Article

Leptin Regulation of the Mesoaccumbens Dopamine Pathway

Department of Medicine and Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Neuron (Impact Factor: 15.05). 10/2006; 51(6):811-22. DOI: 10.1016/j.neuron.2006.09.006
Source: PubMed

ABSTRACT

Leptin is an adipose-derived hormone that acts on hypothalamic leptin receptors to regulate energy balance. Leptin receptors are also expressed in extrahypothalamic sites including the ventral tegmental area (VTA), critical to brain reward circuitry. We report that leptin targets DA and GABA neurons of the VTA, inducing phosphorylation of signal-transducer-and-activator-of-transcription-3 (STAT3). Retrograde tracing combined with pSTAT3 immunohistochemistry show leptin-responsive VTA neurons projecting to nucleus accumbens (NAc). Assessing leptin function in the VTA, we showed that ob/ob mice had diminished locomotor response to amphetamine and lacked locomotor sensitization to repeated amphetamine injections, both defects reversed by leptin infusion. Electrically stimulated DA release from NAc shell terminals was markedly reduced in ob/ob slice preparations, and NAc DA levels and TH expression were lower. These data define a role for leptin in mesoaccumbens DA signaling and indicate that the mesoaccumbens DA pathway, critical to integrating motivated behavior, responds to this adipose-derived signal.

Download full-text

Full-text

Available from: Emmanuel N Pothos
  • Source
    • "Por example, in thè VTA, orexin neurons coming from thè LH adivate dopaminergic neurons, enhance dopamine signaling in thè NAc, and increase intake of palatable food (Narita et al., 2006; Zheng et al., 2007). Leptin directly hyperpolarizes VTA dopaminergic neurons, plays an important role in regulating dopamine levels in thè NAc, and suppresses thè incentive value of food and other rewards (Figlewicz et al., 2006; Fulton et al., 2006; Hommel et al., 2006). Moreover, NPY can act on NPY receptors on VTA dopaminergic neurons to increase dopamine release in thè NAc and regulate food-motivated behavior (Jewett et al., 1995; Korotkova et al., 2006; Tracy et al., 2008). "

    Full-text · Chapter · Dec 2015
  • Source
    • "This couldDownloaded from be due to incomplete deletion in the VTA of mice injected with AAV-Cre-GFP and/or the contribution of LepRb outside the VTA in conditional LepRb knockout mice. JAK2/STAT3 is a major signaling pathway stimulated by leptin in the VTA (Fulton et al., 2006;Hommel et al., 2006;Morton et al., 2009;Liu et al., 2011). To explore the molecular mechanisms underlying leptin action on anxiety, we examined the influence of the pretreatment with the JAK2/STAT3 inhibitor AG-490 in the VTA on systemic leptin injection-induced anxiolytic effects. "

    Preview · Article · Oct 2015 · The International Journal of Neuropsychopharmacology
  • Source
    • "As obese individuals commonly exhibit increased serum levels of leptin, hyperphagia in obesity is attributed to insensitivity to circulating leptin and disruption of leptin signalling in the hypothalamus (El-Haschimi et al., 2000;Munzberg et al., 2004;Enriori et al., 2007). Leptin also binds to specific leptin receptors (ObR) on dopaminergic neurons in the VTA, inhibiting dopamine signalling in the NAc (Figlewicz et al., 2003;Hommel et al., 2006;Trinko et al., 2011) and the central nucleus of the amygdala (Leshan et al., 2010), providing a regulatory link between energy homeostasis and reward-related behavior (Fulton et al., 2006). Although leptin acts as a satiety signal (Trinko et al., 2011;Kanoski et al., 2012), it has also been shown that intraventricular leptin reduces the self-administration of sucrose (Figlewicz et al., 2006;Hommel et al., 2006) and decreased the rewarding effects of drugs of abuse such as opioids (Lim et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the neurobiological substrates that encode learning about food-associated cues and how those signals are modulated is of great clinical importance especially in light of the worldwide obesity problem. Inappropriate or maladaptive responses to food-associated cues can promote over consumption, leading to excessive energy intake and weight gain. Chronic exposure to foods rich in fat and sugar alters the reinforcing value of foods and weakens inhibitory neural control, triggering learned, but maladaptive, associations between environmental cues and food rewards. Thus, responses to food-associated cues can promote cravings and food-seeking by activating mesocorticolimbic dopamine neurocircuitry, and exert physiological effects including salivation. These responses may be analogous to the cravings experienced by abstaining drug addicts that can trigger relapse into drug self-administration. Preventing cue-triggered eating may therefore reduce the over consumption seen in obesity and binge eating disorder. In this review we discuss recent research examining how cues associated with palatable foods can promote reward-based feeding behaviors and the potential involvement of appetite-regulating peptides including leptin, ghrelin, orexin and melanin concentrating hormone. These peptide signals interface with mesolimbic dopaminergic regions including the ventral tegmental area to modulate reactivity to cues associated with palatable foods. Thus, a novel target for anti-obesity therapeutics is to reduce non-homeostatic, reward driven eating behavior, which can be triggered by environmental cues associated with highly palatable, fat and sugar rich foods. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2015 · British Journal of Pharmacology
Show more