title: Subsecond Regulation of Synaptically Released Dopamine by COMT in the Olfactory Bulb.
abstract: The efficacy of neurotransmission depends on multiple factors, including presynaptic vesicular release of transmitter, postsynaptic receptor populations and clearance/inactivation of the transmitter. In the olfactory bulb (OB), short axon cells (SACs) form an interglomerular circuit that uses GABA and dopamine (DA) as cotransmitters. Selective optical activation of SACs causes GABA and DA co-release, resulting in a fast, postsynaptic GABA inhibitory response and a slower G-protein-coupled DA rebound excitation. In most systems, vesicular release of DA is cleared by the dopamine transporter (DAT). However, in the OB, high levels of specific DA metabolites suggest that enzymatic catalysis by catechol-O-methyl-transferase (COMT) predominates over DAT re-uptake. To assess this possibility we measured the amount of the DA breakdown enzyme, COMT, present in the OB. Compared with the striatum, the brain structure richest in DA terminals, the OB contains 50% more COMT per unit of tissue. Furthermore, the OB has dramatically less DAT compared with striatum, supporting the idea that COMT enzymatic breakdown, rather than DAT recycling, is the predominant mechanism for DA clearance. To functionally assess COMT inactivation of vesicular release of DA we used fast-scan cyclic voltammetry and pharmacological blockade of COMT. In mice expressing ChR2 in tyrosine hydroxylase-containing neurons, optical activation of SACs evoked robust DA release in the glomerular layer. The COMT inhibitor, tolcapone, increased the DA signal ∼2-fold, whereas the DAT inhibitor GBR12909 had no effect. Together, these data indicate that the OB preferentially employs COMT enzymatic inactivation of vesicular release of DA.
  
  
  
  In the olfactory bulb (OB), odors are encoded by glomerular activation patterns. Dopaminergic short axon neurons (SACs) form an extensive network of lateral connections that mediate cross talk among glomeruli, releasing GABA and DA onto sensory nerve terminals and postsynaptic neurons. DA neurons are ∼10-fold more numerous in OB than in ventral tegmental areas that innervate the striatum. We show that OB has abundant expression of the DA catalytic enzyme catechol-O-methyl-transferase (COMT), but negligible expression of the dopamine transporter. Using optogenetics and fast-scan cyclic voltammetry, we show that inhibition of COMT increases DA signals ∼2-fold. Thus, in contrast to the striatum, which has the brain's highest proportion of DAergic synapses, the DA catalytic pathway involving COMT predominates over re-uptake in OB.
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Renee
authors.identifier: 0000-0003-0918-091X
authors.initials: R
authors.lastname: Cockerham
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Shaolin
authors.identifier: 0000-0003-3351-8642
authors.initials: S
authors.lastname: Liu
authors.affiliation: CHDI Foundation/CHDI Management, New York, New York 10001, and.
authors.forename: Roger
authors.identifier: 0000-0002-7217-0119
authors.initials: R
authors.lastname: Cachope
authors.affiliation: Kawasaki Medical School, Matsushima, Kurashiki-City, Okayama.
authors.forename: Emi
authors.initials: E
authors.lastname: Kiyokage
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Joseph F
authors.identifier: 0000-0001-5086-7559
authors.initials: JF
authors.lastname: Cheer
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Michael T
authors.identifier: 0000-0001-6250-8414
authors.initials: MT
authors.lastname: Shipley
authors.affiliation: University of Maryland School of Medicine, Baltimore, Maryland 21201, apuche@som.umaryland.edu.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Puche
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D000075402:Channelrhodopsins; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009830:Olfactory Bulb / Q000166:cytology* / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D000075402:Channelrhodopsins; D050483:Dopamine Plasma Membrane Transport Proteins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D015102:3,4-Dihydroxyphenylacetic Acid; D014446:Tyrosine 3-Monooxygenase; C000593198:COMT protein, mouse; D002394:Catechol O-Methyltransferase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D004298:Dopamine; D006719:Homovanillic Acid
keywords: COMT; dopamine; enzymatic; olfactory; transporter; voltammetry