title: Dose-dependent loss of motor function after unilateral medial forebrain bundle rotenone lesion in rats: a cautionary note.
abstract: The organic pesticide rotenone is a neurotoxin suspected to cause Parkinson's disease (PD) symptoms by selectively targeting and compromising the survival of dopaminergic neurons. Rotenone in rodent models reproduces key features of human PD by impairing the mitochondrial electron transport chain, leading to intracellular alpha-synuclein aggregates and functional impairments typical for PD. The present study characterized the dose-response relationship of standard rotenone concentrations in motor impairments in a rat model. Rats received a single medial forebrain bundle injection of 4, 8, or 12μg of rotenone. Animals were assessed in skilled limb use, skilled and non-skilled walking and exploratory activity as well as drug-induced rotation. The results revealed rotational bias and stable impairments in skilled walking and gross motor function up to five weeks post injection. However, transient motor deficits facilitated rapid improvement of skilled reaching success. Mainly the temporal aspects of skilled and non-skilled motor performance were responsive to different rotenone concentrations. By contrast, drug-induced rotation and nigral TH+ cell loss were not influenced by different rotenone doses. Rats infused with 8μg and 12μg seemed to have reached a ceiling effect in motor deficits as they were not distinguishable in behavioral measures. Most strikingly, the stereological and morphological analyses revealed non-specific toxicity of vehicle and rotenone infusions that caused macroscopic lesions beyond nigral boundaries. These findings suggest that sensitivity of comprehensive motor tests to subtle modulation of dopamine function is independent of dopamine cell loss per se. Furthermore, caution is advised concerning non-specific toxicity of rotenone and vehicle substances in experimental animal models.
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada. kleina@cardiff.ac.uk
authors.forename: Alexander
authors.initials: A
authors.lastname: Klein
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Gidyk
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Shriner
authors.forename: Keri L
authors.initials: KL
authors.lastname: Colwell
authors.forename: Nadine A
authors.initials: NA
authors.lastname: Tatton
authors.forename: William G
authors.initials: WG
authors.lastname: Tatton
authors.forename: Gerlinde A
authors.initials: GA
authors.lastname: Metz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007839:Functional Laterality / Q000502:physiology*; D007306:Insecticides / Q000633:toxicity*; D008474:Medial Forebrain Bundle / Q000293:injuries* / Q000503:physiopathology; D009068:Movement / Q000187:drug effects; D009069:Movement Disorders / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D012402:Rotenone / Q000633:toxicity*; D013239:Stereotyped Behavior / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D007306:Insecticides; D012402:Rotenone; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine