Lactose facilitates the intestinal absorption of lead in weanling rats.

The milk sugar lactose is known to facilitate calcium absorption and has been shown to enhance the uptake of essential trace metals from the intestines as well. Its physiological role as the major carbohydrate source for suckling mammals is thus complemented by its ability to facilitate the absorption of necessary minerals. The studies reported here show that the intestinal absorption of lead and its uptake into blood, liver, kidney, and bone are also increased by lactose in young weanling rats. These data extend the known range of lactose facilitation of mineral absorption to a nonessential, toxic element, confirming the nonspecificity of its action on the gut. In addition, they suggest an explanation for some of the conflicting evidence regarding the prophylactic efficacy of milk in lead poisoning.

Scotopic vision deficits in young monkeys exposed to lead.

Rhesus monkeys were reared on diets designed to produce blood lead concentrations of 14 (untreated), 55, or 85 micrograms per 100 milliliters for the first year of life. Eighteen months later, blood lead levels were normal in all animals. At this time, however, visual discrimination performance in the 85-microgram group was impaired under dim light relative both to their own performance under bright light and to the performance of the other groups under all light levels used. We interpret these results to reflect a deleterious, enduring impairment of scotopic visual function (night blindness) as a result of early lead intoxication.

Effects of toluene, acrolein and vinyl chloride on motor activity of Drosophila melanogaster.

The data generated by current high-throughput assays for chemical toxicity require information to link effects at molecular targets to adverse outcomes in whole animals. In addition, more efficient methods for testing volatile chemicals are needed. Here we begin to address these issues by determining the utility of measuring behavioral responses of Drosophila melanogaster to airborne volatile organic compounds (VOCs) as a potential model system for discovering adverse outcome pathways and as a method to test for toxicity. In these experiments, we measured motor activity in male and female flies to determine concentration-effect functions for three VOCs that differ in their mode of action: toluene, a narcotic; acrolein, an irritant; and vinyl chloride, a hepatocarcinogen. These experiments were conducted in Flyland, an outbred population of flies derived from 40 lines of the Drosophila Genetics Reference Panel (DGRP) (Mackay et al., 2012), in preparation for subsequent experiments with individual lines of the DGRP. Systematic, concentration-related changes in activity were observed with toluene, but not with acrolein; high concentrations of vinyl chloride reduced activity by a small amount. Despite higher activity levels in males than in females under control conditions, the sexes were equally sensitive to toluene. Transient increases in activity at the onset and offset of exposure to toluene and vinyl chloride suggested that the flies detected changes in air quality at concentrations that did not persistently suppress activity. The effects and potency of toluene are consistent with those observed in rodents. The lack of clear concentration-related changes in response to acrolein and vinyl chloride shows limitations of this method is for screening toxicity attributed to VOCs. This abstract does not reflect U.S. EPA policy.

Prenatal exposure to vapors of gasoline-ethanol blends causes few cognitive deficits in adult rats.

Developmental exposure to inhaled ethanol-gasoline fuel blends is a potential public health concern. Here we assessed cognitive functions in adult offspring of pregnant rats that were exposed to vapors of gasoline blended with a range of ethanol concentrations, including gasoline alone (E0) and gasoline with 15% or 85% ethanol (E15 and E85, respectively). Rat dams were exposed for 6.5h daily to the vapors at concentrations of 0, 3000, 6000, or 9000 ppm in inhalation chambers from gestational day (GD) 9 through 20. Cage controls (offspring of non-exposed dams that remained in the animal facility during these exposures) were also assessed in the E0 experiment, but showed no consistent differences from the offspring of air-exposed controls. Offspring were tested as adults with trace fear conditioning, Morris water maze, or appetitive operant responding. With fear conditioning, no significant effects were observed on cue or context learning. In the water maze, there were no differences in place learning or escaping to a visible platform. However, during the reference memory probe (no platform) male rats exposed prenatally to E85 vapor (6000 and 9000 ppm) failed to show a bias for the target quadrant. Across studies, females (treated and some controls) were less consistent in this measure. Males showed no differences during match-to-place learning (platform moved each day) in any experiment and females showed only transient differences in latency and path length in the E0 experiment. Similarly, no differences were observed in delayed match-to-sample operant performance of E0 males or females; thus this test was not used to evaluate effects of E15 or E85 vapors. During choice reaction time assessments (only males were tested) decision and movement times were unimpaired by any prenatal exposure, while anticipatory responses were increased by vapors of E0 (9000 ppm) and E15 (6000 and 9000 ppm), and the latter group also showed reduced accuracy. E85 vapors did not disrupt any choice reaction time measure. Finally, no response inhibition deficit was observed in a differential reinforcement of low rate (DRL) response schedule in males or females in the E15 or E85 experiments. In summary, prenatal exposure to these fuel blends produced few deficits in adult offspring on these cognitive tests. Significant effects found during a water maze probe trial and choice reaction time tests were observed at vapor concentrations of 6000 ppm or higher, a concentration that is 4-6 orders of magnitude higher than those associated with normal automotive fueling operations and garages. Similar effects were not consistently observed in a previous study of inhaled ethanol, and thus these effects cannot be attributed to the concentration of ethanol in the mixture.

