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

Abstract

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.

Rapid immunohistological measurement of tyrosine hydroxylase in rat midbrain by near-infrared instrument-based detection

“…Several reports have quantified relative tyrosine hydroxylase levels using near-infrared detection as part of a larger study [38][39][40][41][42]. However, the lesions were all produced differently from this report.…”

“…The most common inducer was 6-OHDA injected directly into a region of the nigrostriatal pathway [38][39][40]. One study employed rAAV overexpression of α-synuclein [42] and another report performed a functional block/agonist approach of the histamine H1 receptor [41]. While we provide functional correlation between motor coordination and TH levels, these studies did not report correlative data on physiological or functional outcomes with TH levels.…”

Long-Term Functional and Cytoarchitectonic Effects of the Systemic Administration of the Histamine H1 Receptor Antagonist/Inverse Agonist Chlorpheniramine During Gestation in the Rat Offspring Primary Motor Cortex

“…Reduced methamphetamine-stimulated motor activity in male and female offspring from pregnant rats treated with chlorpheniramine has been reported recently by our group. Interestingly, only males showed reduced speed movement under basal conditions, suggesting sex-specific alterations ( Márquez-Valadez et al, 2019 ), this being the reason why only male animals were included in the present study. However, it will be important to assess females in future studies.…”

“…We recently reported that only male pups from chlorpheniramine-treated rats during pregnancy (same dose and time of administration as in this study) showed a decrease in movement speed, in this work, we therefore use only male offspring ( Márquez-Valadez et al, 2019 ).…”

“…At gestation day E12, pregnant rats were randomly assigned to each experimental group (control or chlorpheniramine). From E12 to E14, the chlorpheniramine group received a daily intraperitoneal injection of the antihistamine (5 mg/kg; Sigma-Aldrich, St Louis, MO, United States), while the control group received vehicle (injectable water; Laboratorios PiSA, Guadalajara, Jal., Mexico) ( Naranjo and de Naranjo, 1968 ; Márquez-Valadez et al, 2019 ).…”