Enteric dysganglionosis resembling intestinal neuronal dysplasia in a foal with bacterial colitis.

A 5-day-old quarter horse colt with a history of hypothermia, agonal breathing, and diarrhea was euthanized. At necropsy, numerous slightly raised, discrete, closely approximated submucosal nodules were observed in the colon and small intestine. Histologically, these nodules were composed of expanded submucosal mesenchyme that contained numerous neurons either individually or in ganglia. Thirty-two percent of these ganglia included 8 or more neurons, in contrast to 6% in an age-matched foal. Some nodules had necrosuppurative inflammation with vasculitis, thrombosis, and bacterial colonization. A few heterotopic neurons were randomly distributed in the mucosa and the muscularis mucosa. Histologic changes were most consistent with intestinal neuronal dysplasia, a disease of the submucosal plexus described in humans.

Developmental lead exposure alters the stimulatory properties of cocaine at PND 30 and PND 90 in the rat.

The aim of this study was to examine the effects of perinatal lead exposure on locomotor responding following acute and repeated cocaine challenges (sensitization). Adult female rats were gavaged daily with 0, 8, or 16 mg lead acetate for 30 days prior to breeding. This exposure regimen was maintained throughout gestation and lactation (perinatal exposure). On Day 21, male pups were weaned and lead exposure was discontinued for the remainder of the study. Beginning on postnatal day (PND) 30 or PND 90, and continuing for 14 successive days, separate groups of perinatally-exposed animals were presented with challenges of 10 mg/kg cocaine HCl (i.p.), and tested for locomotor responding. Following this testing period, dose-effect profiles were determined, with animals receiving daily injections of 0, 10, 20, and 40 mg/kg cocaine. The results indicated that both at PND 30 and PND 90 lead-exposed animals were less responsive to the initial administration of cocaine, but exhibited a supersensitivity to the stimulatory effects associated with repeated administration of cocaine, i.e., behavioral sensitization to cocaine was augmented by perinatal lead exposure. Analyses of blood lead levels following the completion of testing revealed that lead levels were below detectable limits for all animals (< 1 microg/dl). Collectively, these findings show that developmental lead contamination produces changes in cocaine sensitivity long after exposure has been discontinued and the toxicant has gained clearance from blood.

Effects of combined lead and cadmium exposure: changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites.

Adult male rats were maintained on 1 of 4 ad-lib diets: Group Control-Diet received a normal laboratory diet that contained no added chemicals: Group Lead-Diet received a diet containing 500 ppm (parts per million) lead: Group Cadmium-Diet received a diet containing 100 ppm cadmium: and Group Lead-Cadmium-Diet received a diet containing both 500 ppm lead and 100 ppm cadmium. After 60 days of exposure to their respective diets, animals were placed on restricted diets (15 g/day) of the identical food received during the exposure period. Each animal was trained to lever press on a fixed-interval 1-min schedule for 21 sessions (1 session day). The results of schedule training showed that lead alone or cadmium alone was associated with increased lever pressing relative to control diet. However, when lead and cadmium were exposed jointly, performance was not significantly different from control performance. Similar attenuation of effects were observed for central neurotransmitter functions. Specifically disturbances in dopamine and serotonin turnover that were produced by lead alone were attenuated by the cotreatment of cadmium and lead. Possible accounts of the apparent antagonism between cadmium and lead are discussed.

The effects of perinatal exposure to lead on the discriminative stimulus properties of cocaine and related drugs in rats.

RATIONALE: Developmental lead exposure may alter responsiveness to cocaine well into adulthood, and ultimately influence drug-use patterns. OBJECTIVES: The present study examined the effect of perinatal lead exposure on the discriminative stimulus properties of cocaine. METHODS: Female rats were treated with 0, 8, or 16 mg lead daily for 30 days before breeding with untreated males. This exposure regimen continued through gestation and until postnatal day (PND) 21, i.e., weaning. At PND 60 male pups were trained to discriminate between saline and cocaine (5 mg/kg) injections. After acquisition, a series of generalization/substitution tests were performed using a cumulative dosing procedure. RESULTS: Developmental lead exposure produced subsensitivity to SKF-82958 (D1-like dopamine receptor agonist), quinpirole (D2-like dopamine receptor agonist), and apomorphine (mixed D1-like/D2-like dopamine receptor agonist); but no differences were evident among lead-treatment groups on generalization/substitution tests with cocaine, d-amphetamine, or GBR-12909. Furthermore, when the kappa-opioid receptor agonist U69,593 was administered prior to cocaine (5 mg/kg), generalization to the cocaine stimulus decreased in control rats, but generalization in lead-exposed rats was not altered. Group differences were not evident in tolerance or recovery of tolerance to cocaine following repeated cocaine administration (60 mg/kg per day for 14 days). Furthermore, no differences were found across groups in concentrations of lead in brain, although pups exposed to 16 mg lead had slightly elevated blood lead concentrations (<7 microg/dl). CONCLUSIONS: These results further a growing research literature that suggests developmental lead exposure can produce long-lasting changes in drug responsiveness, even after exposure to the toxicant has been discontinued.

Differential ability of astroglia and neuronal cells to accumulate lead: dependence on cell type and on degree of differentiation.

The apparent ability of astroglia to serve as a lead (Pb) sink in the mature brain may result from either their strategic location, between the blood-brain barrier and neurons, or from intrinsic differences between the ability of astroglia and neurons to accumulate this metal. This phenomenon may be dependent on the degree of cell differentiation. In order to address the latter possibility, Pb accumulation was compared among the following cell culture models: (1) mature and immature rat astroglia, (2) undifferentiated SY5Y human neuroblastoma cells and SY5Y cells differentiated with nerve growth factor, (3) immature rat astroglia grown in differently conditioned media, some of which induce partial differentiation, and (4) rat astroglia and SY5Y cells in co-culture. Astroglial cultures, prepared from 1-day-old rat cerebral hemispheres, were exposed to 1 microM Pb after either 14 (immature) or 21 (mature) days in culture. Pb content of the cells was measured by atomic absorption spectroscopy. Immature astroglia took up less Pb when glutathione (GSH) was added to the medium, suggesting that GSH may regulate Pb uptake in these cells. Undifferentiated neuroblastoma cells accumulated more Pb than did the differentiated ones. Astroglia accumulated up to 24 times more Pb than did neuronal cells. This ability was enhanced by exposure to conditioned medium from a neuroblastoma cell line, but not by endothelial cell-conditioned medium, although this medium induced the expression of a glutamate-activated Ca2+ response. Our findings are in agreement with in vivo studies, and thus validate the use of these cell-culture models for future studies on differential mechanisms of Pb uptake.

Analysis of Pb2+ entry into cultured astroglia.

Astroglia serve as a presumptive lead (Pb) sink in the brain; therefore, this study examined Pb entry into cultured rat astroglia utilizing the Ca2+ fluorophore indo-1 as a tool for detecting Pb2+ entry during acute exposure. The interactions of Pb2+ with indo-1 were analyzed by fluorescence spectrophotometry in a cell-free system. The emission spectrum of Pb2+/indo-1 was substantially different from that of Ca2+/indo-1 due to suppression of indo-1 fluorescence emission intensity. Next, we established the presence of L-type Ca2+ channels in astroglial cultures and demonstrated that Pb accumulation is enhanced under serum-free conditions and by the application of Bay-K 8644. Because acute exposure is of less toxicologic relevance than repeated low-level exposure, we then examined Pb uptake in cultures treated for up to 1 week with Pb. AAS revealed that Pb accumulation was accompanied by an increase in total cellular [Ca]. In addition, differences in basal indo-1 fluorescence levels and differences in responsiveness to ionomycin were observed. Ionomycin induced an increase in the fluorescence ratio in untreated cells but cells treated for 1 day with Pb showed no response to ionomycin. However, cells treated for 3 and 7 days showed a partial response to ionomycin. TPEN was used to evaluate the interactions of Pb2+ with indo-1 and only cells treated for 7 days showed a response to TPEN. Thus, the present study characterizes Pb2+ entry into astroglia via L-type Ca2+ channels and presents the possibility of using indo-1 for analysis of Pb2+ uptake and the subsequent neurotoxic events in astroglia.

Cadmium exposure attenuates the initiation of behavioral sensitization to cocaine.

