In utero cocaine-induced dysfunction of dopamine D1 receptor signaling and abnormal differentiation of cerebral cortical neurons.
Monoamines modulate neuronal differentiation, and alteration of monoamine neurotransmission during development produces specific changes in neuronal structure, function, and pattern formation. We have previously observed that prenatal exposure to cocaine in a clinically relevant animal model produces increased length of pyramidal neuron dendrites in the anterior cingulate cortex (ACC) postnatally. We now report that cocaine administered intravenously to pregnant rabbits at gestational stages preceding and during cortical histogenesis results in the early onset of hypertrophic dendritic outgrowth in the embryonic ACC. Confocal microscopy of DiI-labeled neurons revealed that the atypical, tortuous dendritic profiles seen postnatally in ACC-cocaine neurons already are apparent in utero. No defects in neuronal growth were observed in visual cortex (VC), a region lacking prominent dopamine innervation. In striking correlation with our in vivo results, in vitro experiments revealed a significant enhancement of spontaneous process outgrowth of ACC neurons isolated from cocaine-exposed fetuses but no changes in neurons derived from visual cortex. The onset of modified growth in vivo is paralleled by reduced D(1A) receptor coupling to its G-protein. These data suggest that the dynamic growth of neurons can be regulated by early neurotransmitter signaling in a selective fashion. Prenatal onset of defects in dopamine receptor signaling contributes to abnormal circuit formation and may underlie specific cognitive and behavioral dysfunction.
Jones
L B
LB
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Stanwood
G D
GD
Reinoso
B S
BS
Washington
R A
RA
Wang
H Y
HY
Friedman
E
E
Levitt
P
P
D000375:Aging; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development*; D003042:Cocaine / Q000633:toxicity*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D005314:Embryonic and Fetal Development; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017966:Pyramidal Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction
D017447:Receptors, Dopamine D1; D019205:GTP-Binding Protein alpha Subunits, Gs; D003042:Cocaine