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Author Notes:

Corresponding author: G.W. Miller, Department of Environmental Health, 1518 Clifton Rd. Claudia Nance Rollins 8007, Emory University, Atlanta, GA 30322, United States. gary.miller@emory.edu.

Subjects:

Research Funding:

This research was supported by T32 NS007480 (Alter), T32 ES012870 (Alter), F31 DA037652 (Stout), R01 ES023839 (Miller), P30 019776 (Miller), and P50 NS071669 (Miller).

Keywords:

  • 5-HT1A
  • 5-HT2
  • Dorsal raphe
  • Parkinson's disease
  • Serotonin
  • Synaptic vesicle
  • VMAT2
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Amphetamines
  • Animals
  • Corpus Striatum
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration
  • Neurons
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Vesicular Monoamine Transport Proteins
  • Neurology
  • Environmental Health

Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degeneration

Tools:

Journal Title:

Experimental Neurology

Volume:

Volume 275

Publisher:

, Pages 17-24

Type of Work:

Article | Post-print: After Peer Review

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 (4-6months 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 (0.1mg/kg) induction of hypothermia. When challenged with the 5HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (1mg/kg), VMAT2 LO mice exhibited a marked increase (50%) in head twitch responses. We observed sparing of serotonergic terminals in aged mice (18-24months) throughout the forebrain by SERT immunohistochemistry and [3H]-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.

Copyright information:

© 2015 Published by Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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