Prenatal Exposure to Methylmercury during Late Gestation Affects Cerebral Opiatergic System in Rat Offspring Paola Zanoli, Cristina Truzzi, Cristina Veneri, Cinzia Brandoli, and Mario Baraldi Department of Pharmaceutical Sciences, School of Pharmacy, University of Modena, Via Campi 183, 41100 Modena, Italy Received July 31, 1995 Pregnant female rats were orally administered a single dose (8 mg/kg) of methylmercury chloride (MMC) on Day 15 of gestation. The binding charac- teristics of opioid receptors were studied in the brain of developing rats at different stages of age. An increased density of opioid receptors was found in whole brain of MMC-exposed rats at 21 days ( receptors) and 60 days ( and  receptors) of age, in comparison with matched controls. An enhanced response to morphine administration was detected in MMC-exposed rat offspring at Day 60 of postnatal life, which, however, was not apparently due to an impaired liver metabolization or renal excretion. Hence, it is reasonable to surmise a possible corre- lation between receptor up-regulation and in- creased response to pharmacological challenge. These data seem to indicate that neurochemical al- terations produced in the rat developing organism by prenatal exposure to methylmercury involve the opiatergic system which undergoes a supersensitiv- ity phenomenon. This effect, which is not detectable in the first postnatal period, shows a delayed onset, being detectable only at the adult stage. These find- ings seem to indicate that pre- and postnatal meth- ylmercury exposure induces latent neurochemical and behavioral alterations which could last even af- ter the clearance of the metal from the brain. © 1997 Academic Press INTRODUCTION Many experimental and clinical studies have in- dicated that the central nervous system is the main target organ of methylmercury toxicity. The devel- oping brain has been demonstrated to be particu- larly susceptible to the toxic action of the metal (Kostial et al., 1978; Jugo, 1979; Eccles and Annau, 1982a; Komulainen, 1988). Behavioral and neurochemical alterations in pre- natally exposed rats have been demonstrated by oth- ers and by us (Bartolome et al., 1984; Cuomo et al., 1984; Komulainen 1988, Cagiano et al., 1990). Re- cently we showed that the administration of a single dose of methylmercury (8 mg/kg) to pregnant rats can alter the binding characteristics of GABA- benzodiazepine (Guidetti et al., 1992) and of musca- rinic receptors systems (Zanoli et al., 1994) in off- spring during early postnatal life. Alterations in- volving the striatal dopaminergic system (Cagiano et al., 1990) were also observed only in the early postnatal stage (14 and 21 days of age). These find- ings taken together suggest the ability of MMC to induce transient effects which seem to be related strictly to the presence of the metal in the brain structures. Rats prenatally exposed to methylmercury, however, also show neurobehavioral disturbances, including learning and memory deficits (Bornhau- sen et al., 1980; Eccles and Annau, 1982b) which in our experience continue even after the normaliza- tion of mercury level in the brain (Cagiano et al., 1990). These data prompted us to suggest that methyl- mercury exposure could induce not only transient but also latent (and maybe permanent) neurochemi- cal and behavioral alterations related to cognitive brain functions. Both the glutamatergic and the opiatergic system have long been implicated in the normal development of the learning and memory system (Haynes, 1984; Baudry and Lynch, 1987; Judd et al., 1987; McDonald and Johnston, 1990). No studies to our knowledge, have investigated the abil- ity of methylmercury to affect the opiatergic system. Hence, the aim of the present study was to investi- gate whether or not pre- and postnatal methylmer- cury exposure could alter  and  opioid receptor development in offspring and their functional re- sponse to pharmacological stimulation in the adult stage of life. ENVIRONMENTAL RESEARCH 74, 48–53 (1997) ARTICLE NO. ER973729 48 0013-9351/97 $25.00 Copyright © 1997 by Academic Press All rights of reproduction in any form reserved.