VTA mTOR Signaling Regulates Dopamine Dynamics, Cocaine-Induced Synaptic Alterations, and Reward. Neuropsychopharmacology 2018 Apr;43(5):1066-1077
Date
10/19/2017Pubmed ID
29039413Pubmed Central ID
PMC5854804DOI
10.1038/npp.2017.247Scopus ID
2-s2.0-85043756812 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
Mechanistic target of rapamycin (mTOR) regulates long-term synaptic plasticity, learning, and memory by controlling dendritic protein synthesis. The mTOR inhibitor rapamycin has been shown to attenuate the behavioral effects of drugs of abuse, including cocaine. Using viral vectors to selectively delete mTOR in the ventral tegmental area (VTA) in adult male mTORloxP/loxP mice, we investigated the role of mTOR in regulating neuronal morphology, basal synaptic transmission, dopamine dynamics, and cocaine-induced synaptic plasticity and rewarding effects. We find that targeted deletion of mTOR in the VTA had no significant effects on soma size and dendritic morphology of VTA neurons but significantly decreased dopamine release and reuptake in the nucleus accumbens (NAc) shell, a major target region. Western blot analysis revealed that mTOR deletion led to decreases in phosphorylated tyrosine hydroxylase (pTH-Ser40) levels in the VTA and dopamine transporter expression in the NAc. mTOR deletion had no significant effects on basal excitatory transmission in VTA dopamine neurons but caused an increase in GABAergic inhibition because of an increase in VTA GABAergic neuron firing. Furthermore, mTOR deletion attenuated conditioned place preference to cocaine and cocaine-induced potentiation of excitation and reduction of GABAergic inhibition in VTA dopamine neurons. Taken together, these results suggest that loss of mTOR in the VTA shifts the balance of excitatory and inhibitory synaptic transmission and decreases dopamine release and reuptake in the NAc. In addition, VTA mTOR signaling regulates cocaine-cue associative learning and cocaine-induced synaptic plasticity in VTA dopamine neurons.
Author List
Liu X, Li Y, Yu L, Vickstrom CR, Liu QSAuthor
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAssociation Learning
Cocaine
Dopamine
Dopamine Plasma Membrane Transport Proteins
GABAergic Neurons
Male
Mice
Mice, Knockout
Microinjections
Neuronal Plasticity
Neurons
Nucleus Accumbens
Reward
Synapses
Synaptic Transmission
TOR Serine-Threonine Kinases
Tyrosine 3-Monooxygenase
Ventral Tegmental Area