Prenatal haloperidol induces a selective reduction in the expression of plasticity-related genes in neonate rat forebrain.
Haloperidol, a dopamine receptor antagonist clinically used as an antipsychotic drug, induces long-term deleterious effects in offspring development when administered prenatally. However, the basis for this overall response to the drug remains unknown. Here we describe that prenatal administration of haloperidol in rats induces a drastic and selective reduction in the expression of plasticity-related genes in neonate forebrain, but not in mesencephalon. GABAergic and enkephalinergic markers such as glutamic acid decarboxylase activity and mRNA, and preproenkephalin mRNA were also diminished in forebrain. However, the expression of other genes such as epidermal growth factor-receptor, glial fibrillary acidic protein, and several proto-oncogenes (src, fos and myc), and a cholinergic marker such as choline acetyltransferase activity were unaltered. In addition, haloperidol promoted a significant decrease in mitotic cell number and cellular density in the striatum, one of the forebrain regions with the highest dopamine receptor density. These findings suggest that prenatal dopamine receptor occupancy may be a critical factor in controlling the development of forebrain target cells through mechanisms involving changes in the expression of plasticity-related genes.
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007.
R
R
Castro
B
B
Brito
J
J
Segovia
J M
JM
Martín-Trujillo
V
V
Notario
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D002147:Calmodulin / Q000096:biosynthesis; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis; D004745:Enkephalins / Q000096:biosynthesis; D005260:Female; D019922:GAP-43 Protein; D015870:Gene Expression / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D016900:Neurofilament Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D011498:Protein Precursors / Q000096:biosynthesis; D011519:Proto-Oncogenes / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis
D000199:Actins; D002147:Calmodulin; D015816:Cell Adhesion Molecules, Neuronal; D004745:Enkephalins; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D010982:Platelet-Derived Growth Factor; D011498:Protein Precursors; D012333:RNA, Messenger; C033660:preproenkephalin; D017479:Receptors, Platelet-Derived Growth Factor; D005968:Glutamate Decarboxylase; D006220:Haloperidol