Received for publication February 25, 2008.
Revised February 24, 2008.
Accepted for publication February 26, 2008.

Messing up with traffic: different effects of antipsychotics on glutamate receptor complexes in vivo (Relates to article by Fumagalli, et al., Fast Forward 4 Feb 2008)

Abstract

Antipsychotics are major drugs for human neuropsychiatric conditions including schizophrenia, mood disorders, Tourette syndrome and Alzheimer's disease. These drugs are divided in two groups--first-generation/typical and second-generation/atypical-- on the base of their propensity to induce extra-pyramidal motor side effects. Furthermore, second-generation antipsychotics have been reported to be superior in addressing cognitive deficits in schizophrenia. Understanding differences between the mechanism of action of first and second-generation antipsychotics thus represents an interesting opportunity for the development of new compounds having better therapeutic action and less side effects. In this issue of Molecular Pharmacology, Fumagalli et al. report that chronic treatment with the first-generation drug haloperidol interferes with the trafficking of both AMPA and NMDA glutamate receptor complexes and associated molecules PSD95 and CaMKII in the rat frontal cortex. In contrast, the second-generation drug olanzapine did not affect glutamate receptor trafficking. The action of haloperidol on glutamate receptor trafficking in specific brain regions may contribute to the low efficacy of this drug on cognitive deficits and to the development of side effects. Overall, antipsychotics have been shown to act upon multiple signaling mechanisms (e.g.: cAMP-PKA, Arrestin 2-Akt-GSK-3 and PLC-inositol-PKC pathways) mostly by blocking D2-class dopamine receptors (first-generation) or D2-class dopamine and 5-HT₂ serotonin receptors (second generation). Identification of specific pathways by which haloperidol affects glutamate receptor trafficking may thus represent an important next step toward the development of better antipsychotic drugs.

Key words: Dopamine, Serotonin, Glutamate, Gi family, Gq/11 family, Anti-psychotics