Chronic cocaine administration causes extensive white matter damage in brain: Diffusion tensor imaging and immunohistochemistry studies

Abstract

The effect of chronic cocaine exposure on multiple white matter structures in rodent brain was examined using diffusion tensor imaging (DTI), locomotor behavior, and end point histology. The animals received either cocaine at a dose of 100 mg/kg (N=19), or saline (N=17) for 28 days through an implanted osmotic minipump. The animals underwent serial DTI scans, locomotor assessment, and end point histology for determining the expressions of myelin basic protein (MBP), neurofilament-heavy protein (NF-H), proteolipid protein (PLP), Nogo-A, aquaporin-4 (AQP-4), and growth associated protein – 43 (GAP-43). Differences in the DTI measures were observed in the splenium (scc) and genu (gcc) of the corpus callosum (cc), fimbria (fi), and the internal capsule (ic). Significant increase in the activity in the fine motor movements and decrease in the number of rearing events were observed in the cocaine treated animals. Reduced MBP and Nogo-A, and increased GAP-43 expressions were most consistently observed in these structures. A decrease in the NF-H expression was observed in fi and ic. The reduced expression of Nogo-A and increased GAP-43 may suggest destabilization of axonal connectivity and increased neurite growth with aberrant connections. Increased GAP-43 suggests drug induced plasticity or a possible repair mechanism response. The findings indicated that multiple white matter tracts are affected following chronic cocaine exposure.

PPAR‐gamma agonist pioglitazone modifies craving intensity and brain white matter integrity in patients with primary cocaine use disorder: a double‐blind randomized controlled pilot trial

“…Due to incidental finding of a brain abnormality (N=1), and scanner maintenance interruption (N=1), only 18 subjects were scanned at both pre- and post-treatment (10 = PLC, 8 = PIO). ROI analyses of FA focused on WM ROI based on several previous studies of WM integrity in cocaine dependence: (1) commissural fibers: the genu and splenium of corpus callosum (CC); (2) projection fibers: the anterior and posterior thalamic radiations; and (3) association fibers: the cingulum and the external capsule (18, 19, 22, 23, 35, 36). …”

“…Evidence for cocaine neurotoxicity comes from many different forms of neuroimaging (15, 16), one of which is white matter (WM) integrity as measured by diffusion tensor imaging (DTI). Multiple studies, both preclinical (17, 18) and human (19–21) show impaired WM integrity is associated with functional consequences, including impulsivity (19), decision making (22) and relapse (23). Importantly, emerging evidence implicates WM integrity across a range of psychiatric disorders and cognitive processes relevant to addiction (24, 25).…”

Microstructural changes to the brain of mice after methamphetamine exposure as identified with diffusion tensor imaging

“…Specifically, a limited yet instructive literature is available for cocaine-exposed rodents. Cocaine-exposed rats show lower FA in the genu and splenium of the corpus callosum and in the internal capsule (Narayana et al, 2009; Narayana et al, 2014). Myelin basic protein was reduced in the splenium of the corpus callosum and both myelin basic protein and neurofilament-heavy protein was reduced in the internal capsule (Narayana et al, 2014).…”

“…Cocaine-exposed rats show lower FA in the genu and splenium of the corpus callosum and in the internal capsule (Narayana et al, 2009; Narayana et al, 2014). Myelin basic protein was reduced in the splenium of the corpus callosum and both myelin basic protein and neurofilament-heavy protein was reduced in the internal capsule (Narayana et al, 2014). The joint observation of lower FA and myelin basic protein supports the inference from the membrane boundary model that lower FA in white matter is associated with myelin loss.…”

GAP-43 in synaptic plasticity: molecular perspectives

“…108 Following one injection of amphetamine, GAP-43 phosphorylation was increased in rat striatum and persisted for 1 week. 109 In cultured PC12 cells, repeated intermittent amphetamine treatment (5 minutes a day for 5 days) induced neurite outgrowth that was associated with an increase in the level of GAP-43 staining.…”