Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.
Dopamine neurons in the ventral tegmental area (VTA) play an important role in the motivational systems underlying drug addiction, and recent work has suggested that they also release the excitatory neurotransmitter glutamate. To assess a physiological role for glutamate corelease, we disrupted the expression of vesicular glutamate transporter 2 selectively in dopamine neurons. The conditional knockout abolishes glutamate release from midbrain dopamine neurons in culture and severely reduces their excitatory synaptic output in mesoaccumbens slices. Baseline motor behavior is not affected, but stimulation of locomotor activity by cocaine is impaired, apparently through a selective reduction of dopamine stores in the projection of VTA neurons to ventral striatum. Glutamate co-entry promotes monoamine storage by increasing the pH gradient that drives vesicular monoamine transport. Remarkably, low concentrations of glutamate acidify synaptic vesicles more slowly but to a greater extent than equimolar Cl(-), indicating a distinct, presynaptic mechanism to regulate quantal size.
Hnasko
Thomas S
TS
Departments of Physiology and Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Chuhma
Nao
N
Zhang
Hui
H
Goh
Germaine Y
GY
Sulzer
David
D
Palmiter
Richard D
RD
Rayport
Stephen
S
Edwards
Robert H
RH
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002395:Catecholamines / Q000378:metabolism; D002461:Cell Line, Transformed; D002712:Chlorides / Q000494:pharmacology; D002794:Choline / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000502:physiology*
D002395:Catecholamines; D002712:Chlorides; D018765:Dopamine Uptake Inhibitors; D008164:Luminescent Proteins; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D012701:Serotonin; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D002794:Choline; D004298:Dopamine