L-DOPA reverses motor deficits associated with normal aging in mice

Abstract

We wished to determine whether L-DOPA, a common treatment for the motor deficits in Parkinson's disease, could also reverse the motor deficits that occur during aging. We assessed motor performance in young (2-3 months) and old (20-21 months) male C57BL/6 mice using the challenge beam and cylinder tests. Prior to testing, mice were treated with L-DOPA or vehicle. Following testing, striatal tissue was analyzed for phenotypic markers of dopamine neurons: dopamine, dopamine transporter, and tyrosine hydroxylase. Although the dopaminergic markers were unchanged with age or L-DOPA treatment, L-DOPA reversed the motor deficits in the old animals such that their motor coordination was that of a young mice. These findings suggest that some of the locomotor deficits that accompany normal aging are responsive to L-DOPA treatment and may be due to subtle alterations in dopaminergic signaling. KeywordsBehavior; dopamine; striatum Aging is usually accompanied by a decline in motor function, a phenomenon that can be observed in laboratory animals as well as in humans. For example, rodents typically exhibit a decline in spontaneous motor activity and motor coordination [1][2][3]7]. Such motor functions appear to be heavily influenced by the dopamine (DA) system [17]. One important piece of evidence for this conclusion comes from studies of Parkinson's disease (PD). In that condition, many of the motor deficits are strongly correlated with the loss of the DA neurons of the nigrostriatal projection [5].Corresponding author: Dr. Jane E. Cavanaugh, Department of Pharmacology, 455 Mellon Hall, Duquesne University, Phone: (412) 396-6358, Fax: (412) 396-4660, cavanaughj@duq.edu. * The first two authors contributed equally to this work.a) The authors have no actual or potential conflicts of interest. b) All animals were maintained in temperature-controlled rooms in the barrier facility maintained by the Division of Laboratory Animal Resources (DLAR) at the University of Pittsburgh. Animals were housed in accordance with Guidelines for the Care and Use of Animals, at 23°C with lights on between 1900 and 0700 hr. Animals were fed and watered ad libitum, and the woodchips in their cages changed every other day. Full-time trained animal care personnel performed all animal handling and maintenance. The director of the DLAR, a trained veterinarian, supervised animal care. All animal care was overseen by the Institutional Animal Care and Use Committee (IACUC).Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. L-DOPA, which increases the availability of DA in striatum, is able to temporarily impr...

The role of ERK1, 2, and 5 in dopamine neuron survival during aging

“…These observations, along with our current data, suggest that age-associated declines in nigral DA neurons (Eriksen et al, 2009; Fearnley and Lees, 1991; Fox et al, 2001; Morgan et al, 1987) and motor functions (Allen et al, 2011; Bennett et al, 1996; Boger et al, 2006; Irwin et al, 1994; Yue et al, 2012) could be a consequence of decreased ERK5 activation resulting from reduced NTF signaling. It may also be noteworthy that inhibition of the ERK5 pathway has been shown to reduce GDNF mRNA and protein levels in some cells (Obara et al, 2011), suggesting a feedback loop in which MEK5-ERK5 signaling is further decreased.…”

“…All reagents were purchased from Sigma-Aldrich (St. Louis, MO) unless otherwise specified. Tissue samples were sonicated in ice-cold 1:20 (w/v) lysis buffer as previously described (Allen et al, 2011). Total homogenate was centrifuged at 11,000 rpm for 30 minutes at 4 °C and the supernatant was collected and stored at −80 °C.…”

Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms

“…It is therefore probable that at later stages, a motor phenotype may have begun to emerge. It is also possible that the motor phenotype was less evident at late time points due to the advanced age of the mice and the decrease in motor acuity that accrues as part of the aging process [ 2 ].…”

Involvement of dopamine signaling in the circadian modulation of interval timing

“…Administration type (i.p.) and pretreatment period for levodopa was obtained from previously published data for motor performance tests in mice (Allen et al ., ). We increased the previously published dose (15 mg/kg, i.p.)…”