BACKGROUND: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. METHODS: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. RESULTS: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. CONCLUSIONS: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
BACKGROUND:Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. METHODS: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. RESULTS: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. CONCLUSIONS:NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
Authors: Golam M I Chowdhury; Kevin L Behar; William Cho; Monique A Thomas; Douglas L Rothman; Gerard Sanacora Journal: Biol Psychiatry Date: 2011-12-09 Impact factor: 13.382
Authors: Anita J Bechtholt-Gompf; Hali V Walther; Martha A Adams; William A Carlezon; Dost Ongür; Bruce M Cohen Journal: Neuropsychopharmacology Date: 2010-06-09 Impact factor: 7.853
Authors: Anita J Bechtholt-Gompf; Karen L Smith; Catherine S John; Hannah H Kang; William A Carlezon; Bruce M Cohen; Dost Ongür Journal: Psychopharmacology (Berl) Date: 2011-01-28 Impact factor: 4.530
Authors: Rong-Jian Liu; Francis S Lee; Xiao-Yuan Li; Francis Bambico; Ronald S Duman; George K Aghajanian Journal: Biol Psychiatry Date: 2011-10-29 Impact factor: 13.382