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Neuroscience. 2012 Mar 1;204:74-82. doi: 10.1016/j.neuroscience.2011.11.065. Epub 2011 Dec 9.

Swim stress differentially affects limbic contents of 2-arachidonoylglycerol and 2-oleoylglycerol.

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Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.


Restraint stress exposures evoke progressively larger increases in 2-arachidonoylglycerol (2-AG) in limbic brain regions as the number of repetitions increases. The Porsolt swim test usually involves two swim exposures separated by 24 h, and we asked whether the 2-AG response differed between the first and second exposures.


Four groups of male C57/Bl6N mice were studied: control; exposed to a single 6 min swim and killed immediately; exposed to a single 6 min swim and killed 24 h later; and exposed to two swims, separated by 24 h, and killed after the second swim. Outcomes were swim behavior, serum corticosterone, and 2-AG and 2-oleoylglycerol (2-OG) contents in amygdala, hippocampus, and prefrontal cortex.


Mean 2-AG contents were not significantly different among the four treatment groups in any brain region and did not correlate with immobility in either forced swim exposure. However, 2-AG contents in all three brain regions only of the mice exposed to two swims were significantly, positively correlated with serum corticosterone concentrations measured at the same time. 2-OG is present in brain and exhibits a striking regional heterogeneity in control mice. 2-OG concentrations in prefrontal cortex were significantly reduced in the mice killed on the second day compared with the mice killed on the first day. As the target of 2-OG in brain is not known, the significance of these observations await further studies.


Although prior exposure to swim stress does not alter brain 2-AG contents upon re-exposure, 2-AG concentrations in brain become significantly correlated with the hypothalamic-pituitary-adrenal (HPA) axis response to stress when prior exposure to the stress has occurred. These data suggest that even a single exposure to a short period of intense stress sensitizes the 2-AG response to re-exposure to that situation and are consistent with a role for endocannabinoid signaling in modulating stress responses.

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