Neurotoxic and pharmacokinetic responses to trichloroethylene as a function of exposure scenario.

Strategies are needed for assessing the risks of exposures to airborne toxicants that vary over concentrations and durations. The goal of this project was to describe the relationship between the concentration and duration of exposure to inhaled trichloroethylene (TCE), a representative volatile organic chemical, tissue dose as predicted by a physiologically based pharmacokinetic model, and neurotoxicity. Three measures of neurotoxicity were studied: hearing loss, signal detection behavior, and visual function. The null hypothesis was that exposure scenarios having an equivalent product of concentration and duration would produce equal toxic effects, according to the classic linear form of Haber's Rule ((italic)C(/italic) times t = k), where C represents the concentration, t, the time (duration) of exposure, and k, a constant toxic effect. All experiments used adult male, Long-Evans rats. Acute and repeated exposure to TCE increased hearing thresholds, and acute exposure to TCE impaired signal detection behavior and visual function. Examination of all three measures of neurotoxicity showed that if Haber's Rule were used to predict outcomes across exposure durations, the risk would be overestimated when extrapolating from shorter to longer duration exposures, and underestimated when extrapolating from longer to shorter duration exposures. For the acute effects of TCE on behavior and visual function, the estimated concentration of TCE in blood at the time of testing correlated well with outcomes, whereas cumulative exposure, measured as the area under the blood TCE concentration curve, did not. We conclude that models incorporating dosimetry can account for differing exposure scenarios and will therefore improve risk assessments over models considering only parameters of external exposure.

Overt orienting in the rat: parametric studies of cued detection of visual targets.

Covert shifts of visual attention in space have been quantified by measuring the effects of visual cues on the detection of visual targets in humans and monkeys maintaining visual fixation. These observations of "covert orienting" have provided important information regarding the neurobiology of visual attention in primates. This article describes a cued spatial target detection task for physically unrestrained rats. Valid cues (spatially contiguous with the target) enhanced target detection, and invalid cues (spatially discontiguous with the target) degraded target detection. Both visual and auditory cues were effective. These validity effects could not be explained by stimulus additivity or response preparation mechanisms, whereas a cue-independent "alerting effect" appeared to reflect response preparation. The effects compare favorably with primate work and suggest that this method may enable assessment of visual attention shifts in rats.

A comparison of the effects of bilateral and unilateral infusions of muscimol into the basal forebrain on cued detection of visual targets in rats.

This study investigated the role of the basal forebrain cholinergic system (BFCS) in rats' performance of a visuospatial attention task. Muscimol was infused bilaterally and unilaterally into the BFCS to inhibit cholinergic projections to the cortex. Muscimol slowed responding without significantly affecting side-bias. Bilateral infusions increased accuracy for all targets, whereas unilateral infusions reduced accuracy for targets contralateral to the infusion and increased accuracy for targets ipsilateral to the infusion. After a low unilateral dose of muscimol, invalid cues impaired detection of contralateral targets and spared detection of ipsilateral targets. A high unilateral dose of muscimol impaired detection of contralateral targets independently of cueing. These results suggest that interhemispheric imbalance in cortical activity by pharmacological manipulation of the BFCS can impair the detection of lateralized visual stimuli.

Behavioral approaches to the assessment of attention in animals.

Increasing awareness that disorders of attention may underlie cognitive dysfunctions associated with intoxication and neurodegenerative disease has stimulated research into the neural bases of attention. Because attention comprises a constellation of hypothetical cognitive processes, it can only be inferred from behavior, of either human or non-human subjects, under appropriate experimental conditions. Many behavioral procedures have been proposed for modeling attention in animals, but not all of these procedures have been systematically associated with specific attentional processes. This review endeavors to evaluate critically the construct validity of these procedures (i.e., to determine the degree to which a given procedure assesses a particular process) and to suggest experiments to improve the conceptual links between these procedures and the processes they purport to assess. Five categories of processes have been identified from the animal literature: orienting, expectancy, stimulus differentiation (including stimulus salience, discrimination of a critical stimulus from its context, and selection among stimuli), sustained attention, and parallel processing. The review discusses the strengths and weaknesses of specific behavioral procedures for assessing these categories of attentional processes and, given the conceptual uncertainties involved, it attempts to summarize the present state of knowledge of the pharmacology and neurobiology of attention.

