Acetylcholinesterase inhibition ameliorates deficits in motivational drive

Keri Martinowich, Kathleen M. Cardinale, Robert J. Schloesser, Michael Hsu, Nigel H. Greig, Husseini K. Manji

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Article number15
JournalBehavioral and Brain Functions
StatePublished - Mar 20 2012
Externally publishedYes


  • Apathy
  • Basal forebrain
  • C-fos
  • Cholinergic
  • Chronic stress
  • FosB
  • Motivation
  • Nucleus accumbens

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Biological Psychiatry
  • Behavioral Neuroscience


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