期刊
JOURNAL OF NEUROTRAUMA
卷 37, 期 1, 页码 27-42出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/neu.2019.6472
关键词
addiction; adolescent; behavior; neuroinflammation; traumatic brain injury
资金
- National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) [P30 DA013429-16, R01DA046833 01, T32 DA007237]
- NIH/National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS086570-01]
- PA-CURE program (Pennsylvania Department of Health)
Although clinical studies identify traumatic brain injury (TBI) as a risk factor for the development of substance use disorder, much remains unknown about the possible underlying pathogenesis and age-specific effects. Thus, the aim of this study is to test the hypothesis that at an age of ongoing maturation, adolescent TBI alters elements of the reward pathway, resulting in increased sensitivity to the rewarding effects of a subthreshold dose of cocaine that does not induce significant behavioral changes in naive, non-injured mice. Specifically, these results were derived from the combination of the controlled cortical impact model of TBI, performed on either adolescent (6 weeks) or young adult (8 weeks) mice, followed by the cocaine-induced conditioned place preference assay 2 weeks later. Using three-dimensional isosurface rendering and volumetric image analysis, TBI was found to induce neuromorphological changes such as decreased dendritic complexity and reduced spine density in brain regions essential for reward perception and processing of drug-induced euphoria. Further, we demonstrated that these neuronal changes may affect the differential expression of dopamine-associated genes. Our analysis also provided evidence for age-related differences in immune response and the distinct involvement of augmented microglial phagocytic activity in the remodeling of neuronal structures in the adolescent TBI brain. Our studies suggest that TBI during adolescence, a period associated with ongoing maturation of dopaminergic systems, may subsequently enhance the abuse liability of cocaine in adulthood.
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