Employing a paired-watering procedure to control for differential fluid intake confounds, adult male rats were exposed in the home cage to water containing 100 ppm cadmium chloride, or a control solution containing no added cadmium chloride. On Day 61 of exposure to their respective watering regimens, half the animals from each condition received 12 repeated daily i.p. injections of 10 mg/kg cocaine-HCl, or saline. Locomotor activity (total distance traveled) was recorded in Digiscan Activity Monitors for a 20-min baseline period prior to each injection, and for a 40-min period post-injection. On Day 13 of testing, all animals received saline injections only in the test chambers, in an effort to evaluate the role of conditioned cues in the expression of cocaine sensitization. On Day 14-16 of testing, all animals received successive daily challenges of 10, 20, and 40 mg/kg cocaine in the test chamber. The results indicated that the initiation (development) of behavioral sensitization to 10 mg/kg cocaine was attenuated in cadmium-exposed rats. Moreover, the supersensitivity to higher doses of cocaine during dose-effect testing that was registered by control animals pretreated with cocaine, was not evident in cadmium-exposed pretreatment animals. These data suggests that environmental contaminants may alter drug responsiveness, and thereby may influence patterns of drug selection and use.

Cellular targets of lead neurotoxicity: in vitro models.

Four types of cells in culture were exposed to lead (Pb) acetate (0.1-1000 microM): astroglia-enriched, oligodendroglia-enriched, and meningeal fibroblast cultures prepared from neonatal rat brains; and human neuroblastoma cultures prepared from the SK-N-SH-SY5Y cell line. The viability (trypan blue dye exclusion and proliferation) of these cell types after Pb exposure was compared in order to identify cellular targets in the central nervous system that were directly susceptible to cytotoxicity. Of the 4 cell types tested, only oligodendroglia showed marked sensitivity to Pb treatment. However, proliferation of the SY5Y cells was temporarily inhibited if the cells were treated 1 day (but not 3 days) after seeding. The potential for thiamin, which is used to treat Pb intoxication in cattle, to prevent this effect was tested. Rather than preventing this toxic effect, however, thiamin (1 mM) exacerbated that inhibition of proliferation. Astroglia and meningeal fibroblasts, which were resistant to Pb toxicity, were shown by atomic absorption analysis to take up Pb from the culture medium and concentrate it intracellularly to at least 55X the extracellular concentration, thus supporting hypotheses that these cells act as Pb sinks in the brain.

Low level lead neurotoxicity in a pregnant guinea pigs model: neuroglial enzyme activities and brain trace metal concentrations.

Specific activities of the astroglial marker glutamine synthetase (GS), and the oligodendroglial marker glycerol-3-phosphate dehydrogenase (GPDH) were measured in the spinal cord of fetal guinea pigs and their dams following chronic exposure to low levels of lead (Pb) during gestation. In addition, the effects of Pb on intracellular trace metals (Cu, Fe, Zn) were measured in the blood, cerebellum and forebrain. Aminolevulinic acid dehydratase (ALAD) and zinc protoporphyrin IX (ZPP) were measured in order to monitor established parameters of Pb-exposure. Pregnant guinea pigs were orally administered 0, 5.5 or 11 mg Pb/kg body weight for 30 or 40 days commencing on day 22 of gestation. Blood Pb levels produced in dams and fetuses were at or near the currently identified "no effect" levels for children (10-30 micrograms/dl). These Pb blood levels produced a significant (P less than 0.05) dose-dependent decrease in GS and GPDH activity in the dams and fetuses. Fe and Zn concentrations in blood, cerebellum and forebrain of both dams and fetuses were significantly (P less than 0.05) decreased in a dose-dependent manner. However, Cu concentrations in the blood, cerebellum and forebrain were decreased in the dams but increased in the fetuses in a dose-dependent fashion. The alteration of trace metal concentrations is a proposed mechanism of Pb neurotoxicity. Blood ALAD activity was significantly (P less than 0.05) decreased and ZPP levels were significantly (P less than 0.05) increased, as expected in Pb-exposed animals. This study presents the first biochemical evidence for the alteration of neuroglial function at low levels of Pb exposure and focuses attention on the fetus as an important Pb target.

Lead (Pb) alters the norepinephrine-induced secretion of luteinizing hormone releasing hormone from the median eminence of adult male rats in vitro.

