Castro R, Brito B, Segovia J, Martín-Trujillo J M, Notario V
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007.
Brain Res Mol Brain Res. 1994 Oct;26(1-2):74-80. doi: 10.1016/0169-328x(94)90076-0.
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.
氟哌啶醇是一种临床上用作抗精神病药物的多巴胺受体拮抗剂，产前给药会对后代发育产生长期有害影响。然而，药物产生这种整体反应的原因尚不清楚。在此我们描述，在大鼠中产前给予氟哌啶醇会导致新生前脑而非中脑中与可塑性相关基因的表达急剧且选择性地减少。前脑中的γ-氨基丁酸能和脑啡肽能标记物，如谷氨酸脱羧酶活性和mRNA以及前脑啡肽原mRNA也减少。然而，其他基因如表皮生长因子受体、胶质纤维酸性蛋白和几种原癌基因（src、fos和myc）的表达，以及胆碱能标记物如胆碱乙酰转移酶活性未发生改变。此外，氟哌啶醇使纹状体（前脑中多巴胺受体密度最高的区域之一）中的有丝分裂细胞数量和细胞密度显著降低。这些发现表明，产前多巴胺受体占据可能是通过涉及可塑性相关基因表达变化的机制控制前脑靶细胞发育的关键因素。
