Enhancement of antidepressant potency by a potentiator of AMPA receptors.
1. AMPA receptor potentiators (ARPs) exhibit antidepressant-like activity in preclinical tests (for example, the forced swim test) that are highly predictive of efficacy in humans. Unlike most currently used antidepressants, ARPs do not elevate extracellular levels of biogenic amines (e.g., 5HT, NE) in prefrontal cortex at doses that are active in the forced swim test. 2. The present series of experiments examined the effects of combining the ARP, LY 392098, with biogenic amine-based antidepressants in the forced swim test. Male, NIH Swiss mice were placed in a cylinder of water and observed for attempted escape behaviors and immobility. 3. LY 392098 dose-dependently decreased immobility as did a range of classical antidepressants. At doses of LY 392098 below those that decreased immobility, this compound significantly increased the potency with which fluoxetine and citalopram (SSRI antidepressants), imipramine (tricyclic antidepressant), duoxetine (norepinephrine/serotonin uptake blocker), nisoxetine (norepinephrine uptake inhibitor), and rolipram (PDE4 inhibitor) decreased immobility in the forced swim test with potency shifts upward of 5-fold (fluoxetine, imipramine, and rolipram). Likewise, ineffective doses of the traditional antidepressants potentiated the effects LY 392098 with shifts in the dose-effect functions that were 10-fold or more for citalopram, fluoxetine, imipramine, and duloxetine. 4. Combined with other evidence for a role of AMPA receptors in the efficacy of antidepressants, the current data suggest that the addition of an ARP may augment the activity and perhaps the onset of the therapeutic effects of biogenic amine and second messenger-based antidepressants.
Li
Xia
X
Neuroscience Discovery Research, Eli Lilly and Co., Lilly Research Laboratories, Corporate Center, Indianapolis, Indiana, USA. li_xia_x1@lilly.com
Witkin
Jeffrey M
JM
Need
Anne B
AB
Skolnick
Phil
P
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000819:agonists; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D015306:Biogenic Monoamines; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C434043:LY 392098