Prenatal Cocaine Exposure Inhibits Neurite Outgrowth Through RAGE Pathway and Activates Altered Expression of Pro‐addictive Cytokines in Primary Neuronal and Glial Cell Cultures

Abstract

BackgroundThe prevalence of neonates exposed to cociane continues to be an endemic within the U.S. An overwhelming amount of evidence has shown that prenatal cocaine exposure is associated with numerous neurological and behavioral abnormalities, as well as structural damage and a deficiency in neurodevelopment with no established underlying mechanisms.PurposeThe present study was designed to investigate biochemical events coupled to cocaine‐induced cytotoxicity of neurons and glial cells seen in exposed offspring.Research Approach:Time pregnant Sprague‐Dawley rats were treated with 40 mg/kg of cocaine HCl on gestational day (GD) 10–21. On postnatal day (PND) 3 the brain tissue of the pups was harvested to yield mixed neuronal and glial cell cultures. A cytokine antibody array determined a decrease in RAGE expression and an increase in TIMP‐1 expression in prenatally exposed pups. Immunocytochemistry (ICC) showed decreased neurite outgrowth in prenatally exposed neurons. ICC also determined there was an increase in dopamine (DA) in prenatally exposed primary cell cultures indicating the presence of DA receptors on astrocytes and oligodendrocytes.. Western Blot analysis quantitatively determined a variation of amphoterin (HMGB1) which is necessary for RAGE activation and pro‐inflammatory cytokine matrix metalloproteinase 9 (MMP‐9) protein expressions between the control and cocaine treated pups.ConclusionThrough in vivo and in vitro studies exposure to cocaine during gestation leads to marked alterations in morphology and function of primary neuronal and glial cell cultures. These findings suggest that exposure to cocaine in utero can ultimately increase the incidence of addiction and development of neurodegenerative diseases and neuropathologies in the affected offspring.