title: Antipsychotic drug actions on gene modulation and signaling mechanisms.
abstract: Schizophrenia is a debilitating chronic mental disorder characterized by significant lifetime risk and high social costs. Although its etiology remains unknown, many of its symptoms may be mitigated by treatment with antipsychotic drugs (APDs). These compounds, generally classified as first- or second-generation antipsychotics, have complex receptor profiles that may account for short-term clinical response and normalization of acute manifestation of the disease. However, APDs have additional therapeutic properties that may not be directly related to receptor mechanisms, but rather involve neuroadaptive changes in selected brain regions. Indeed the neurodevelopmental origin of schizophrenia suggests that the disease is characterized by neuroanatomical and pathophysiological impairments that, at molecular level, may reflect compromised neuroplasticity; the process by which the brain adapts to changes in a specific environment. Accordingly, it is possible that the long-term clinical efficacy of APDs might result from their ability in modulating systems crucially involved in neuroplasticity and cellular resilience. We have reviewed and discussed the results of several studies investigating the post-receptor mechanisms in the action of APDs. We specifically focused on intracellular signaling cascades (PKA, DARPP-32, MAPK, Akt/GSK-3, beta arrestin-2), neurotrophic factors and the glutamatergic system as important mediators for antipsychotic drug induced-neuroplasticity. Altogether, these data highlight the possibility that post-receptor mechanisms will eventually be promising targets for the development of novel drugs that, through their impact on neuroplasticity, may contribute to the improved treatment of patients diagnosed with schizophrenia.
authors.affiliation: Center of Neuropharmacology, Department of Pharmacological Sciences, Universita' degli Studi di Milano, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Molteni
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Fabio
authors.initials: F
authors.lastname: Fumagalli
authors.forename: Marco Andrea
authors.initials: MA
authors.lastname: Riva
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D017448:Receptors, Dopamine D2; D017470:Receptors, Glutamate; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3