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The dopaminergic and histaminergic systems are the first to appear during the development of the nervous system. Through the activation of H 1  receptors (H 1 Rs), histamine increases neurogenesis of the cortical deep layers, while reducing the dopaminergic phenotype (cells immunoreactive to tyrosine hydroxylase, TH + ) in embryo ventral mesencephalon. Although the function of histamine in neuronal differentiation has been studied, the role of H 1 Rs in neurogenesis has not been addressed. For this purpose, the H 1 R antagonist/inverse agonist chlorpheniramine was systemically administered (5 mg/kg, i.p.) to pregnant Wistar rats (gestational days 12–14, E12–14), and control and experimental embryos (E14 and E16) and pups (21-day-old) were evaluated for changes in nigro-striatal development. Western blot and immunohistochemistry determinations showed a significant increase in the dopaminergic markers’ TH and PITX3 in embryos from chlorpheniramine-treated rats at E16. Unexpectedly, 21-day-old pups from the chlorpheniramine-treated group, showed a significant reduction in TH immunoreactivity in the substantia nigra  pars compacta  and dorsal striatum. Furthermore, striatal dopamine content, evoked [ 3 H]-dopamine release and methamphetamine-stimulated motor activity were significantly lower compared to the control group. These results indicate that H 1 R blockade at E14–E16 favors the differentiation of dopaminergic neurons, but hampers their migration, leading to a decrease in dopaminergic innervation of the striatum in post-natal life.

frontiers in neuroscience

The Systemic Administration of the Histamine H1 Receptor Antagonist/Inverse Agonist Chlorpheniramine to Pregnant Rats Impairs the Development of Nigro-Striatal Dopaminergic Neurons