Ontogeny of dopaminergic D-2 receptors in the rat nervous system: characterization and detailed autoradiographic mapping with [125I]iodosulpride.

[125I]Iodosulpride, a highly selective and sensitive probe for dopamine D-2 receptors, was used to study the expression of these receptors in binding studies performed on membranes and serial autoradiographic sections, throughout pre- and postnatal developmental periods. D-2 receptors were first detected autoradiographically in sensory and sympathetic ganglia at the embryonic age of 12 days, i.e. much earlier than in previous studies. In membrane binding studies, D-2 receptors were found to be modulated by guanylnucleotides as early as at embryonic day 15, suggesting that they were already functionally coupled to a regulatory G protein. The overall development of D-2 receptors in the central nervous system occurred according to a caudorostral gradient and was accompanied by a slightly but significantly increased affinity for dopamine, possibly related to the late expression of a D-2 receptor subclass. The ontogeny of D-2 receptors was compared to that of tyrosine hydroxylase immunoreactivity as reported by others and taken as an index of dopaminergic innervation. Despite some variations due to experimental conditions, this comparison resulted in the definition of various situations. In some major projection areas (e.g. caudate putamen at embryonic day 14) there was a simultaneous appearance of both dopaminergic markers whereas in most others (e.g. n. accumbens or olfactory tubercles at embryonic day 20) the appearance of D-2 receptors was preceded by 1-4 days by that of tyrosine hydroxylase immunoreactivity. However, in a few projection areas (e.g. the bed nucleus of the stria terminalis at embryonic day 21), D-2 receptors appeared 3-4 days earlier than tyrosine hydroxylase immunoreactivity. In areas of dopaminergic perikarya, e.g. substantia nigra and ventral tegmental area, where they largely correspond to somatodendritic autoreceptors, D-2 receptors appeared at embryonic days 17 and 21 respectively, i.e. 3-8 days after tyrosine hydroxylase immunoreactivity, suggesting that dopamine synthesis and release is not feedback regulated by autoreceptors at initial developmental stages. In areas where D-2 receptors are present in the absence of any established dopaminergic innervation (e.g. discrete layers of the hippocampus, cerebellum, parietal cortex or in cranial nerve nuclei), they generally appeared at a late stage, i.e. during the second or even the third postnatal week. Finally, there was transient and roughly concomitant expression of both D-2 receptors and tyrosine hydroxylase immunoreactivity in some areas such as spinal ganglia or the lateral ventricle floor, consistent with a possible development function of dopamine mediated by D-2 receptors.