title: Involvement of tissue plasminogen activator in stress responsivity during acute cocaine withdrawal in mice.
abstract: There is evidence that increased release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) contributes to stress responsivity during cocaine withdrawal (WD). Recent studies suggest that tissue plasminogen activator (tPA) in the CeA is a downstream effector protein for CRF after acute "binge" cocaine administration. The purpose of this study was to determine if tPA modulates cocaine WD-induced stress responsivity. Wild-type (WT) and tPA-deficient (tPA - / - ) mice were subjected to chronic (14 days) "binge" cocaine (45 mg/kg per day) or its acute (1 day) WD. Extracellular tPA activity, CRF mRNA levels, and plasma corticosterone (CORT) levels were measured in tPA - / -  and WT mice. Extracellular tPA activity was reduced by 50% in the CeA and medial amygdala of WT mice after chronic cocaine and returned to basal levels after acute WD. Unlike WT mice, tPA - / -  mice did not display elevated amygdalar CRF mRNA levels during cocaine WD. In comparison to WT mice, tPA - / -  mice showed a blunted plasma CORT response during acute WD. These results demonstrate that tPA activity in the amygdala (Amy) is altered by chronic cocaine exposure, and further suggest an involvement of tPA in modulating amygdalar CRF stress responsive system and hypothalamic-pituitary-adrenal axis in response to acute cocaine WD.
authors.affiliation: Laboratory of Biology of Addictive Diseases, The Rockefeller University, New York, NY, 10065, USA. zhouya@rockefeller.edu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rajani
authors.initials: R
authors.lastname: Maiya
authors.forename: Erin H
authors.initials: EH
authors.lastname: Norris
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
authors.forename: Sidney
authors.initials: S
authors.lastname: Strickland
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D003042:Cocaine / Q000009:adverse effects*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000502:physiology*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D010959:Tissue Plasminogen Activator; D003042:Cocaine; D003345:Corticosterone