In the present study, we evaluated the in vitro effects of lead (Pb) on basal and stimulated luteinizing hormone releasing hormone (LHRH) and Prostaglandin E2 (PGE2) secretion. Median eminences (ME) were removed from brains of adult male rats and preincubated for 15 minutes in Krebs-Ringer bicarbonate glucose buffer in an atmosphere of 95% O2-5% CO2. These media were discarded and all MEs were subjected to one of the following experiments. In Experiment 1, all MEs were incubated for 30 minutes in medium only. These media were collected and replaced with medium only (controls) or with medium containing Pb doses ranging from 5 to 20 microM. After this 60-minute incubation, media were collected, then replaced with new medium containing 60 microM norepinephrine (NE), or NE plus each dose of Pb, then incubated for a final 30-minute period. Experiment 2 was conducted as above, except PGE2 (2.8 microM) replaced the NE. In both experiments, the amounts of LHRH released was measured by RIA. In experiment 3, NE was again used for the challenge; however, this time, the amount of PGE2 released was measured by RIA. Results indicate that Pb did not alter basal LHRH release, but compared with controls, significantly blocked NE-induced LHRH release in a dose-related manner. Conversely, Pb had no effect on the PGE2-induced release of LHRH. Additionally, Pb did not alter basal PGE2 release; however, it significantly blocked the NE-induced release of PGE2. Since NE-induced LHRH release is mediated by PGE2, these results support the hypothesis that Pb is capable of altering the hypothalamus and suggest that this effect is due, at least in part, to the diminished PGE2 synthesis/release within the ME, resulting in diminished LHRH secretion.

Dietary cadmium exposure alters characteristics of training, substitution, and tolerance when morphine is used as a discriminative stimulus.

This study examined the possibility that cadmium, a toxicant in high concentration in all tobacco products, may alter the stimulus properties of morphine. Adult male rats were exposed to regular laboratory chow (Group Control) or chow containing 100 ppm added cadmium chloride (Group Cadmium). Following an initial 30 day exposure period, control and cadmium-exposed animals were trained to discriminate between i.p. injections of 3.00 mg/kg morphine sulfate and vehicle (distilled water) in a two-choice drug discrimination task. Subsequently, the morphine dose-effect generalization function (0.75-6.00 mg/kg) was determined for control and cadmium-exposed animals. Additional substitution tests were conducted with increasing doses of the high efficacy mu agonist fentanyl (0.0016-0.04 mg/kg), the intermediate efficacy mu agonist (-)-metazocine (0.60-5.00 mg/kg), and the kappa agonist (+/-)-bremazocine (0.03-0.12 mg/kg). Also, increasing doses of the selective mu antagonist naloxone (0.0008-0.50 mg/kg) were presented against the training dose of morphine (3.00 mg/kg) and 0.02 mg/kg fentanyl. Finally, training was discontinued, and control and cadmium-exposed animals were injected with 8.00 mg/kg morphine in the home cage every 12 hr for 2 weeks, prior to redetermining the morphine dose effect function. Following a 1 week recovery period where morphine injections were discontinued, a final determination of the morphine dose-effect function was made. The results of the investigation indicated that cadmium exposure, without affecting the rate-changing properties of the drugs, slowed initial acquisition of the morphine discrimination, decreased the potency of selective doses of naloxone with respect to antagonizing the stimulus effects of morphine and fentanyl, and blocked the development of tolerance to morphine. Morphine, fentanyl, and (-)-metazocine generalized (substituted) equally across both groups, while (+/-)-bremazocine failed to substitute for the morphine stimulus in either group. These findings add to the growing literature on the interaction between metal poisoning and drug selection/abuse.

The effects of cadmium on ethanol self-administration using a sucrose-fading procedure.

Rats were exposed for 70 days to either a diet containing 100 ppm cadmium (Group Cadmium) or a control diet with no additives (Group Control). Subsequently, all animals were trained to lever press for a 20% sucrose solution. Across several phases, sucrose was faded out as the reinforcer and gradually replaced with a 10% ethanol solution. A subsequent operant choice (concurrent) test, during which pressing one lever resulted in a dipper presentation of ethanol and the other lever provided water, was followed by a single-lever test where sucrose was reinstated as the reinforcer. The results showed that although cadmium-treated rats lever pressed more than controls during the early phases of the sucrose-fading procedure, animals exposed to cadmium lever pressed at lower rats than controls for ethanol during the concurrent test. There were no group differences on the final sucrose test. The possibility that cadmium may alter sensitivity to ethanol is discussed.

A possible feline model for human blepharospasm.

