Neuropeptide-Y alters VTA dopamine neuron activity through both pre- and postsynaptic mechanisms

Abstract

The mesocorticolimbic dopamine system, the brain's reward system, regulates many different behaviors including food intake, food reward, and feeding-related behaviors, and there is increasing evidence that hypothalamic feeding-related neuropeptides alter dopamine neuron activity to affect feeding. For example, neuropeptide-Y (NPY), a strong orexigenic hypothalamic neuropeptide, increases motivation for food when injected into the ventral tegmental area (VTA). How NPY affects the activity of VTA dopamine neurons to regulate feeding behavior is unknown, however. In these studies we have used whole cell patch-clamp electrophysiology in acute brain slices from mice to examine how NPY affects VTA dopamine neuron activity. NPY activated an outward current that exhibited characteristics of a G protein-coupled inwardly rectifying potassium channel current in ~60% of dopamine neurons tested. In addition to its direct effects on VTA dopamine neurons, NPY also decreased the amplitude and increased paired-pulse ratios of evoked excitatory postsynaptic currents in a subset of dopamine neurons, suggesting that NPY decreases glutamatergic transmission through a presynaptic mechanism. Interestingly, NPY also strongly inhibited evoked inhibitory postsynaptic currents onto dopamine neurons by a presynaptic mechanism. Overall these studies demonstrate that NPY utilizes multiple mechanisms to affect VTA dopamine neuron activity, and they provide an important advancement in our understanding of how NPY acts in the VTA to control feeding behavior. Neuropeptide-Y (NPY) has been shown to act on mesolimbic dopamine circuits to increase motivated behaviors toward food, but it is unclear exactly how NPY causes these responses. Here, we demonstrate that NPY directly inhibited a subset of ventral tegmental area (VTA) dopamine neurons through the activation of G protein-coupled inwardly rectifying potassium currents, and it inhibited both excitatory postsynaptic currents and inhibitory postsynaptic currents onto subsets of dopamine neurons through a presynaptic mechanism. Thus NPY uses multiple mechanisms to dynamically control VTA dopamine neuron activity.

Complex patterns of dopamine‐related gene expression in the ventral tegmental area of male zebra finches relate to dyadic interactions with long‐term female partners

“…These include genes for the well‐studied modulators of VTA dopaminergic neuronal activity, glutamate and GABA, as well as numerous candidate genes related to neuromodulators that are reported to modify VTA dopaminergic neuronal activity either directly or indirectly (eg, by influencing GABAergic neuronal activity). These candidates include genes related to histamine, melanocortin, melatonin and serotonin …”

Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes

“…Neurons containing leptin receptors in the lateral hypothalamic area mediate leptin action on the mesolimbic system and contribute to the control of energy balance (Leinninger et al, 2011). Similarly, NPY acts on mesolimbic dopamine circuits to increase motivated behaviors toward food (West and Roseberry, 2017). In addition, the use of psychotropic medications, which have well-documented effects on the dopamine system, have also been reported to affect peripheral and central glucose/insulin metabolism, both directly through actions on glucose and insulin pathways and indirectly through behavioral/lifestyle effects (e.g.…”

Alpha‐melanocyte stimulating hormone increases the activity of melanocortin‐3 receptor‐expressing neurons in the ventral tegmental area

“…Acute brain slices were prepared in a manner similar to that described previously (Roseberry et al . ; Stuhrman & Roseberry, ; West & Roseberry, ). Briefly, adult mice were anaesthetized with isofluorane and decapitated.…”