Attenuation of alpha2A-adrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood.
Brain alpha2-adrenergic receptors (alpha2-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 alpha2-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 alpha2A-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 alpha2A-ARs on the days 2-4 of their life, produced a marked acute decrease in the levels of both alpha2A-AR mRNA and [3H]RX821002 binding sites in the brainstem into which drugs were injected. The decrease of alpha2A-AR expression in the neonatal brainstem influenced the development of this receptor system in the brain regions as evidenced by the increased number of [3H]RX821002 binding sites in the hypothalamus of adult animals with both neonatal alpha2A-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 alpha2A-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.
Shishkina
G T
GT
Institute of Cytology and Genetics, Lavrentjev Av. 10, Novosibirsk 630090, Russia.
Kalinina
T S
TS
Dygalo
N N
NN
D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal; D015139:Blotting, Southern / Q000379:methods; D001933:Brain Stem / Q000187:drug effects* / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D019329:Idazoxan / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018782:Maze Learning / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014316:Tritium / Q000493:pharmacokinetics
C547770:Adra2a protein, rat; D000317:Adrenergic alpha-Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018341:Receptors, Adrenergic, alpha-2; D014316:Tritium; C058525:2-methoxyidazoxan; D009638:Norepinephrine; D019329:Idazoxan