NPY Y2 receptors in the central amygdala reduce cued but not contextual fear

• Published in: Neuropharmacology 2015-12, Vol.99, p.665-674
• Main Authors: Verma, D., Wood, J., Lach, G., Mietzsch, M., Weger, S., Heilbronn, R., Herzog, H., Bonaventure, P., Sperk, G., Tasan, R.O.
• Format: Article
• Language: English
• Subjects: Amygdala; Animals; Benzamides - administration & dosage; Central Amygdaloid Nucleus - drug effects; Central Amygdaloid Nucleus - metabolism; Central Nervous System Agents - administration & dosage; Cues; Dependovirus - genetics; Extinction, Psychological - drug effects; Extinction, Psychological - physiology; Fear - drug effects; Fear - physiology; Fear conditioning; Fear extinction; Genetic Vectors; Male; Mental Recall - drug effects; Mental Recall - physiology; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y - administration & dosage; Neuropeptide Y - genetics; Neuropeptide Y - metabolism; Neuropsychological Tests; NPY; Peptide Fragments - administration & dosage; Peptide Fragments - genetics; Peptide Fragments - metabolism; Piperazines - administration & dosage; Receptors, Neuropeptide Y - agonists; Receptors, Neuropeptide Y - antagonists & inhibitors; Receptors, Neuropeptide Y - genetics; Receptors, Neuropeptide Y - metabolism; Viral vectors; Y2 receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.08.038

The amygdala is fundamental for associative fear and extinction learning. Recently, also the central nucleus of the amygdala (CEA) has emerged as a site of plasticity actively controlling efferent connections to downstream effector brain areas. Although synaptic transmission is primarily mediated by glutamate and GABA, neuropeptides critically influence the overall response. While neuropeptide Y (NPY) acting via postsynaptic Y1 receptors exerts an important anxiolytic and fear-reducing action, the role of the predominantly presynaptic Y2 receptors is less defined. To investigate the role of Y2 receptors in the CEA we employed viral-vector mediated over-expression of the Y2 selective agonist NPY3-36 in fear conditioning and extinction experiments. NPY3-36 over-expression in the CEA resulted in reduced fear expression during fear acquisition and recall. Interestingly, this effect was blocked by intraperitoneal injection of a brain-penetrant Y2 receptor antagonist. Furthermore, over-expression of NPY3-36 in the CEA also reduced fear expression during fear extinction of CS-induced but not context-related fear. Again, fear extinction appeared delayed by peripheral injection of a Y2 receptor antagonist JNJ-31020028. Importantly, mice with over-expression of NPY3-36 in the CEA also displayed reduced spontaneous recovery and reinstatement, suggesting that Y2 receptor activation supports a permanent suppression of fear. Local deletion of Y2 receptors in the CEA, on the other hand, increased the expression of CS-induced freezing during fear recall and fear extinction. Thus, NPY inhibits fear learning and promotes cued extinction by reducing fear expression also via activation of presynaptic Y2 receptors on CEA neurons. •Neuropeptide Y plays an important role in modulating emotional-affective behavior.•The central extended amygdala is crucially involved in the modulation of fear behavior.•Viral-vector mediated over-expression of a NPY Y2 receptor agonist in the central amygdala reduces fear expression.•Y2 receptor antagonists increase fear expression and antagonize long-term fear suppression.•Local deletion of Y2 receptors in the central amygdala increases fear expression.