Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degenerationReportar como inadecuado

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Journal Title:

Experimental Neurology


Volume 275


Elsevier | 2016-01-01, 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.

Subjects: Biology, Neuroscience - Health Sciences, Pharmacology - Health Sciences, Medicine and Surgery - 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-propylaminotetralin - Amphetamines - Animals - Corpus Striatum - Mice - Mice, Transgenic - Nerve Degeneration - Neurons - Receptor, Serotonin, 5-HT1A - Serotonin - Vesicular Monoamine Transport Proteins - Neurology - Environmental Health -

Autor: Shawn P. Alter, Kristen A. Stout, Kelly M. Lohr, Tonya N. Taylor, Kennie R. Shepherd, Minzheng Wang, Thomas Guillot III, Gary Mil



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