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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.