Behavioral Effects of Neuropeptide Y

Abstract

Neuropeptide Y (NPY), a 36-amino acid neurotransmitter that is widely distributed throughout the nervous system, antagonizes behavioral consequences of stress/depression and attenuates ethanol-seeking behavior through actions within the brain. The anxiolytic actions of NPY were initially demonstrated by microinjection of exogenous ligands directly into the brain, and then by genetically modified animals. There is also evidence to suggest that altered NPY signaling may contribute to anxiety disorders and depression in humans. NPY reduces anxiety, at least in part, by acting on NPY Y1 receptors in the lateral/ basolateral nuclei of the amygdala. Importantly, NPY is anxiolytic across a wide range of animal models normally thought to reflect different aspects of emotionality and is more potent than other endogenous compounds. Thus, NPY likely acts on a common core mechanism of emotionality and behavioral stress. Recent research—genetic and pharmacological—suggests that NPY is also involved with voluntary ingestion of ethanol. Low levels (or the absence) of NPY promote high ethanol drinking, and enhanced NPY signaling prevents excessive ethanol consumption. Furthermore, brain tissue from alcoholics was found to have abnormally low levels of NPY when compared to control tissue. While the neuroanatomical substrate is unknown, NPY modulates ethanol intake by acting on the NPY Y1 and Y2 receptors. An interesting possibility is that high ethanol-seeking behavior is secondary to high levels of anxiety. Viewed this way, alterations of normal NPY activity may induce emotional disturbance, which in turn becomes a risk factor for alcoholism. Thus, drugs targeting the central NPY system may serve as useful therapeutic agents against stress-related disorders and alcoholism. Based on the current literature, compounds aimed at the Y1 and/or Y2 receptor(s) appear to be promising candidates.