Selective neuronal toxicity of cocaine in embryonic mouse brain cocultures.

Abstract

Cocaine exposure in utero causes severe alterations in the development of the central nervous system. To study the basis of these teratogenic effects in vitro, we have used cocultures of neurons and glial cells from mouse embryonic brain. Cocaine selectively affected embryonic neuronal cells, causing first a dramatic reduction of both number and length of neurites and then extensive neuronal death. Scanning electron microscopy demonstrated a shift from a multipolar neuronal pattern towards bi-and unipolarity prior to the rounding up and eventual disappearance of the neurons. Selective toxicity of cocaine on neurons was paralleled by a concomitant decrease of the culture content in microtubuleassociated protein 2 (MAP2), a neuronal marker measured by solid-phase immunoassay. These effects on neurons were reversible when cocaine was removed from the culture medium. In contrast, cocaine did not affect astroglial cells and their glial fibrillary acidic protein (GFAP) content. Thus, in embryonic neuronal-glial cell cocultures, cocaine induces major neurite perturbations followed by neuronal death without affecting the survival of glial cells. Provided similar neuronal alterations are produced in the developing human brain, they could account for the qualitative or quantitative defects in neuronal pathways that cause a major handicap in brain function following in utero exposure to cocaine.

Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling

“…Cocaine exposure (100 μM -500 μM) induced apoptosis in cortical neurons of fetal mice (Nassogne et al, 1997;Nassogne et al, 1998). Further, fetal cocultures exposed to cocaine lead to neurite perturbations followed by neuronal death with no effect on survival of glial cells (Nassogne et al, 1995). In addition, apoptosis indicated by condensed and fragmented nuclei was observed progressively 2-4 days after cocaine exposure in embryonic cerebral neurons, which was blocked by cycloheximide, indicating involvement of proteins (Nassogne et al, 1997;Nassogne et al, 1998).…”

The Circadian System Is a Target and Modulator of Prenatal Cocaine Effects

“…However, the extent of the damage and whether it is in part due to confounding environmental, genetic or psychological factors remains controversial [4]. In contrast, studies in animal models, including rodents and primates, clearly show that prenatal cocaine exposure has deleterious effects on the developing brain, affecting both cognitive functions and emotional responses [5], [6].…”

Phenotypes ofDrosophilaBrain Neurons in Primary Culture Reveal a Role for Fascin in Neurite Shape and Trajectory

“…In vitro studies of neuron-morphogenesis defects caused by drugs of abuse, for example, complement in vivo analyses of brain development and behavior (Nassogne et al, 1995;Lindsley et al, 2003;Robinson and Kolb, 2004). In the realm of neurogenetic disease, cell-culture models of spinal muscular atrophy suggest roles for the causative gene in neurite outgrowth and axonal transport that were not apparent from spinal cord histopathology (Briese et al, 2005).…”