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


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.

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Available from: Emmanuel N Pothos, Sep 30, 2015
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    • "Receptors for 5-HT, leptin, or ghrelin are also found in extra-arcuate (ARC) targets, including pontine, brainstem, and midbrain structures. Although the direct access of circulating hormones such as ghrelin or leptin to these structures lying away from the blood brain barrier (BBB) entry point is still a matter of debate, injection of these hormones into the ventral tegmental area (VTA) or parabrachial nucleus (PBN) can inhibit feeding (Abizaid et al., 2006; Figlewicz et al., 2003; Fulton et al., 2006; Hommel et al., 2006; Jerlhag et al., 2007; Lee et al., 1998; Naleid et al., 2005; Quarta et al., 2009; Zigman et al., 2006). These observations raise the question of the specific contribution of ARC versus extra-ARC neurons in the balance between reward-driven or energy-driven nutrient intake. "
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    ABSTRACT: Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake-a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 08/2015; DOI:10.1016/j.cmet.2015.07.011 · 17.57 Impact Factor
    • "This system is responsive not only to a variety of glutamatergic inputs from local (Dobi et al, 2010) and distal (Geisler et al, 2007) neuronal sources, but also to a number of state variables mediated by blood-borne factors including leptin (Figlewicz et al, 2003; Krugel et al, 2003; Hommel et al, 2006; Liu et al, 2011; Thompson and Borgland, 2013). Leptin is an endogenous inhibitor of food reward (Figlewicz et al, 2007; Domingos et al, 2011) that has both direct (Fulton et al, 2006a; Krugel et al, 2003; Leinninger et al, 2009; Davis et al, 2011; Domingos et al, 2011) and indirect (Leinninger et al, 2009) effects on brain reward function and that is depressed in heroin addicts (Housová et al, 2005) and fluctuates abnormally during craving for alcohol (Kiefer et al, 2005) or nicotine (al'Absi et al, 2011). "
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    ABSTRACT: Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats: First, we report that cocaine and the expectancy of cocaine each depress plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates (i) the ability of cocaine to elevate dopamine levels in nucleus accumbens (ii) the ability of cocaine to establish a conditioned place preference, and (iii) the ability of cocaine-predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus while leptin represents an endogenous antagonist of the habit-forming and habit-sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine.Neuropsychopharmacology accepted article preview online, 05 August 2015. doi:10.1038/npp.2015.230.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2015; DOI:10.1038/npp.2015.230 · 7.05 Impact Factor
    • "Metabolic status has long been known to modulate the response to drugs of abuse (Carr, 2007). More recently it was established that peripherally derived hormones such as leptin and insulin, the levels of which are largely regulated by caloric load and diet composition, target the VTA to affect reward-relevant behaviors and psychostimulant action (Abizaid et al, 2006; Fulton et al, 2006; Labouebe et al, 2013). Though study of the interaction between metabolic hormones and DA-dependent behavior and signaling has received considerable attention, little is known about how dietary lipids affect mesolimbic function apart from major metabolic changes associated with weight gain. "
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    ABSTRACT: Over consumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared to low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain and plasma levels of leptin, insulin and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes.Neuropsychopharmacology accepted article preview online,
    Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.207 · 7.05 Impact Factor
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