Leptin regulation of the mesoaccumbens dopamine pathway.
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.
Fulton
Stephanie
S
Department of Medicine and Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Pissios
Pavlos
P
Manchon
Ramon Pinol
RP
Stiles
Linsey
L
Frank
Lauren
L
Pothos
Emmanuel N
EN
Maratos-Flier
Eleftheria
E
Flier
Jeffrey S
JS
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D007150:Immunohistochemistry / Q000379:methods; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000697:Central Nervous System Stimulants; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C515447:leptin receptor, mouse; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine