Antipsychotic drug actions on gene modulation and signaling mechanisms

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 neuro plasticity; 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. (C) 2009 Elsevier Inc. All rights reserved.