Identification of a sensitive period of prenatal cocaine exposure that alters the development of the anterior cingulate cortex.
Administration of cocaine to pregnant rabbits produces robust and long-lasting anatomical, neurochemical and behavioral alterations in their offspring. For example, exposure to cocaine following implantation [embryonic day (E) 8] through gestation (E29) produces increased length and decreased bundling of layer III and V pyramidal neuron dendrites, increased parvalbumin expression in the dendrites of interneurons, and increased GABA levels in the anterior cingulate cortex (ACC) and other dopamine-rich cortical areas. We have investigated the presence of a sensitive period of in utero exposure during specific developmental epochs prior to and during the onset of cortical development that might be capable of producing such effects. Cocaine (3 mg/kg i.v., twice daily) or saline was administered during embryonic days E16-E25 (onset and peak of corticogenesis), E8-E15 (prior to cortical plate formation), E8-E25 or E8-E29 as in earlier studies. Examination of the ACC in offspring exposed from E8 to E25 and from E16 to E25 were found to induce alterations in the development of pyramidal neurons and interneurons that are nearly identical to those induced by the complete exposure (E8-E29) paradigm. No alterations were observed following the E8-E15 cocaine exposure. These data suggest that exposure to cocaine during E16-E25, the time of peak corticogenesis, appearance of cortical monoamines and onset of D(1) dopamine receptor expression, is necessary and sufficient to produce long-term effects on the organization of excitatory pyramidal neurons and inhibitory interneurons in the ACC.
Stanwood
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GD
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. gstanwoo@oitt.edu
Washington
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RA
Levitt
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P
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development*; D003042:Cocaine / Q000633:toxicity*; D003712:Dendrites / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011817:Rabbits; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D003042:Cocaine