title: Acetylcholinesterase inhibition ameliorates deficits in motivational drive.
abstract: BACKGROUND
  Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes.
  
  
  METHODS
  We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes.
  
  
  RESULTS
  CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens.
  
  
  CONCLUSIONS
  Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive.
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-3711, USA. keri.martinowich@libd.org
authors.forename: Keri
authors.initials: K
authors.lastname: Martinowich
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Cardinale
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schloesser
authors.forename: Michael
authors.initials: M
authors.lastname: Hsu
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
mesh_terms: D059445:Anhedonia; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002908:Chronic Disease; D004328:Drive; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D019417:Hindlimb Suspension; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009042:Motivation / Q000187:drug effects*; D009420:Nervous System / Q000503:physiopathology; D010641:Phenotype; D010830:Physostigmine / Q000031:analogs & derivatives / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011803:Quinine / Q000494:pharmacology; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000523:psychology; D013550:Swimming / Q000523:psychology; D013649:Taste
chemical_list: D002800:Cholinesterase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D010830:Physostigmine; D011803:Quinine; C092280:phenserine