other side effects. The
introduction of atypical antipsychotics has signed a pivotal advance in schizophrenia
therapy. Several mechanisms (5HT2A/D2R affinity ratio, receptors pleiotropism,
D2R fast dissociation) have been proposed to explain the mechanism of action
of new generation APS. A novel strategy in order to regulate dopamine CNS
circuitries is based on dopamine partial agonism. A dopamine partial agonist
can be conceptualized as a compound with full affinity for dopamine receptors
(usually D2R) but low intrinsic activity (measured by biological intracellular
effect such as cAMP inihibition), thus it has been hypothesized that a partial
dopamine agonist may act as an antagonist where and when the CNS dopamine
concentration is relatively high and as an agonist when the dopamine concentration
is relatively low.