Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests

• Published in: Neuroscience letters 2013-06, Vol.546, p.6-10
• Main Authors: Andreasen, Jesper T., Gynther, Mikko, Rygaard, Allan, Bøgelund, Trine, Nielsen, Simon D., Clausen, Rasmus P., Mogensen, Jesper, Pickering, Darryl S.
• Format: Article
• Language: English
• Subjects: AMPA receptor potentiator; Animals; Antidepressive Agents - administration & dosage; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; Depression; Depression - drug therapy; Depression - metabolism; Depression - prevention & control; Excitatory Amino Acid Agonists - administration & dosage; Female; Glutamate; Glutamic Acid - metabolism; Hindlimb Suspension; Mice; Mouse forced swim test; Mouse tail suspension test; Neurotransmitter Agents - metabolism; NMDA receptor antagonist; Receptors, AMPA - agonists; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Swimming; Synaptic Transmission; Treatment Outcome; Up-Regulation
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2013.04.045

•Antidepressants increase the ratio of AMPAR-to-NMDAR-mediated neurotransmission.•Increasing AMPAR-to-NMDAR-mediated transmission may promote antidepressant effects.•The AMPAR potentiator PIMSD enhanced the effect of the NMDAR antagonist MK-801.•The AMPAR potentiator PIMSD enhanced the effect of nicotine.•The AMPAR potentiator PIMSD enhanced the effect of the antidepressant escitalopram. Monoamine-based antidepressant drugs increase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function and decrease N-methyl-d-aspartate receptor (NMDAR) function. The NMDAR antagonist ketamine shows potent antidepressant action in humans and the antidepressant-like effects of ketamine and monoamine-based antidepressants in rodents depend on increased AMPAR throughput. Further, the antidepressant-like effects of monoamine-based antidepressants are enhanced by AMPAR potentiation and by NMDAR antagonism. This has led to a hypothesis that antidepressant efficacy involves an increases ratio of AMPAR-to-NMDAR-mediated neurotransmission. To further elucidate the interaction of AMPAR, NMDAR and monoamine transmission we tested combinations of the AMPAR positive allosteric modulator (AMPA potentiator), (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD), with: the uncompetitive NMDAR antagonist MK-801; nicotine, which has potent glutamate-releasing properties; and the selective serotonin reuptake inhibitor escitalopram using the mouse forced swim (mFST) and tail suspension tests (mTST). MK-801, nicotine or escitalopram did not induce antidepressant-like effects in either of the two tests. PIMSD enhanced the effect of MK-801 in the mFST, supporting the hypothesis that increasing AMPAR-to-NMDAR-mediated neurotransmission conveys antidepressant action. Nicotine-induced glutamate release simultaneously activates NMDARs and AMPARs and showed no net effect in the mFST when given alone. However, increasing the ratio of AMPAR-to-NMDA-R transmission by favouring AMPAR throughput with PIMSD revealed an antidepressant-like action of nicotine in the mFST. PIMSD also enhanced the effect of escitalopram treatment in the mFST and mTST, supporting existing evidence and suggesting a synergistic effect of simultaneously facilitating monoamine transmission and increasing the ratio of AMPAR-to-NMDAR throughput. No synergistic effects of the PIMSD+MK-801 or PIMSD+nicotine were found in the mTST, indicating a differential sensitivity of mFST and