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Perspective

Messing Up with Traffic: Different Effects of Antipsychotic Agents on Glutamate Receptor Complexes in Vivo

Department of Anatomy and Physiology, Cellular Neurobiology Unit, Université Laval, Le Centre de recherche Université Laval Robert-Giffard, Québec City, Québec, Canada

Antipsychotic agents 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 basis of their propensity to induce extrapyramidal 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 antipsychotic agents 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. (p. 1484) report that long-term treatment with the first-generation drug haloperidol interferes with the trafficking of both -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate glutamate receptor complexes and associated molecules post-synaptic densities 95 and Ca²⁺calmodulin-dependent protein kinase 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-protein kinase A, βArrestin 2-Akt-GSK-3, and phospholipase C-inositol-protein kinase C 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.

Address correspondence to: Dr. Jean-Martin Beaulieu, Cellular Neurobiology Unit, CRULRG, 2601 Chemin de la Canardière, Suite F-6500, Beauport (Québec) G1J 2G3, Canada. E-mail: martin.beaulieu{at}crulrg.ulaval.ca

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Dynamic Regulation of Glutamatergic Postsynaptic Activity in Rat Prefrontal Cortex by Repeated Administration of Antipsychotic Drugs

Fabio Fumagalli, Angelisa Frasca, Giorgio Racagni, and Marco Andrea Riva
MolPharm 2008 73: 1484-1490. [Abstract] [Full Text]