Acetylcholinesterase inhibition ameliorates deficits in motivational drive

Behavioral and Brain Functions

Keri Martinowich²  Kathleen M Cardinale⁴  Robert J Schloesser⁴  Michael Hsu⁴  Nigel H Greig³  Husseini K Manji¹ 

[1] Johnson & Johnson Pharmaceutical Research and Development, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560 USA

[2] Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 N. Wolfe Street, Suite 300, Baltimore, MD 21205 USA

[3] Laboratory of Neuroscience, Section on Drug Design and Development, National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD 20892-3711, USA

[4] Mood 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

关键词: Basal forebrain;    Nucleus accumbens;    c-fos;    FosB;    Cholinergic;    Chronic stress;    Motivation;    Apathy;   

Others  :  797540
DOI  :  10.1186/1744-9081-8-15

 received in 2011-06-20, accepted in 2012-03-20,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Martinowich et al; licensee BioMed Central Ltd.

【 图 表 】

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