Modulation of Anxiety and Neuropeptide Y-Y1 Receptors by Antisense Oligodeoxynucleotides

TLDR

Neuropeptide Y’s role in the brain is poorly understood due to a lack of specific receptor antagonists. The authors created an antisense oligodeoxynucleotide targeting the NH₂‑terminus of the rat Y1 receptor and applied it both in cortical neuron cultures and via repeated lateral ventricle injections, selectively reducing cortical Y1 receptor density. The antisense treatment lowered Y1 receptor density, blunted the usual cAMP decrease after Y1 activation, and induced anxiety‑like behavior, showing that targeted Y1 inhibition can provoke an anxiety state.

Abstract

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 NH 2 -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.