[Mechanism of molecular action of neuroleptics]

The discovery of the neurotransmitter function of dopamine in the central nervous system opened the most successful chapter in the pharmacological treatment of psychosis. It is a generally accepted fact that the antipyschotic action of neuroleptics depends upon blockade of D2 receptors, in part because all of currently used neuroleptics share that action, and in part because for all typical neuroleptics there is a tight correlation between D2 receptor affinity and clinical potency. The differencial effect of atypical neuroleptics has been correlated with the ratio of affinities of for the D2 and the 5HT2A receptors. Alternatively, it has been proposed that the lack of motor side effects is due to fast dissociation of the ligand from the D2 receptor. Regardless of the receptor interaction involved, it is evident that ligand-receptor interactions, occuring over miliseconds, cannot fully account for clinical effects observed over weeks or months. Chronic neuroleptic treatment causes structural and morpholog ical changes in striatum, accumbens and prefrontal and limbic cortex that distinguish between typical and atypical drugs, and thar are correlated with sustained changes in the expression of transcription factors, immediate early genes, second messengers and neuropeptides.