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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    • "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). "

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    • "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. "

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    • "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). "
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