title: Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degeneration.
abstract: We previously demonstrated that mice with reduced expression of the vesicular monoamine transporter 2 (VMAT2 LO) undergo age-related degeneration of the catecholamine-producing neurons of the substantia nigra pars compacta and locus ceruleus and exhibit motor disturbances and depressive-like behavior. In this work, we investigated the effects of reduced vesicular transport on the function and viability of serotonin neurons in these mice. Adult (4-6 months of age), VMAT2 LO mice exhibit dramatically reduced (90%) serotonin release capacity, as measured by fast scan cyclic voltammetry. We observed changes in serotonin receptor responsivity in in vivo pharmacological assays. Aged (months) VMAT2 LO mice exhibited abolished 5-HT1A autoreceptor sensitivity, as determined by 8-OH-DPAT (0.1 mg/kg) induction of hypothermia. When challenged with the 5HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (1 mg/kg), VMAT2 LO mice exhibited a marked increase (50%) in head twitch responses. We observed sparing of serotonergic terminals in aged mice (18-24 months) throughout the forebrain by SERT immunohistochemistry and [(3)H]-paroxetine binding in striatal homogenates of aged VMAT2 LO mice. In contrast to their loss of catecholamine neurons of the substantia nigra and locus ceruleus, aged VMAT2 LO mice do not exhibit a change in the number of serotonergic (TPH2+) neurons within the dorsal raphe, as measured by unbiased stereology at 26-30 months. Collectively, these data indicate that reduced vesicular monoamine transport significantly disrupts serotonergic signaling, but does not drive degeneration of serotonin neurons.
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Alter
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Stout
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Lohr
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
authors.forename: Tonya N
authors.initials: TN
authors.lastname: Taylor
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
authors.forename: Kennie R
authors.initials: KR
authors.lastname: Shepherd
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
authors.forename: Minzheng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Guillot
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States; Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA, United States. Electronic address: gary.miller@emory.edu.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000662:Amphetamines; D050493:Vesicular Monoamine Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; C041336:4-iodoamphetamine; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin
keywords: 5-HT1A; 5-HT2; Dorsal raphe; Parkinson's disease; Serotonin; Synaptic vesicle; VMAT2