Attenuation of α2a-adrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood

Brain alpha(2)-adrenergic receptors (alpha(2)-ARs) have been implicated in the regulation of anxiety, which is associated with stress. Environmental treatments during neonatal development could modulate the level of brain alpha(2)-AR expression and alter anxiety in adults, suggesting possible involvement of these receptors in early-life programming of anxiety state. The present study was undertaken to determine whether the reduction of the expression of A subtype of these receptors most abundant in the neonatal brain affects anxiety-related behavior in adulthood. We attenuated the expression of alpha(2A)-ARs during neonatal life by two different sequence specific approaches, antisense technology and RNA interference. Treatment of rats with the antisense oligodeoxynucleotide or short interfering RNA (siRNA) against alpha(2A)-ARs on the days 2-4 of their life, produced a marked acute decrease in the levels of both alpha(2A)-AR mRNA and [H-3]RX821002 binding sites in the brainstem into which drugs were injected. The decrease of alpha(2A)-AR expression in the neonatal brainstem influenced the development of this receptor system in the brain regions as evidenced by the increased number of [H-3]RX821002 binding sites in the hypothalamus of adult animals with both neonatal alpha(2A)-AR knockdown treatments; also in the frontal cortex of antisense-treated, and in the hippocampus of siRNA-treated adult rats. These adult animals also demonstrated a decreased anxiety in the elevated plus-maze as evidenced by an increased number of the open arm entries, greater proportion of time spent in the open arms, and more than a two-fold increase in the number of exploratory head dips. The results provide the first evidence that the reduction in the brain expression of a gene encoding for alpha(2A)-AR during neonatal life led to the long-term neurochemical and behavioral alterations. The data suggests that alterations in the expression of the receptor-specific gene during critical periods of brain development may be involved in early-life programming of anxiety-related behavior. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.