1985 — 1986 |
Newland, M. Christopher Christopher |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Behavioral Toxicity of Methanol and Ethanol @ University of Rochester |
0.97 |
1990 — 1991 |
Newland, M. Christopher Christopher |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Caffeine-Induced Supersensitivity to Adenosine Agonists @ Auburn University At Auburn
Adenosine analogs have been suggested as virtually non-toxic hypnotics or anticonvulsants. However, chronic caffeine exposure may induce supersensitivity to adenosine analogs and thereby enhance their potency and influence their safety. The proposed study is aimed at characterizing the pharmacological and behavioral specificity of adenosine supersensitivity. Preliminary data show that rats consuming caffeine (0.5 mg/ml) in their drinking water from 30 to about 150 days of age become supersensitive to hypnotic effects of the adenosine agonist 1-PIA when compared to rats drinking only tap water. Theses groups did not differ on 1-PIA's effect on caffeine or water consumption or on muscle strength as measured by the ability to hang from a rod. This observation provides functional support for in-vitro observations of upregulation of adenosine receptors following chronic caffeine. The proposed studies are designed to replicate the observation of supersensitivity and extend it to operant behavior. Rats will be trained on a multiple schedule in which one component is a conventional fixed- interval schedule of reinforcement selected to enable direct comparisons with the extant literature showing behavioral effects of methylxanthines, adenosine analogs, and sedative/hypnotic drugs. In the other component the rat must hold down the lever for a specified duration. This task was selected for sensitivity and because it has been shown to be detect to motor effects of chemical exposure. To characterize pharmacological specificity, drugs from other pharmacological classes, including psychomotor stimulants and adrenergic agonists, will also be examined. Such data will enable quantitative comparisons how chronic caffeine use influence the behavioral actions of drugs. The provisional hypothesis is that chronic exposure to caffeine induces supersensitivity that is specific to adenosine agonists and tolerance that is specific to methylxanthines.
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1.009 |
1995 — 1999 |
Newland, M. Christopher Christopher |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Behavioral Teratology of Methylmercury @ Auburn University At Auburn
Methylmercury is neurotoxic to the developing organism. Human and animal studies concur on methylmercury's sensory, motor, and' cognitive effects after acute or transient exposure to high levels. Exposure to very low levels can produce subtle but detectable and long-lasting effects on the behavior of offspring. Studies with rodents had used exposure levels ranging from 0.5 to 10 mg/kg/day with one or a few administrations during gestation, but several investigators have reported effects on operant behavior at levels as low as 0.05 mg/kg/day. In a recent study conducted by the PI in collaboration with the Institute for Hygiene, Lund University, Sweden, monkeys showed delayed effects of prenatal methylmercury exposure in behavior maintained by concurrent schedules of reinforcement. Severe learning deficits were manifested in behavior during transition states in monkeys that appeared normal and even behaved normally on more conventional, steady-state baselines. The proposed studies build on those observations in a new species and examine low levels of exposure. Rats will be exposed to 0, 0.05, or 0.5 mg/kg/day of methylmercury during gestation. When adults, lever-pressing will be maintained under concurrent schedules of reinforcement in which a rich lever produces reinforcement at a higher rate than the lean one. When the schedules on the levers are reversed, behavior shifts to the newly rich lever but, in preliminary studies, more slowly in exposed animals. Behavior change is quantified by fitting a logistic function to measures of responding taken as the transition progresses. The resulting parameters are used in developing dose-effect relationship and identifying behavioral and neural mechanisms of neurotoxicity. The proposed studies are designed to I) replicate in rats the effects reported in monkeys 2) examine a refinement recently developed by the PI to shorten transitions from 4 weeks to I day, 3) identify environmental moderators of methylmercury's effects, 4) probe for neurochemical mechanisms of damage and 5) identify sensitivity of aged animals. This proposal is a modification of one previously submitted and the modifications entail 1) eliminating parallel studies conducted with monkeys in Lund, 2) developing rapid transitions, and 3) detailed examination of other determinants of methylmercury 's developmental neurotoxicity.
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1.009 |
2001 — 2005 |
Newland, M. Christopher Christopher |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurotoxicity of Methylmercury Across the Lifespan @ Auburn University At Auburn
DESCRIPTION: (ADAPTED FROM APPLICANT'S ABSTRACT) Fetal exposure to methylmercury (MeHg) has long-lasting effects on sensory-motor function, schedule-controlled behavior, learning (not memory) and sensitivity to certain behaviorally active drugs. Human and animal studies now associate developmental or adult MeHg exposure with age-related declines in certain behavioral functions. Nutritional influences also modify mercury's neurotoxicity, although how these interact through the lifespan is not well understood. This is important both mechanistically and because of concerns that a low RfD for MeHg would decrease consumption of fish, a source of selenium and n-3 fatty acids, especially docosahexanoic acid (DHA). In previous work, rats on a chow diet consuming 40 or 500 mg/kg/day Hg (as MeHg) showed age- and dose-related decrements on high-rate operant behavior, retarded learning, and altered sensitivity to amphetamine and pentobarbital. Proposed studies extend these observations by examining age and diet as modifiers of MeHg's neurobehavioral toxicity. High-rate operant behavior will be examined using a refined procedure (targeted percentile schedule) that maintains high response rates but without lowering reinforcement rates if behavior deteriorates. Concurrent schedule performance in transition, which now can be conducted in single sessions, will be the measure of learning. Fixed-interval (FI) schedule performance will be examined per se and as a baseline for drug challenges. Female rats will start one of three diets (modified semipurified, DHA-enriched, Se-enriched) for two weeks, then MeHg exposure (0. 0.5, or 5 ppm in drinking water) for two weeks, then they will be mated. Maternal rats will continue the diets and mercury exposure to 30 months of age, and their behavior examined under a targeted percentile schedule of reinforcement. During this time they will receive selected drug challenges. At death mercury levels in blood and brain, Se (in the Se cohort) and DHA in the DHA cohort) will be examined. Offspring will be maintained on the different diets and used as follows: 1) Hg and Se or FA profile determination PN1; 2) FI schedule performance in transition with drug challenges: 3) Targeted percentile schdule performance, and 4) Concurrent schedule performance in transition with drug challenges. Items 2-4 will be conducted as adults and 3-4 to 30 months of age. At death Hg and either Se or FA profiles will be determined, depending on the cohort.
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1.009 |