Countervailing Modulation ofI_hby Neuropeptide Y and Corticotrophin-Releasing Factor in Basolateral Amygdala As a Possible Mechanism for Their Effects on Stress-Related Behaviors

Abstract

Stress and anxiety-related behaviors controlled by the basolateral amygdala (BLA) are regulated in vivo by neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF): NPY produces anxiolytic effects, whereas CRF produces anxiogenic effects. These opposing actions are likely mediated via regulation of excitatory output from the BLA to afferent targets. In these studies, we examined mechanisms underlying the effects of NPY and CRF in the BLA using whole-cell patch-clamp electrophysiology in rat brain slices. NPY, even with tetrodotoxin present, caused a dose-dependent membrane hyperpolarization in BLA pyramidal neurons. The hyperpolarization resulted in the inhibition of pyramidal cells, despite arising from a reduction in a voltage-dependent membrane conductance. The Y1 receptor agonist, F 7P 34 NPY, produced a similar membrane hyperpolarization, whereas the Y1 antagonist, BIBO3304 [(R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N 2-(diphenylacetyl)-argininamide trifluoroacetate], blocked the effect of NPY. The NPY-inhibited current was identified as Ih, which is active at and hyperpolarized to rest. Responses to NPY were occluded by either Cs+ or ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride), but unaffected by the GIRK-preferring blockers Ba 2+ and SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride]. Application of CRF, with or without TTX present, depolarized NPY-sensitive BLA pyramidal neurons, resulting from an increase in Ih. Electrophysiological and immunocytochemical data were consistent with a major role for the HCN1 subunit. Our results indicate that NPY, via Y1 receptors, directly inhibits BLA pyramidal neurons by suppressing a postsynaptic Ih, whereas CRF enhances resting Ih, causing an increased excitability of BLA pyramidal neurons. The opposing actions of these two peptides on the excitability of BLA output cells are consistent with the observed behavioral actions of NPY and CRF in the BLA.

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

“…Furthermore, no significant change in input resistance (MO) was observed after the application of L-P NPY (400 nM) (baseline: 70.6±7.7; L-P NPY (400 nM): 66.6±5.3; wash: 66.1 ± 4.7; F (2,18) ¼ 0.69, P ¼ 0.513; data not shown). Finally, we observed no consistent responses of the resting membrane potential to L-P NPY application (baseline (mean ± SEM, mV): À 60.4 ± 0.16; L-P NPY: À 60.1 ± 0.56; wash: À 61.2 ± 0.6; F (2,18) ¼ 1.5, P ¼ 0.242) that would suggest modulation of HCN channels underlying I h as reported previously (Giesbrecht et al, 2010).…”

“…However, direct effects of GABA rather than evoked GABAergic synaptic responses were measured; thus, a distinction between extrasynaptic and synaptic receptor populations could explain this dichotomy as scaffolding and anchoring proteins (eg AKAPs) would be expected to regulate the nature of signaling between receptors and effectors in synaptic compartments. Giesbrecht et al (2010) previously reported a significant hyperpolarization of membrane potential caused by NPY or the Y 1 R agonist F 7 P 34 NPY. Our data are not necessarily inconsistent with these findings, as their study selected cells based on their membrane potential response, while we included all neurons irrespective of the effect of NPY on membrane potential.…”

“…Regulation of excitability in BLA neurons by Y 1 Rs has been suggested to involve a variety of mechanisms, including enhancing GABA inhibition (Kask et al, 1996), activating Kir3 channels (Sosulina et al, 2008), and increasing I h current (Giesbrecht et al, 2010). However, to our knowledge, the modulation of postsynaptic GABA A receptors by NPY receptor activation has never been directly and systematically studied.…”

“…Recently, Giesbrecht et al (2010) suggested that NPY, acting through the Y 1 R subtype, also inhibits pyramidal neurons in the BLA by suppressing a hyperpolarizationactivated, depolarizing current (I h ). The intracellular mechanisms by which NPY receptor activation in the BLA produces this additional postsynaptic membrane effect are also not well understood.…”

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

“…Furthermore, effort is directed to potential therapeutics, prevention and diagnostics of obesity-related disorders. Many of feeding-related receptor agonists act not only in the hypothalamus but also in extrahypothalamic, telencephalic, mesencephalic and metencephalic areas thereby contributing to the regulation of behavior, as has been confirmed by numerous studies [5,[7][8][9][10][11][12][13][14][15][16][17]. Consequently, rising attention is paid to ligands of feeding-related GPCRs as potential tools for the investigation of their role in behavioral disturbances.…”