2,4-Dithiobiuret in rats: cognitive facilitation after acute injection precedes motor impairment after repeated daily injections.

2,4-Dithiobiuret (DTB) is a sulfonated derivative of urea that is used as a reducing agent in chemical manufacture. Its low acute toxicity to rodents belies a peripherally mediated, delayed-onset muscle weakness which develops during repeated daily exposure. In experiment 1, a standard dose regimen of DTB (0.5 mg/kg per day IP for 5 days) was used to induce motor dysfunction as a way to dissociate peripheral and central influences on a test of cognitive and motor function in rats. Sixteen male rats were trained to perform a Delayed Matching-to-Position/Visual Discrimination (DMTP/VD) task which permits quantification of working memory (matching accuracy), reference memory (discrimination accuracy), and motor function (choice response latency and nosepoke inter-response time, IRT). The first dose of DTB significantly increased matching accuracy; during the following week, DTB reduced matching accuracy, increased choice response latency and nosepoke IRT, and reduced trial completion. Discrimination accuracy remained unaffected. Experiment 2 explored the effects of single administrations of DTB on DMTP/VD. Sixteen other trained rats were divided into two groups with equal matching accuracy. One group received DTB (0.5,1.0, and 2.0 mg/kg, IP) in separate injections at least 1 week apart; the other group received vehicle at the same times. Matching accuracy increased significantly in the treated rats and not in the controls following each dose of DTB. The magnitude of this increase was dose dependent, and lasted from 1 to 8 weeks after each injection. Discrimination accuracy, response latency, nosepoke IRT and trial completion remained unaffected throughout the study. After DTB, matching accuracy was less easily disrupted by scopolamine (0.1-0.3 mg/kg, IP). However, DTB did not alter the rats' response to reducing the distance between the response levers, to reversal of the matching rule to a nonmatching rule, or to challenge with MK-801 (0.05-0.10 mg/kg, IP). These data indicate that acute DTB causes a long-lasting facilitation of working memory in rats in the absence of any of the indications of motor impairment which follow repeated, daily injections of the chemical.

Detection of visual signals by rats: effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention.

Central cholinergic and adrenergic pathways support the attentional processes necessary for detecting and reporting temporally unpredictable stimuli. To assess the functional effects of pharmacological manipulations of these pathways, male Long-Evans rats performed a two-choice, discrete-trial signal-detection task in which food was provided for pressing one lever after presentation of a signal (a 300-ms light flash), and for pressing a second lever at the end of a trial lacking a signal. Seven signal intensities were presented during each 1-h session in a pseudo-random order across three 100-trial blocks. After acquisition of a stable performance baseline, the acute effects of chlordiazepoxide (0, 3, 5, 8 mg/kg i.p.), pilocarpine (0, 1.0, 1.8, 3.0 mg/kg s.c.), scopolamine 0, 0.030, 0.056, 0.100 mg/kg s.c.), nicotine (0, 0.08, 0.25, 0.75 mg/kg s.c.), mecamylamine (0, 1.8, 3.0, 5.6 mg/kg i.p.), clonidine (0, 0.003, 0.010, 0.030 mg/kg s.c.), and idazoxan (0, 1, 3, 10 mg/kg s.c.) were assessed. Five measures of performance were analyzed: response failures; the proportion of "hits" [P(hit): the proportion of correct responses on signal trials]; the proportion of "false alarms" [P(fa): the proportion of incorrect responses on non-signal trials]; and response times (RT) for hits and for correct rejections. All drugs which slowed responding affected RT for hits and correct rejections equivalently, suggesting little or no influence of motor slowing on choice accuracy. Chlordiazepoxide reduced P(hit) at low signal intensities only, without affecting P(fa) or RT, consistent with sensory impairment (reduced visual sensitivity). All other drugs except nicotine reduced P(hit) at high signal intensities preferentially, suggesting a non-visual source of the impairment. Scopolamine, mecamylamine and clonidine affected both P(hit) and P(fa); pilocarpine and idazoxan reduced P(hit) without affecting P(fa). Nicotine at 0.75 mg/kg decreased P(hit) in the first block of trials; at 0.08 mg/kg it increased P(hit) in the second block; no dose affected P(fa). RTs were increased by pilocarpine, scopolamine, mecamylamine and clonidine, but not by nicotine or idazoxan. The data suggest that drugs which reduce cholinergic or adrenergic tone (scopolamine, mecamylamine and clonidine) impair sustained attention by decreasing the detection of signals and by increasing the false alarm rate, whereas drugs which elevate cholinergic or adrenergic tone (pilocarpine, nicotine and idazoxan) decrease attention by impairing detection of signals without affecting the false alarm rate. In contrast, the GABA-facilitating drug chlordiazepoxide appeared to affect visual thresholds rather than attention.

