Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides.
The function of neuropeptide Y, one of the most abundant peptide transmitters of the mammalian brain, remains unclear because of a lack of specific receptor antagonists. An antisense oligodeoxynucleotide corresponding to the NH2-terminus of the rat Y1 receptor was constructed and added to cultures of rat cortical neurons. This treatment resulted in a reduced density of Y1 (but not Y2) receptors and diminished the decrease in adenosine 3',5'-monophosphate (cAMP) usually seen after Y1 receptor activation. Repeated injection of the same oligodeoxynucleotide into the lateral cerebral ventricle of rats was followed by a similar reduction of cortical Y1 (but not Y2) receptors. Such antisense-treated animals displayed behavioral signs of anxiety. Thus, specific inhibition of neurotransmitter receptor expression can be accomplished in the living brain and demonstrates that altered central neuropeptide Y transmission produces an anxiety-like state.
Wahlestedt
C
C
Department of Neurology and Neuroscience, Cornell University Medical College, New York, NY 10021.
Pich
E M
EM
Koob
G F
GF
Yee
F
F
Heilig
M
M
D000818:Animals; D001007:Anxiety; D001483:Base Sequence; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian; D007858:Learning; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009478:Neuropeptide Y / Q000502:physiology*; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism
D009478:Neuropeptide Y; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D017476:Receptors, Neuropeptide Y; D000242:Cyclic AMP