Commentary A role for AMPA receptors in mood disorders Andrew Alt, Eric S. Nisenbaum, David Bleakman, Jeffrey M. Witkin * Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA biochemical pharmacology 71 (2006) 1273–1288 article info Keywords: AMPA receptor potentiators Brain-derived neurotrophic factor (BDNF) DARPP-32 Depression GLU A1 TrkB Abbreviations: AMPA, a-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid cAMP, adenosine 3 0 ,5 0 -cyclic monophosphate CNQX, 6-cyano-7- nitroquinoxaline-2,3-dione CX516, piperidine, 1-(6-quinoxalinylcarbonyl)-(9CI), Ampalex, BDP 12 CX691, piperidine, 1-(2,1,3-benzoxadiazol-5- ylcarbonyl)-(9CI), Farampator, Org 24448 DARPP-32, dopamine- and cAMP-regulated phosphoprotein of M r 32,000 DNQX, 6,7-dinitroquinoxaline-2, 3-dione GCPR, G-protein-coupled receptor GYKI 53655, 7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N, 8-dimethyl-monohydrochloride-(9CI) abstract Major antidepressant agents increase synaptic levels of monoamines. Although the mono- amine hypothesis of depression remains a cornerstone of our understanding of the patho- physiology of depression, emerging data has suggested that the a-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor subtype of glutamate receptor may also play a pivotal role in depression. Positive allosteric modulators of AMPA receptors increase brain levels of brain-derived neurotrophic factor (BDNF) that impacts the viability and generation of neurons in key brain structures. AMPA receptor potentiators are active in rodent models predictive of antidepressant efficacy. The mechanisms by which AMPA receptor potentiators produce these biological effects, however, are uncertain. Current evidence points to an antidepressant mechanism that is independent of monoaminergic facilitation that is driven by neurogenesis, a process facilitated by increased BDNF expres- sion. However, alternative hypotheses need to be considered given uncertainties in the relationship between BDNF increases and the effects of conventional antidepressant med- ications. Electrophysiological and protein conformational data indicate that structural variants of AMPA receptor potentiators can differentially modulate AMPA receptor- mediated currents, although the manner in which this impacts antidepressant efficacy is yet to be understood. Conventional antidepressants such as fluoxetine positively modulate AMPA receptors. This potentiation is engendered by specific phosphorylation pathways activated through the dopamine- and cAMP-regulated phosphoprotein of M r 32,000 (DARPP- 32). Other novel compounds with antidepressant-like effects in rodents may also produce their in vivo effects through potentiation of AMPA receptors. Thus, AMPA receptor poten- tiation might be a general mechanism through which the clinical outcome of antidepressant efficacy is achieved. # 2005 Elsevier Inc. All rights reserved. * Corresponding author at: Psychiatric Discovery Group, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285-0501, USA. Tel.: +1 317 277 4470; fax: +1 317 276 7600. E-mail address: jwitkin@lilly.com (J.M. Witkin). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/biochempharm 0006-2952/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2005.12.022