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Brain Behav. 2019 Mar;9(3):e01222. doi: 10.1002/brb3.1222. Epub 2019 Feb 20.

Divergent effects of repeated cocaine and novel environment exposure on locus coeruleus c-fos expression and brain catecholamine concentrations in rats.

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Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan.
Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan.
Research and Development Service, John D. Dingell VA Medical Center, Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan.



Chronic administration of cocaine causes a disinhibited, hyperexploratory response to novel environments. As the norepinephrine (NE) system regulates exploration and is dysregulated following cocaine exposure, we hypothesized that this cocaine-mediated hyperexploratory response is associated with increased locus coeruleus (LC) reactivity.


To test this hypothesis, we used dual fluorescent in situ hybridization immunofluorescence to analyze novelty-induced c-fos and tyrosine hydroxylase expression in the LC and high-pressure liquid chromatography to measure dopamine (DA) and NE concentrations in key catecholamine projection regions following exposure to cocaine.


Repeated cocaine exposure followed by a 14-day drug-free period increased exploration of novel environments, replicating previous findings. Novelty exposure increased LC c-fos expression, increased anterior cingulate NE, and decreased ventral tegmental area DA. Cocaine exposure decreased amygdala (AMY) DA, but had no effect on LC c-fos expression or NE in any tested brain region. No interactions between cocaine and novelty were found. Open arm exploration was positively correlated with LC c-fos expression and NE concentrations in both the anterior cingulate and nucleus accumbens, and negatively correlated with AMY DA concentration.


Our findings confirm that exposure to novel environments increases LC activity and NE in the anterior cingulate cortex, that long-term exposure to cocaine dysregulates AMY DA, and that disinhibited exploration in novel environments correlates with NE and DA in regions that modulate risk-taking and avoidance behavior. Further studies investigating the effects of cocaine on brain catecholamine systems are important in understanding the long-lasting effects of cocaine on brain function.


cocaine; locus Coeruleus; norepinephrine; novelty

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