Dose-dependent loss of motor function after unilateral medial forebrain bundle rotenone lesion in rats: A cautionary note

• Published in: Behavioural brain research Vol. 222; no. 1; pp. 33 - 42
• Main Authors: Klein, Alexander, Gidyk, Darryl C., Shriner, Alexandra M., Colwell, Keri L., Tatton, Nadine A., Tatton, William G., Metz, Gerlinde A.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 12.09.2011; Elsevier
• Subjects: Adult and adolescent clinical studies; Analysis of Variance; Animals; Apomorphine - pharmacology; Behavior, Animal - drug effects; Behavioral psychophysiology; Biological and medical sciences; Brain - metabolism; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine; Dose-Response Relationship, Drug; Environmental toxins; Exploratory Behavior - drug effects; Female; Functional Laterality - physiology; Fundamental and applied biological sciences. Psychology; Insecticides - toxicity; Intracerebral; Medial Forebrain Bundle - injuries; Medial Forebrain Bundle - physiopathology; Medical sciences; Movement - drug effects; Movement Disorders - etiology; Movement Disorders - pathology; Movement Disorders - physiopathology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurons - drug effects; Neurons - metabolism; Organic mental disorders. Neuropsychology; Parkinson's disease; Pesticide; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychomotor Performance - drug effects; Psychopathology. Psychiatry; Rats; Rats, Long-Evans; Rotenone - toxicity; Skilled movement; Stereotyped Behavior - drug effects; Tyrosine 3-Monooxygenase - metabolism; Environmental toxins; Parkinson's disease; Dopamine; Intracerebral; Pesticide; Skilled movement; Rat; Central nervous system; Parkinson disease; Encephalon; Degenerative disease; Motricity; Medial forebrain bundle; Nervous system diseases; Rodentia; Motor skill; Catecholamine; Cerebral disorder; Rotenone; Toxin; Vertebrata; Mammalia; Animal; Central nervous system disease; Body movement; Neurotransmitter; Lesion; Extrapyramidal syndrome
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2011.03.018

► Intracerebrally injected rotenone causes PD-like symptoms. ► Some of the behavioral deficits are transient; repeated training improves motor deficits. ► Vehicle (PG/DMSO) causes cell loss. ► Higher rotenone concentrations cause unspecific cell loss. 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.