Modifications in brain CaM kinase II after long-term treatment with desmethylimipramine.
The present study investigated the effect of long-term (15 mg/kg for 15 days) and acute (15 mg/kg, single administration) treatment with desmethylimipramine, a tricyclic antidepressant drug, on calcium/calmodulin-dependent protein kinase II (CaMKII), a kinase implicated in the mechanism of antidepressant drug action. Similar to selective and non-selective serotonin reuptake inhibitors, long-term, but not acute, treatment with desmethylimipramine markedly increased the activity of CaMKII in the hippocampal synaptic vesicle fraction (+51.9%). The kinase activity was also increased in the same fraction of frontal cortex (+24.2%) and in the striatum (+45.9%), although in this last area the mechanism appeared to be different because the protein level of the kinase was also markedly increased (+43.7%). However, the effect of treatment was not restricted to the presynaptic kinase, because CaMKII activity was also increased in the total cellular cytosol in cortical areas. The autonomous (calcium-independent) activity of CaMKII was assayed for the first time after antidepressant treatment, and found to be increased in synaptic vesicles of all three areas. These results confirmed the involvement of CaMKII in antidepressant drug action and suggested that modulation of transmitter release is a primary component in the action of psychotropic drugs.
Consogno
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IRCCS Centro S. Giovanni di Dio, FBF, Brescia, Italy.
Racagni
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Popoli
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D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D002147:Calmodulin / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D003863:Depression / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003891:Desipramine / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure
D002147:Calmodulin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium; D003891:Desipramine