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      Galanin-induced decreases in nucleus accumbens/striatum excitatory postsynaptic potentials and morphine conditioned place preference require both galanin receptor 1 and galanin receptor 2

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          Abstract

          The neuropeptide galanin has been shown to alter the rewarding properties of morphine. To identify potential cellular mechanisms that might be involved in the ability of galanin to modulate opiate reward, we measured excitatory postsynaptic potentials (EPSPs), using both field and whole-cell recordings from striatal brain slices extracted from wild-type mice and mice lacking specific galanin receptor (GalR) subtypes. We found that galanin decreased the amplitude of EPSPs in both the dorsal striatum and nucleus accumbens. We then performed recordings in slices from knockout mice lacking either the GalR1 or GalR2 gene, and found that the ability of galanin to decrease EPSP amplitude was absent from both mouse lines, suggesting that both receptor subtypes are required for this effect. In order to determine whether behavioral responses to opiates were dependent on the same receptor subtypes, we tested GalR1 and GalR2 knockout mice for morphine conditioned place preference (CPP). Morphine CPP was significantly attenuated in both GalR1 and GalR2 knockout mice. These data suggest that mesolimbic excitatory signaling is significantly modulated by galanin in a GalR1-dependent and GalR2-dependent manner, and that morphine CPP is dependent on the same receptor subtypes.

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          Most cited references49

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          Major increases in opioid analgesic abuse in the United States: concerns and strategies.

          The problem of abuse of and addiction to opioid analgesics has emerged as a major issue for the United States in the past decade and has worsened over the past few years. The increases in abuse of these opioids appear to reflect, in part, changes in medication prescribing practices, changes in drug formulations as well as relatively easy access via the internet. Though the use of opioid analgesics for the treatment of acute pain appears to be generally benign, long-term administration of opioids has been associated with clinically meaningful rates of abuse or addiction. Important areas of research to help with the problem of opioid analgesic abuse include the identification of clinical practices that minimize the risks of addiction, the development of guidelines for early detection and management of addiction, the development of opioid analgesics that minimize the risks for abuse, and the development of safe and effective non-opioid analgesics. With high rates of abuse of opiate analgesics among teenagers in the United States, a particularly urgent priority is the investigation of best practices for treating pain in adolescents as well as the development of prevention strategies to reduce diversion and abuse.
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            Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis.

            The nucleus accumbens (NAc) is a critical element of the mesocorticolimbic system, a brain circuit implicated in reward and motivation. This basal forebrain structure receives dopamine (DA) input from the ventral tegmental area (VTA) and glutamate (GLU) input from regions including the prefrontal cortex (PFC), amygdala (AMG), and hippocampus (HIP). As such, it integrates inputs from limbic and cortical regions, linking motivation with action. The NAc has a well-established role in mediating the rewarding effects of drugs of abuse and natural rewards such as food and sexual behavior. However, accumulating pharmacological, molecular, and electrophysiological evidence has raised the possibility that it also plays an important (and sometimes underappreciated) role in mediating aversive states. Here we review evidence that rewarding and aversive states are encoded in the activity of NAc medium spiny GABAergic neurons, which account for the vast majority of the neurons in this region. While admittedly simple, this working hypothesis is testable using combinations of available and emerging technologies, including electrophysiology, genetic engineering, and functional brain imaging. A deeper understanding of the basic neurobiology of mood states will facilitate the development of well-tolerated medications that treat and prevent addiction and other conditions (e.g., mood disorders) associated with dysregulation of brain motivation systems.
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              The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease.

              The galanin peptide family consists of the "parental" galanin, galanin-message-associated peptide (GMAP) which derives from the same peptide precursor gene product as galanin, galanin-like peptide (GALP) encoded by a different gene, and the recently discovered peptide alarin which is encoded by a splice variant of the GALP gene. The galanin receptor family currently comprises 3 members, GalR1, GalR2, and GalR3, which are all G-protein-coupled receptors. This review will provide an overview of the comprehensive, pharmacological characterization of endogenous and synthetic galanin receptor ligands and their interactions with the galanin receptors, a summary of the various (pleiotropic) biological actions of galanin and GALP (and alarin), and briefly discuss the implications of pathological changes for health and disease and potential clinical therapeutics. Since its discovery more than 20 years ago, a large number of putative physiological functions have been ascribed to galanin, and active research still continues to validate these functions and determine their importance for physiology and pathology. Since the more recent identification of GALP, considerable research has identified functions for this peptide in the central nervous system (CNS), but the identity of its preferred, native receptor is still unknown. Little is known of the role of alarin apart from evidence of its expression and a vasoactive action in the skin. The wide range of functions of the galanin peptide family indicates an essential role for galanin signaling in "mind and body homeostasis" and a potential therapeutic efficacy in a variety of human diseases, particularly epilepsy, Alzheimer's disease, and diabetes.
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                Author and article information

                Journal
                European Journal of Neuroscience
                Eur J Neurosci
                Wiley
                0953816X
                May 2013
                May 2013
                February 07 2013
                : 37
                : 9
                : 1541-1549
                Affiliations
                [1 ]Division of Molecular Psychiatry; Department of Psychiatry; Yale University School of Medicine; 34 Park Street - 3rd floor research; New Haven; CT; 06508; USA
                [2 ]Department of Neurobiology; Yale University School of Medicine; New Haven; CT; USA
                Article
                10.1111/ejn.12151
                3648588
                23387435
                2f5869c1-fecf-4d38-b9ea-038106fba9b9
                © 2013

                http://doi.wiley.com/10.1002/tdm_license_1.1

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