'Benign essential blepharospasm' is a human eyelid disorder of unknown aetiology characterized by involuntary, bilateral, and disabling spasmodic contracture of the orbicularis oculi muscle. Treatments are frequently disappointing. Here we report what might be a first step toward developing an animal model for exploring mechanisms of the disorder and potential treatments. We surgically implanted stimulating electrodes into brain areas known to supply input to the lateral division of the facial nerve nucleus to induce blinking by electrical stimulation. Single-pulse stimuli at or near the facial, parabrachial, red, and interstitial nuclei produced consistent stimulus-induced eyelid contractions. Responses were ipsilateral to stimulation, except for the interstitial nucleus where contralateral responses occurred. Little or no other movements of the face, head, or body occurred at eye-blink threshold voltages. When these sites were stimulated with pulse trains, eyelid closures followed stimulus frequency and tended to fuse into constant closure. Thresholds at each stimulus site remained constant during three days of testing. Drug treatments produced no consistent effect on eye-blink threshold from any stimulation site, even when general behaviour was affected. We conclude that these input pathways to the facial nucleus may contribute to blepharospasm and that future neurochemical and electrophysiological study of these pathways may produce a suitable animal model for understanding this disorder.

Innervation of the feline eyelids.

The innervation of the eyelids is incompletely understood. This is a particular problem for those who wish to develop animal models of eyelid dysfunction in humans. Blepharospasm, for example, is a disease of uncontrolled eyelid spasm that is difficult to manage clinically because the aetiology is not understood. The anatomical literature on eyelid innervation is sparse and even conflicting. We attempted to study eyelid innervation, both sensory and motor, with injection of horseradish peroxidase (HRP) into the superior eyelid, inferior eyelid, and bulbar conjunctiva. We used 13 anesthetized weanling cats. Shape and structure of the facial nucleus varied along its rostrocaudal extent, but there was a clear demarcation of lateral and medial division. HRP-filled facial nucleus cells were ipsilateral to the injection site, and label appeared throughout the rostrocaudal length. All injection sites, including bulbar conjunctiva, labelled facial nucleus neurons located with overlapping distribution, predominantly in the dorsal part of the lateral division. Likewise, heavy labelling occurred throughout the entire ipsilateral cranial cervical ganglion and the trigeminal ganglion in all kittens. Injection of upper or lower eyelids caused some labelling in the second through the fourth cervical spinal ganglia.

Brain and plasma levels of cocaine and benzoylecgonine in lead-expose and cadmium-exposed rats following acute or chronic intraperitoneal administration of cocaine.

Previous investigations of metal/cocaine interactions have shown that chronic oral exposure to inorganic lead or cadmium attenuates the psychoactive effects of acute or repeated administration of cocaine. The purpose of this investigation was to assess the possibility that such interactive effects may derive from metal-induced disturbances in cocaine pharmacokinetics, i.e., delivery of cocaine to critical biologic sites may be disrupted by metal contamination. In this study, adult male rats were exposed to purified diets containing 250 ppm lead acetate (Group Lead), 100 ppm cadmium chloride (Group Cadmium), or unadulterated laboratory chow (Group Control); n = 48/exposure condition. Following ad libitum access to their respective diets in the home cage for 45 days, half the animals from each exposure regimen received single daily IP injections of 5, 10, or 20 mg/kg cocaine HCl for a period of 7 days (n = 8/group). The remaining half the animals received repeated daily injections of saline during this pretreatment phase. On the day following pretreatment, animals previously receiving cocaine injections were administered a single cocaine test challenge at a dose equal to that received in pretreatment. Similarly, saline pretreatment animals received either 5, 10, or 20 mg/kg cocaine. The results of this investigation did not reveal reliable evidence of metal-related differences in brain levels of cocaine. Plasma cocaine and benzoylecgonine (BE) levels also were essentially the same for control and metal-exposed animals. The failure to show that lead or cadmium alters the disposition of cocaine in brain or plasma underscores the need to pursue alternative accounts of metal/cocaine interactions.

Perinatal exposure to lead attenuates the conditioned reinforcing properties of cocaine in male rats.

The purpose of this study was to examine the effects of developmental lead exposure on drug responsiveness later in the life cycle. Adult female rats were gavaged daily with 0, 8, or 16 mg lead for 30 days before breeding with non-exposed males. The respective exposure regimens were maintained throughout gestation and lactation (perinatal exposure). In Experiment 1, at postnatal day (PND) 30 or 90, pups were trained with 0, 1.25, 2.5, or 5 mg/kg cocaine HCl (IP) in a biased conditioned place preference (CPP) procedure. At both PND 30 and 90, an attenuation in CPP was present in animals exposed to 8 or 16 mg lead relative to control rats. Using an identical lead-exposure regimen, a conditioned place aversion (CPA) procedure with 0, 10, 20, or 40 mg/kg lithium chloride (IP) was employed for Experiment 2. No significant differences were present among pups from each lead-exposure group conditioned and tested at PND 30 or 90, thus suggesting that an impairment of associative mechanisms was not solely responsible for the pattern of attenuation present in Experiment 1. Subsequent analyses of blood-lead in all experiments demonstrated concentrations below 5 microg/dl for all animals at PND 30 and below detectable limits (<1 microg/dl) at PND 90. The findings suggested attenuation in cocaine reinforcement with perinatal lead exposure even though the metal apparently had gained clearance from soft tissue.

