Chronic imipramine downregulates cyclic AMP signaling  in rat hippocampus.
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are synthesized by adenylate cyclase and guanylyl cyclase and degraded by phosphodiesterases. Antidepressant treatment action is hypothesized to occur through increased cAMP signaling; however, antidepressants are also reported to increase phosphodiesterase-4 expression. We addressed this paradox by systematically studying elements of intracellular signaling in the hippocampus of rats chronically treated with imipramine. We observed decreases in cAMP levels, which were congruent with our findings of increased gene expression for phosphodiesterases and decreased adenylate cyclase. Immunoassay results showed unchanged cGMP and brain-derived neurotrophic factor levels. We conclude that in contrast with the assumption of antidepressant-mediated increases in cAMP levels, longterm imipramine treatment may have the opposite effect, namely decreased hippocampal cAMP.
Reierson
Gillian W
GW
Department of Psychiatry and Behavioral Sciences, Center on Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Mastronardi
Claudio A
CA
Licinio
Julio
J
Wong
Ma-Li
ML
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000096:biosynthesis; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000929:Antidepressive Agents, Tricyclic; D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D006152:Cyclic GMP; D007099:Imipramine