Neuropeptide S receptor gene variation modulates glutamatergic anterior cingulate cortex activity during CCK-4 induced panic

Abstract

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S(NPS)system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time x genotype interaction was detected (p = .008), with significantly lower anterior cingulate Glx/Cr levels in T allele carriers as compared to AA homozygotes 5 minutes after injection (p = .003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate glutamatergic activity in the ACC during acute states of stress and anxiety, with blunted, i. e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers.