Adolescent cocaine exposure causes enduring macroscale changes in mouse brain structure.
Cocaine dependence is associated with abnormalities in brain structure in humans. However, it is unclear whether these differences in brain structure predispose an individual to drug use or are a result of cocaine's action on the brain. This study investigates the impact of chronic cocaine exposure on brain structure and drug-related behavior in mice. Specifically, mice received daily cocaine or saline injections for 20 d during two developmental time periods: adolescence (27-46 d old) and young adulthood (60-79 d old). Following 30 d of abstinence, either fixed brain T2 weighted magnetic resonance images were acquired on a 7 T scanner at 32 μm isotropic voxel dimensions or mice were assessed for sensitization to the locomotor stimulant effects of cocaine. Three automated techniques (deformation-based morphometry, striatum shape analysis, and cortical thickness assessment) were used to identify population differences in brain structure in cocaine-exposed versus saline-exposed mice. We found that cocaine induced changes in brain structure, and these were most pronounced in mice exposed to cocaine during adolescence. Many of these changes occurred in brain regions previously implicated in addiction including the nucleus accumbens, striatum, insular cortex, orbitofrontal cortex, and medial forebrain bundle. Furthermore, exposure to the same cocaine regimen caused sensitization to the locomotor stimulant effects of cocaine, and these effects were again more pronounced in mice exposed to cocaine during adolescence. These results suggest that altered brain structure following 1 month of abstinence may contribute to these persistent drug-related behaviors, and identify cocaine exposure as the cause of these morphological changes.
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
Anne L
AL
Wheeler
Jason P
JP
Lerch
M Mallar
MM
Chakravarty
Miriam
M
Friedel
John G
JG
Sled
Paul J
PJ
Fletcher
Sheena A
SA
Josselyn
Paul W
PW
Frankland
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*
D018765:Dopamine Uptake Inhibitors; D003042:Cocaine