RESUMO
Neonatal treatments can disrupt prepulse inhibition (PPI) of startle response later in life. Alpha2A-adrenergic receptors (alpha2A-ARs) regulate the release of brain neurotransmitters that may influence PPI. The authors examined the effects of short-term reduction in the neonatal brainstem alpha2A-ARs on subsequent development of this receptor system and acoustic startle reflex in rats. Administration of antisense oligodeoxynucleotide complementary to the alpha2A-ARs on Days 2-4 of life reduced receptor expression in the brainstem by Day 5. The treatment increased alpha2-AR numbers in the cortex, hippocampus, and amygdala at 40 days of age, and in cortex and hypothalamus at 90 days of age. Transient increases in hippocampal and amygdalar alpha2-ARs were accompanied by attenuation of acoustic startle response and impairment of PPI.
Assuntos
Tronco Encefálico/metabolismo , Idazoxano/análogos & derivados , Inibição Psicológica , Receptores Adrenérgicos alfa 2/metabolismo , Reflexo Acústico/fisiologia , Reflexo de Sobressalto/fisiologia , Antagonistas Adrenérgicos alfa/farmacocinética , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Tronco Encefálico/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idazoxano/farmacocinética , Oligonucleotídeos Antissenso/farmacologia , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/biossíntese , Ensaio Radioligante/métodos , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/genética , Reflexo Acústico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Trítio/farmacocinéticaRESUMO
The densities of alpha2-adrenergic receptors, labeled by 3H-clonidine or 3H-RX821002, reach a peak in the rat brainstem during the first week of its life. This enables the agonist of alpha2-adrenergic receptor clonidine, which is used as a component of anaesthetic solution in infants and children, to have specific effects in this structure of the developing brain. Clonidine was injected into the fetal brain (5 microg in 5 microl of saline) or subcutaneously to the pups (1, 10 microg in 50 microl of saline) 3 days before investigation. Clonidine increased the level of apoptotic enzyme caspase-3 mRNA expression, as measured by RT-PCR and enhanced the DNA fragmentation, as determined by gel electrophoresis, in the brainstem of the 21-day-old fetuses and 8-day-old rats. In the cortex of 8-day-old rat, the alpha2-adrenergic receptors are at a much lower level than the brainstem. Clonidine treatment had no evident effects on caspase-3 mRNA level and DNA fragmentation in the cortex of an 8-day-old rat. The data suggest that clonidine facilitates cell death in the developing brainstem. This drug effect provides a potential mechanism whereby clonidine during early life could induce long-lasting alterations in brain neurochemistry, autonomic functions and behavior.