ausblenden:
Schlagwörter:
anxiety, basolateral amygdala, fear, paravetricular nucleus, promoter fragmentation
Zusammenfassung:
Neuropeptide S (NPS) has generated substantial interest due to its
anxiolytic and fear-attenuating effects in rodents, while a
corresponding receptor polymorphism associated with increased NPS
receptor (NPSR1) surface expression and efficacy has been implicated in
an increased risk of panic disorder in humans. To gain insight into this
paradox, we examined the NPS system in rats and mice bred for high
anxiety-related behavior (HAB) versus low anxiety-related behavior, and,
thereafter, determined the effect of central NPS administration on
anxiety- and fear-related behavior. The HAB phenotype was accompanied by
lower basal NPS receptor (Npsr1) expression, which we could confirm via
in vitro dual luciferase promoter assays. Assessment of shorter Npsr1
promoter constructs containing a sequence mutation that introduces a
glucocorticoid receptor transcription factor binding site, confirmed via
oligonucleotide pull-down assays, revealed increased HAB promoter
activity-an effect that was prevented by dexamethasone. Analogous to the
human NPSR1 risk isoform, functional analysis of a synonymous single
nucleotide polymorphism in the coding region of HAB rodents revealed
that it caused a higher cAMP response to NPS stimulation. Assessment of
the behavioral consequence of these differences revealed that
intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as
well as the impaired cued-fear extinction in HAB rats and the enhanced
fear expression in HAB mice, respectively. These results suggest that
alterations in the NPS system, conserved across rodents and humans,
contribute to innate anxiety and fear, and that HAB rodents are
particularly suited to resolve the apparent discrepancy between the
preclinical and clinical findings to date.
