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Logo of behbrainBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleBehavioral and Brain Functions : BBFJournal Front Page
 
Behav Brain Funct. 2012; 8: 15.
Published online Mar 20, 2012. doi:  10.1186/1744-9081-8-15
PMCID: PMC3328273
Acetylcholinesterase inhibition ameliorates deficits in motivational drive
Keri Martinowich,corresponding author1,3 Kathleen M Cardinale,1 Robert J Schloesser,1 Michael Hsu,1 Nigel H Greig,2 and Husseini K Manji4
1Mood and Anxiety Disorders Program (MAP), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), 35 Convent Drive, Building 35, Room 1C-1012, Bethesda, MD 20892-3711, USA
2Laboratory of Neuroscience, Section on Drug Design and Development, National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD 20892-3711, USA
3Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 N. Wolfe Street, Suite 300, Baltimore, MD 21205 USA
4Johnson & Johnson Pharmaceutical Research and Development, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560 USA
corresponding authorCorresponding author.
Keri Martinowich: keri.martinowich/at/libd.org; Kathleen M Cardinale: kcardinale1/at/gmail.com; Robert J Schloesser: SchloesR/at/mail.nih.gov; Michael Hsu: potonchair/at/gmail.com; Nigel H Greig: greign/at/grc.nia.nih.gov; Husseini K Manji: HManji/at/its.jnj.com
Received June 20, 2011; Accepted March 20, 2012.
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.
Keywords: Apathy, Motivation, Chronic stress, Cholinergic, FosB, c-fos, Nucleus accumbens, Basal forebrain
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