title: A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection.
abstract: Age-related deficits in motor and cognitive functioning may be driven by perturbations in calcium (Ca(2+)) homeostasis in nerve terminals, mechanisms that are also thought to mediate the neurotoxicity of methylmercury (MeHg). Calcium-channel blockers (CCBs) protect against MeHg toxicity in adult mice, but little is known about their efficacy in other age groups. Two age groups of BALB/c mice were exposed to 0 or 1.2mg/kg/day MeHg and 0 or 20mg/kg/day of the CCB nimodipine for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and the retired breeders on PND 296. High-rate operant behavior was maintained under a percentile schedule, which helped to decouple response rate from reinforcer rate. Responding was analyzed using a log-survivor bout analysis approach that partitioned behavior into high-rate bouts separated by pauses. MeHg-induced mortality did not depend on age but nimodipine neuroprotection was age-dependent, with poorer protection occurring in older mice. Within-bout response rate (a marker of sensorimotor function) was more sensitive to MeHg toxicity than bout-initiation rate (a marker of motivation). Within-bout rate declined almost 2 months prior to overt signs of toxicity for the MeHg-only retired breeders but not adults, suggesting greater delay to toxicity in younger animals. Motor-based decrements also appeared in relatively healthy adult MeHg+NIM animals. Aging appeared to alter the processes underlying Ca(2+) homeostasis thereby diminishing protection by nimodipine, even in mice that have not reached senescence. The study of MeHg exposure presents an experimental model by which to study potential mechanisms of aging.
authors.affiliation: Department of Psychology, Auburn University, AL 36849, United States.
authors.forename: Andrew Nathanael
authors.initials: AN
authors.lastname: Shen
authors.affiliation: Department of Psychology, University of Alabama, Tuscaloosa, AL 35487, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Cummings
authors.affiliation: Department of Psychology, Auburn University, AL 36849, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Pope
authors.affiliation: Department of Psychology, Indiana University Southeast, New Albany, IN 47150, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoffman
authors.affiliation: Department of Psychology, Auburn University, AL 36849, United States. Electronic address: newlamc@auburn.edu.
authors.forename: M Christopher
authors.initials: MC
authors.lastname: Newland
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000502:physiology / Q000523:psychology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015331:Cohort Studies; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004198:Disease Susceptibility; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D008807:Mice, Inbred BALB C; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology*; D012054:Reinforcement, Psychology; D016019:Survival Analysis
chemical_list: D002121:Calcium Channel Blockers; D008767:Methylmercury Compounds; D018696:Neuroprotective Agents; D009553:Nimodipine; C004925:methylmercuric chloride
keywords: Aging; Bout analysis; Calcium homeostasis; Methylmercury; Motor function; Nimodipine