Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 4 • April 2013

Stuck in an Apathetic Rut? Cholinesterase Inhibition
Ameliorates Apathy and Loss of Motivational Drive in Mice

Scientists studying neural mechanisms for apathetic behavior report1 that a cholinesterase inhibitor (phenserine was used in this study) reversed many of the signs of apathy in male C57BL/6 mice) subject to chronic restraint stress. As the authors explain, apathy shares some overlapping features with depression, but is not the same. Apathy “can be distinguished [from depression] by lack of dysphoric symptoms including sadness, hopelessness and guilt.”1 Instead, apathetic animals exhibit extreme withdrawal of involvement and a paucity of emotion, a state characterized by a lack of motivation in relation to goal-oriented and self-initiated activity.

The authors wanted to test whether facilitating the cholinergic system could ameliorate the apathetic state induced by chronic restraint stress. It is not clear why they used the particular cholinesterase inhibitor (phenserine) that they did, but it is interesting to note that the final author of the paper (who is usually the scientist who runs the lab where the work is done) is listed as a paid employee of Johnson & Johnson Pharmaceutical Research under “Competing Interests” at the end of the paper. This MAY (just a speculation on our part) indicate that the cholinesterase inhibitor is a product of Johnson & Johnson Pharmaceutical Research.

Several features of the apathetic behavior exhibited by the control animals were ameliorated in the experimental animals treated with the cholinesterase inhibitor. “Overall, CRS [chronic restraint stress]-exposed mice displayed significant decreases in exploratory behavior such as rear-up and sniff, as well as in locomotor behaviors including walk slowly, remain low, and hang cuddled for several hours directly prior to the onset of the dark cycle and before the onset of the light cycle, suggesting a decrease in initiation of non-essential activities. However, directly prior to dark cycle onset, inactive behaviors such as twitch and rest increased in the CRS mice.”1 The researchers observed accumulation of deltaFosB in the MS/vDB, said to be one of the major basal forebrain cholinergic nuclei, suggesting that this area had undergone significant changes in gene expression as a result of CRS.

The authors note that two other papers reported that the cholinesterase inhibitors galantamine and donepezil lead to increased dopamine release in the NAcc (nucleus accumbens), an area associated with motivation and reward and speculate that the behavioral effects of phenserine in this paper may have resulted from activating cholinergic interneurons in brain areas associated with motivation and reward.


  1. Martinowich et al. Acetylcholinesterase inhibition ameliorates deficits in motivational drive. Behav Brain Funct. 8:15 (2012)

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