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.
