Development of specificity and stereoselectivity of rat brain dopamine receptors

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Abstract
Prenatal exposure to the neuroleptic haloperidol has been reported to produce an enduring decrement in the number of dopamine D2 receptors in rat striatum and a persistent diminution of a dopamine dependent behavior, stereotypy.17 The ontogeny of rat brain dopamine binding sites has been studied in terms of the kinetic properties and phenotypic specificity in rat fetal brain through early post-natal development. Sites showing some properties of the D2 binding site can be found prior to gestational day (GD) 18, can be labeled with [3H]dopamine or [3H]spiroperidol and can be displaced with dopaminergic agonists and antagonists.5 Saturation kinetics for specific [3H]spiroperidol has previously been found to occur on or about GD 18.1.5 It is of interest that the critical period for the prenatal effect of haloperidol to reduce striatal D2 binding sites, GD''s 15-18,18 coincides with the period during which dopamine binding sites lack true specificity, but can be labeled with dopaminergic ligands. In these experiments the development of stereoselectivity of the brain dopamine binding sites has been examined. When rat mothers were given either the neuroleptic(+)-butaclamol or its therapeutically inactive isomer (-)-butaclamol during the critical period GD''s 15-18, the number of [3H]spiroperidol binding sites in striata of offspring was significantly reduced by both stereoisomers. This is in marked contrast to the postnatal treatment effect by a neuroleptic in which upregulation of striatal D2 binding sites occurs only by treatment with the therapeutically active isomer (+)-butaclamol. In vitro studies of the direct effect of the stereoisomers of butaclamol indicate that the recognition sites detected during fetal brain development with [3H]spiroperidol do not distinguish between the isomers of butaclamol. The point at which stereoselectivity is apparent also appears to be the point at which the prenatal neuroleptic effect is no longer operative and the mature response to increase the number of dopamine binding sites occurs.