Ventral tegmental area neurotensin signaling links the lateral hypothalamus to locomotor activity and striatal dopamine efflux in male mice.
Projections from the lateral hypothalamic area (LHA) innervate components of the mesolimbic dopamine (MLDA) system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), to modulate motivation appropriately for physiologic state. Neurotensin (NT)-containing LHA neurons respond to multiple homeostatic challenges and project to the VTA, suggesting that these neurons could link such signals to MLDA function. Indeed, we found that pharmacogenetic activation of LHA NT neurons promoted prolonged DA-dependent locomotor activity and NAc DA efflux, suggesting the importance of VTA neurotransmitter release by LHA NT neurons for the control of MLDA function. Using a microdialysis-mass spectrometry technique that we developed to detect endogenous NT in extracellular fluid in the mouse brain, we found that activation of LHA NT cells acutely increased the extracellular concentration of NT (a known activator of VTA DA cells) in the VTA. In contrast to the prolonged elevation of extracellular NAc DA, however, VTA NT concentrations rapidly returned to baseline. Intra-VTA infusion of NT receptor antagonist abrogated the ability of LHA NT cells to increase extracellular DA in the NAc, demonstrating that VTA NT promotes NAc DA release. Thus, transient LHA-derived NT release in the VTA couples LHA signaling to prolonged changes in DA efflux and MLDA function.
Division of Metabolism, Endocrinology and Diabetes (C.M.P., G.M.L., C.L.K., I.E.G., A.M., J.C.J., M.G.M.), Department of Internal Medicine and Departments of Chemistry (J.-M.T.W., O.S.M., R.T.K.) and Molecular and Integrative Physiology (M.B.A., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109-1055.
Christa M
CM
Patterson
Jenny-Marie T
JM
Wong
Gina M
GM
Leinninger
Margaret B
MB
Allison
Omar S
OS
Mabrouk
Chelsea L
CL
Kasper
Ian E
IE
Gonzalez
Alexander
A
Mackenzie
Justin C
JC
Jones
Robert T
RT
Kennedy
Martin G
MG
Myers
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity; D017072:Neostriatum / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009496:Neurotensin / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000378:metabolism*; D015398:Signal Transduction; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism*
D009496:Neurotensin; D004298:Dopamine