Mechanisms of action of the antidepressants fluoxetine and the substance P antagonist L-000760735 are associated with altered neurofilaments and synaptic remodeling.
Antidepressants are widely prescribed in the treatment of depression, although the mechanism of how they exert their therapeutic effects is poorly understood. To shed further light on their mode of action, we have attempted to identify a common proteomic signature in guinea pig brains after chronic treatment with two different antidepressants. Both fluoxetine and the substance P receptor (NK(1)R) antagonist (SPA) L-000760735 altered cortical expression of multiple heat shock protein 60 forms along with neurofilaments and related proteins that are critical determinants of synaptic structure and function. Analysis of NK(1)R-/- mice showed similar alterations of neurofilaments confirming the specificity of the effects observed with chronic NK(1)R antagonist treatment. To determine if these changes were associated with structural modification of synapses, we carried out electron microscopic analysis of cerebral cortices from fluoxetine-treated guinea pigs. This showed an increase in the percentage of synapses with split postsynaptic densities (PSDs), a phenomenon that is characteristic of activity-dependent synaptic rearrangement. These findings suggest that cortical alterations of the neurofilament pathway and increased synaptic remodeling are associated with the mechanism of these two antidepressant drug treatments and may contribute to their psychotherapeutic actions.
Neuroscience Research Centre, Merck, Sharp and Dohme, Eastwick Road, Harlow, Essex CM20 2QR, UK. paul_guest@merck.com
Paul C
PC
Guest
Michael R
MR
Knowles
Sylvain
S
Molon-Noblot
Kamran
K
Salim
David
D
Smith
Fraser
F
Murray
Philippe
P
Laroque
Stephen P
SP
Hunt
Carmen
C
De Felipe
Nadia M
NM
Rupniak
George
G
McAllister
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005473:Fluoxetine / Q000494:pharmacology*; D006168:Guinea Pigs; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000648:ultrastructure*; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis / Q000172:deficiency; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D000928:Antidepressive Agents; D006360:Heat-Shock Proteins; D016900:Neurofilament Proteins; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D005473:Fluoxetine