Developmental exposure to methylmercury alters behavioral sensitivity to d-amphetamine and pentobarbital in adult rats Erin B. Rasmussen, M. Christopher Newland* Department of Psychology, 228 Thach Hall, Auburn University, Auburn, AL 36830 USA Received 3 September 1999; accepted 13 September 2000 Abstract Female rats were exposed to 0, 0.5, or 6.4 ppm methylmercury in their drinking water before mating, and throughout gestation and lactation. When the female offspring were 4 ± 6 months old, they were trained to respond under a multiple differential reinforcement of high rate (DRH) 9:4 Ð Extinction schedule of reinforcement. No differences among exposure groups were apparent in steady-state behavior. Drug challenges were conducted with multiple doses of d-amphetamine, scopolamine, pentobarbital, haloperidol, and dizocilpine, drugs selected for their different pharmacological effects. The ED 50 values for amphetamine's reinforcement rate-reducing effects for the control, 0.5-, and 6.4-ppm groups were 3.1, 1.9, and 0.9 mg amphetamine/kg body weight, respectively, demonstrating an increased sensitivity to d- amphetamine in methylmercury-exposed rats. Rats in the 6.4-ppm group also demonstrated a relative insensitivity to pentobarbital. Further, these exposed rats exhibited an inverted U-shaped dose ± effect curve under the pentobarbital dose ± effect determination, while controls showed only a declining curve. Exposed rats did not respond differentially to haloperidol, scopolamine, or dizocilpine, suggesting specificity. The present data suggest an involvement of catecholaminergic and GABAergic activity in methylmercury's neurotoxicity. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Methylmercury; Developmental exposure; Catecholamine sensitivity; GABA sensitivity 1. Introduction Pharmacological challenges are useful in uncovering subtle toxicant-induced behavioral effects and revealing potential neurochemical mechanisms of action [1,38]. Under this preparation, drugs with well-established neurochemical effects are administered to toxicant-exposed and unexposed animals, and differences in drug sensitivity are examined. A single drug alone, and certainly a single dose, is insufficient for characterization because such an approach cannot reveal whether the effect is specific to the drug examined or represents a general change in sensitivity to any behavio- rally active agent. Instead, a full dose ± effect profile using drugs specific to several neurochemical substrates is neces- sary to reveal pharmacological specificity and dose-related effects. Such a design can uncover much about the beha- vioral relevance of putative neurochemical substrates of neurotoxicity [1,38]. Acute administration of d-amphetamine has revealed methylmercury-related effects on endpoints such as loco- motor activity [10], acquisition of a differential reinforce- ment of a low rate (DRL) schedule [16], and acquisition and rates of lever pressing [20]. These effects were not evident in the absence of the drug challenge. Since d-amphetamine promotes the release of dopamine and norepinephrine [6], the reports implicate involvement of the catecholamine systems in methylmercury's effects. Another report, using a single dose of apomorphine [12], supports these sugges- tions. Most of these studies, however, relied on only a single drug or, sometimes, only a single dose. It is not clear whether methylmercury's effects were specific to dopamine or norepinephrine systems, and whether the effects were related to the dose of d-amphetamine. A generic sensitivity to any behaviorally active drug could exist. In the present study, female rats were exposed to 0, 0.5, or 6.4 ppm of methylmercury (MeHg) in their water before, during, and after gestation resulting in exposure of about 0, 40, and 500 mg/kg/day, respectively, during gestation. The offspring were trained as adults to perform under a differ- ential reinforcement of high rate (DRH) schedule. The * Corresponding author. Tel.: +1-334-844-6479; fax: +1-334-844- 4447. E-mail address: newlamc@mail.auburn.edu (M.C. Newland). Neurotoxicology and Teratology 23 (2001) 45± 55 0892-0362/01/$ ± see front matter D 2001 Elsevier Science Inc. All rights reserved. PII:S0892-0362(00)00112-4