Cocaine administration in pregnant rabbits alters cortical structure and function in their progeny in the absence of maternal seizures.
Previous studies have reported that cocaine exposure in utero results in structural and functional alterations in the development of the anterior cingulate cortex (ACC). In the present study, the effects of maternal cocaine dosage and of cocaine-elicited maternal seizures on the progeny were studied. The incidence of maternal generalized tonic clonic seizures (GTCSs) elicited by cocaine was recorded. No GTCSs were elicited in pregnant rabbits by doses of 2 or 3 mg/kg of cocaine, but GTCSs were sometimes elicited by the highest dose (4 mg/kg per injection). We analyzed the offspring of cocaine-exposed and control animals using three assays of ACC development: (i) the structure of apical dendrites of pyramidal neurons, (ii) the distribution of a calcium binding protein (parvalbumin) in the dendrites of GABAergic neurons, and (iii) coupling of D1-like receptors and their G proteins. In all progeny of rabbits exposed to 3 or 4 mg/kg of cocaine during pregnancy, there was a significant change in the structure of apical dendrites, a significant increase in the number of dendrites of GABAergic neurons which were parvalbumin immunoreactive, and a significant reduction in D1/G protein coupling. In assays of apical dendrites, the effects on offspring of rabbits given 2 mg/kg cocaine were as pronounced as in offspring of rabbits given 3 or 4 mg/kg, but the effects on parvalbumin immunoreactivity and D1/G protein coupling were reduced at this low dose. Thus, previous findings of ACC developmental abnormalities in offspring of rabbits given a dose of 4 mg/kg were replicated, the effects were shown to be dose-related and to be independent of maternal seizures. A mechanism by which dysfunction of the D1 receptor system could mediate cocaine-associated changes in all three parameters of ACC structure and function is discussed.
Murphy
E H
EH
Department of Neurobiology and Anatomy, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, PA 19129, USA.
Fischer
I
I
Friedman
E
E
Grayson
D
D
Jones
L
L
Levitt
P
P
O'Brien-Jenkins
A
A
Wang
H Y
HY
Wang
X H
XH
D000818:Animals; D015415:Biomarkers; D002540:Cerebral Cortex / Q000187:drug effects* / Q000648:ultrastructure; D003042:Cocaine / Q000494:pharmacology*; D003712:Dendrites / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009294:Narcotics / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000032:analysis; D010320:Parvalbumins / Q000032:analysis; D011247:Pregnancy; D017966:Pyramidal Cells / Q000648:ultrastructure; D011817:Rabbits; D012640:Seizures / Q000473:pathology* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D015415:Biomarkers; D008869:Microtubule-Associated Proteins; D009294:Narcotics; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D003042:Cocaine