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COMMENTARY Neuropeptide Y Pathways in Anxiety-Related Disorders Yvan Dumont and Rémi Quirion A nxiety reflects a state of cognitive and behavioral pre- paredness that an organism mobilizes in response to a potential threat. Anxiety can be conceptualized as having two components: state and trait. Trait anxiety refers to an individual’s personality and predisposition for anxiety, whereas state anxiety refers to the emotional response generated by a perceived threat. Traditional research in anxiety in humans and animal models have focused on understanding neurologic deficits in individuals with the pathologic anxiety conditions including panic disorder, posttraumatic stress disorder, general- ized anxiety disorder, social anxiety disorder, agoraphobia, obsessive-compulsive disorder, and specific phobias (1). More recently, specific studies have attempted to evaluate key compo- nents that could explain why some individuals do not develop psychopathology when exposed to trauma and other risk factors of anxiety or depression while others do (1). Multiple studies, including the studies reported in this issue of Biological Psychiatry, have consistently demonstrated that neuro- peptide Y (NPY) can act as an endogenous anxiolytic. Genetic and pharmacologic experiments suggested that in addition to the NPY Y1 and Y2 receptors, the Y4 and Y5 subtypes could have significant roles in anxiety-related behaviors (1). Additionally, NPY and its receptors are enriched in brain regions believed to be implicated in anxiety. Hypothalamic and amygdalar NPY and NPY receptors are differentially expressed in stress-resilient and stress-susceptible rodents. Elevated NPY messenger RNA and iodine-125 peptide YY binding sites were observed in stress-resilient compared with stress- susceptible animals, and animals that displayed higher levels of anxiety showed greater memory impairments (2). Using a nonhu- man primate model of anxious temperament, Roseboom et al. (3) have identified NPY-related mechanisms possibly underlying the development of early life anxiety. Their results suggest that higher levels of Y1 and Y5 receptors in the central nucleus of the amygdala (CeA) are associated with reduced anxiety-related behaviors. Animals with higher levels of Y1 and Y5 receptor mRNA in the CeA were also characterized by increased metabolism in the right dorsolateral prefrontal cortex and dorsal prefrontal cortex, respectively. Similar studies using genetic manipulation of the NPY system in various amygdaloid nuclei could provide additional information about the NPY-related neuronal circuitry involved and establish the specific role of Y1 and Y5 receptors in reducing anxious behaviors and promoting stress resilience. The amygdaloid body is composed of functionally and anatomically distinct subnuclei such as the basolateral amygdala (BLA) and the CeA. Selective manipulation of these various subnuclei using genetic strategies and optogenetics has demon- strated their interconnectivity and distinct roles in controlling various anxiety-related behaviors. The BLA is primarily composed of two neuronal cell types—glutamatergic pyramidal projection neurons and GABAergic interneurons. It has been shown that 75%–90% of neurons expressing Y1 receptors were glutamatergic calcineurin immunopositive cells, whereas only 10% were found to be expressed in GABAergic interneurons (4). It is also known that Y1 receptors are enriched in the CeA, whereas both Y1-immunoreactive and Y5-immunoreactive cells and fibers are present in the BLA (5). A conditional inactivation of Y1 receptors restricted to gluta- mate neurons (Y1R rfb ) generated mice displaying increased anxiety, reduced body weight, decreased amounts of adipose tissue, lowered serum leptin levels, and higher corticosterone levels (6). Using a similar approach but targeting a different neuronal circuitry, Longo et al. (7) report that the deletion of Y1 receptors in Y5 receptor–containing neurons (Y1R Y5R / ) pro- duced mice with some similarities but also major differences compared with the earlier models. Although increased anxiety was observed in both models, increased hypothalamic-pituitary- adrenal axis activity and decreased body weight were not observed in Y1R Y5R / mice. The phenotype observed in Y1R Y5R / mice was independent of gender and maternal care, in contrast to the Y1R rfb mice. Improved spatial reference memory was noted in Y1R Y5R / mice, confirming the possible role of Y1 receptors in learning and memory (8). The Y1 and Y5 receptor genes are located on the same chromosome with the Y5 gene being transcribed in opposite direction to the Y1 gene from a common promoter region. Although Y5 receptors are usually observed in brain regions expressing the Y1 subtype, the reverse is not true (5). It has been shown that Y1 receptors are mainly expressed in glutamatergic neurons in the BLA (4). Longo et al. (7) reported that 50% of neurons that expressed both Y1 and Y5 receptors are GABAergic neurons, whereas only 25% are glutamatergic neurons. It is likely that NPY, acting on different receptor subtypes, activates distinct neuronal circuits to regulate anxiety-related behaviors. What about a role for other NPY receptor subtypes in stress and anxiety? On one hand, the conditional deletion of the Y2 gene in the BLA and CeA generated an anxiolytic-like phenotype (1). On the other hand, mice lacking Y2 receptors specifically in GABAergic neurons (VGAT-Y2R knockout) had decreased Y2 receptor levels in CeA, without altering anxiety-like behavior, suggesting that the anxiogenic effects of Y2 receptor activation involved non-GABAergic neurons (9). At the present time, limited information is available on Y4 receptors except that total Y4 knockout mice appeared to display an anxiolytic phenotype (1). Studies using conditional knockout models are required to demonstrate further the roles of the Y2 and Y4 receptors in anxiety-related behaviors. Finally, taking into account the two studies reported here as well as others, what about the potential clinical uses of NPY- related molecules for the treatment of anxious behaviors? Most human trials so far have focused on the potential usefulness of central nervous system–acting NPY antagonists (Y1 and Y5) in the treatment of obesity (10). Results have been disappointing possibly secondary to poor bioavailability or pharmacokinetics Address correspondence to Yvan Dumont, Ph.D., Douglas Institute Research Centre, 6875 LaSalle Boulevard, Montreal, QC, Canada, H4H 1R3; E-mail: [email protected]. From the Douglas Mental Health University Institute (YD, RQ), and Depart- ment of Psychiatry (RQ), McGill University, Montreal, Quebec, Canada. Received and accepted Sep 23, 2014. 0006-3223/$36.00 BIOL PSYCHIATRY 2014;76:834–835 http://dx.doi.org/10.1016/j.biopsych.2014.09.015 & 2014 Society of Biological Psychiatry