Chronic exposure to lead attenuates cocaine-induced behavioral activation.

Adult, male rats were exposed to a diet containing 500 ppm (0.05%) lead for 105 days before testing for cocaine-related changes in activity using a Digiscan activity system. Behavioral testing occurred on 6 successive test days. Activity was recorded for 20 min prior to and 40 min after IP injections of either 10, 20, or 40 mg/kg cocaine HCl, with saline injections on the day preceding each drug test day. Cocaine-induced behavioral activation was evident in control diet animals for all three doses (10, 20, and 40 mg/kg). While 10 mg/kg cocaine HCl did not produce behavioral activation in lead-treated animals, both 20 and 40 mg/kg did result in increased activity comparable to that observed in control counterparts.

Chronic lead exposure attenuates ethanol-induced hypoalgesia.

Adult male rats were exposed to drinking fluid containing either 500 ppm lead acetate (group lead), or an equivalent concentration of sodium acetate (group control) for 61 days prior to pain reactivity testing using a tail-flick procedure. Rats were placed in restraining tubes for a 20 min acclimation period, and then baseline tail-flick latencies in response to a radiant heat source were measured. Subsequently, half the animals from each group were serially injected IP with either 1.0, 2.0, or 3.0 g/kg body weight of a 20% v/v ethanol solution, and the other half were injected with an equivalent volume of saline. Tail-flick latencies were reassessed at 20-min intervals over the next 2 h. Results indicated dose-dependent ethanol-induced hypoalgesia at all doses, but at the two higher doses the magnitude of the hypoalgesic response was significantly greater in the group control animals than in the group lead animals across the 2-h postinjection period. Results are discussed in terms of an attenuation of the pharmacological properties of ethanol by lead.

Differential effects of adult and perinatal lead exposure on morphine-induced locomotor activity in rats.

The effects of adult and perinatal lead treatment on the development of locomotor sensitization produced with repeated morphine administration was investigated. In Experiment 1, adult male rats received a diet containing 250 ppm lead acetate or a control diet for 43 days. Animals then received 10 mg/kg morphine sulfate or water vehicle (ip) and locomotor activity was monitored for 14 consecutive days. While both control and lead-exposed animals demonstrated a locomotor sensitization to morphine, the magnitude of the increased locomotor response was reduced in lead-treated animals. Subsequent analysis of blood-lead in the adult lead-exposed animals indicated residue levels ranging between 20 and 30 microg/dl. In Experiment 2, adult female rats were treated daily with 0, 8, or 16 mg lead via gavage for 30 days before breeding with non-exposed males. Lead exposure in dams continued through gestation and until pups were weaned at postnatal day (PND) 21. At PND 60, male offspring received morphine or vehicle challenges identical to those described in Experiment 1. Animals perinatally exposed to dams receiving 16 mg lead daily demonstrated an enhanced behavioral response to morphine relative to control animals. Analysis of offspring blood indicated lead levels below detectable limits (<1 microg/dl) for all animals. The results suggest exposure to lead at environmentally relevant levels produces long-lasting changes in drug-induced behavior, and the developmental period in which lead exposure occurs is a significant contributor to the manifestation of these effects.

The effects of cadmium exposure on ethanol pharmacokinetics.

Twenty-four adult male rats were exposed in the home cage to water containing 100 ppm added cadmium chloride. An additional 24 animals were pair-watered with water containing no added cadmium. Following 60 days of exposure to their respective watering regimens, one third of the animals in each exposure group (N = 8/condition) received IP injections of 1.0, 2.0, or 3.0 g/kg ethanol (20% v/v). Serum alcohol concentrations were measured at 15, 30, 60, 120, 180, 240, and 360 min postinjection. Although serum alcohol concentrations increased with dose for both cadmium-exposed and control animals, there was no indication at any dose of group differences. The lack of differences in ethanol pharmacokinetics reported here is instructive with respect to improving our understanding of the mechanisms underlying cadmium/ethanol interactions.