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: 15.98). 10/2006; 51(6):811-22. DOI: 10.1016/j.neuron.2006.09.006
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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.

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    • "Humans and animal studies have demonstrated associations between obesity and impaired reward function but it has not been clear if they are a consequence of the obese state, to what degree they depend on dietary components and if metabolic changes are involved. While genetic components underlying obesity can affect DA signaling and modulate reward sensitivity in humans (Stice and Dagher, 2010; Stice et al, 2008) and rodents (Fulton et al, 2006; Geiger et al, 2009; Shin et al, 2011) several lines of evidence suggest secondary influence of the obese state on reward functions (Davis et al, 2008; Fulton et al, 2006; Geiger et al, 2009; Johnson et al, 2010; Shin et al, 2011). Our results show that a diet rich in saturated fat independent of weight gain and related metabolic changes impairs sensitivity to the rewarding and locomotor effects of AMPH and elicits neuroadaptations in the NAc coincident with reduced D1R signaling. "
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    • "leptin and the remaining do not respond . The reason for these differential effects of leptin on LHA GABAergic neurons is unknown ( Leinninger et al . , 2009 ) . Nevertheless , ablation of leptin receptors from LHA GABAergic neurons that project to the VTA specifically decreases mesolimbic DA release and contributes to the development of obesity ( Fulton et al . , 2006 ; Leinninger et al . , 2009 ) . Feeding peptides can also directly modulate the activity of mesolimbic DA neurons . For example , DA neurons in the VTA express receptors to leptin ( Hommel et al . , 2006 ) , ghrelin , insulin , orexin , melanocortin and GLP - 1 ( Narayanan et al . , 2010 ; Dossat et al . , 2011 ; Dossat et al . , 2013 )"
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    • "Stress-induced dopamine release is also associated with high leptin (Burghardt et al., 2012). Leptin activates dopamine neurons in the VTA of the midbrain reducing dopamine neuronal firing and increases dopamine availability (Fulton et al., 2006; Hommel et al., 2006). Selective deletion of LepRb from midbrain dopamine neurons results in increased anxiety-like behavior, but not depressive-like behavior (Liu et al., 2011). "
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