In utero cocaine-induced dysfunction of dopamine D-1 receptor signaling and abnormal differentiation of cerebral cortical neurons

Monoamines modulate neuronal differentiation, and alteration of monoamine n eurotransmission during development produces specific changes in neuronal s tructure, function, and pattern formation. We have previously observed that prenatal exposure to cocaine in a clinically relevant animal model produce s increased length of pyramidal neuron dendrites in the anterior cingulate cortex (ACC) postnatally. We now report that cocaine administered intraveno usly to pregnant rabbits at gestational stages preceding and during cortica l histogenesis results in the early onset of hypertrophic dendritic outgrow th in the embryonic ACC. Confocal microscopy of DiI-labeled neurons reveale d that the atypical, tortuous dendritic profiles seen postnatally in ACC-co caine neurons already are apparent in utero. No defects in neuronal growth were observed in visual cortex (VC), a region lacking prominent dopamine in nervation. In striking correlation with our in vivo results, in vitro exper iments revealed a significant enhancement of spontaneous process outgrowth of ACC neurons isolated from cocaine-exposed fetuses but no changes in neur ons derived from visual cortex. The onset of modified growth in vivo is par alleled by reduced D-1A receptor coupling to its G-protein. These data sugg est that the dynamic growth of neurons can be regulated by early neurotrans mitter signaling in a selective fashion. Prenatal onset of defects in dopam ine receptor signaling contributes to abnormal circuit formation and may un derlie specific cognitive and behavioral dysfunction.