d-Amphetamine-induced "floating limb" syndrome in young rhesus monkeys.

Acute d-amphetamine administration to young rhesus monkeys (N = 10) caused a motor syndrome of hypoactivity and chorea-like postures and motor movements which we have termed "floating limb". Frequently after subcutaneous injections of 0.3 or 0.6 mg/kg d-amphetamine, an affected monkey raised one or both legs or arms and held the limb(s) motionless in the air. Affected limbs were usually returned to a normal position if they appeared to enter the animal's visual field. In other cases, the monkey assumed bizarre and contorted postures which were held for prolonged periods. Such postures were often accompanied by gentle repetitive brushing of the ears and facial hair with extremities of the affected limbs. Quantification of the frequency of these movements showed that they occurred regularly for 90-150 min after d-amphetamine. Hydroxyamphetamine, a peripherally-acting amphetamine analog, did not induce floating limb, indicating that the behavior was probably mediated by central actions of d-amphetamine. A similar disorder has been reported occasionally in other studies with monkeys and cats. It may be related to the chorea that is seen in humans after the use of amphetamine and other stimulants. d-Amphetamine treatment in young monkeys may provide a viable model of human choreoathetoid disorders induced by disease or drug use.

Use of 6-hydroxydopamine to deplete brain catecholamines in the rhesus monkey: effects on urinary catecholamine metabolites and behavior.

The purpose of this study was to determine: 1) whether 6-hydroxydopamine (6-OHDA), previously shown to deplete brain catecholamines (CA) in rodents, depletes brain CA in rhesus monkeys; 2) whether depletion of brain CA produces changes in behavior; and, 3) whether urinary output of 3-methoxy-4-hydroxyphenylglycol (MHPG) reflects brain norepinephrine (NE) depletions. Repeated intracerebroventricular (ICV) injection of 6-OHDA (N = 20; 15.5-73.3 mg/subject) produced chronic changes in social behavior and, at higher dosages, reduced output of urinary MHPG. However, 4 weeks after the last ICV 6-OHDA injection, urinary MHPG excretion returned to baseline values and whole brain CA content was not reliably different from control. A single treatment with 6-OHDA microinjected into the substantia nigra (SN) (N = 12; 120-240 microgram/subject) produced chronic whole brain depletions of brain CA without depleting serotonin. Reductions in brain CA were associated with a specific set of motor behaviors, aphagia, and adipsia. SN 6-OHDA produced greater brain NE depletions than ICV 6-OHDA, but urinary MHPG output was not reduced. SN 6-OHDA treated subjects showed chronic changes in social behavior and were more sensitive to the operant response rate decreasing effects of alpha-methyl-para-tyrosine (AMPT) than control subjects. Subjects with the largest depletions of brain dopamine (DA) (greater than 90%) were hypokinetic, rigid, and had a distal limb tremor. These results show that SN but not ICV injection of 6-OHDA can deplete brain CA in the rhesus monkey. The most prominent behavioral changes were characterized by disturbances in motor function. Urinary MPHG output does not reflect depletions of brain NE in this species.

Selective removal of cholinergic neurons in the basal forebrain alters cued target detection.

A spatial orienting task was used to assess attention in rats with selective cholinergic lesions of the basal forebrain. The task required each rat to press a lever in response to a visual target that could occur in one of two locations. A target could be preceded by a cue that either accurately predicted the location of the target (valid) or appeared in the location opposite the target (invalid). Target detection was facilitated by valid cues and degraded by invalid cues in control rats. Performance of rats with lesions was equivalent to that of control rats for valid cues, but reflected an increased cost of invalid cueing. These data support a modulatory role for the basal forebrain cholinergic system in visuospatial attention.

A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans.

The literature on behavioral effects of exposure to toluene is difficult to assess due, in part, to a wide variety of exposure conditions employed and outcomes measured. This study investigated whether previous experiments would be more consistent with each other if toluene exposure parameters were expressed not as concentration and duration, but as estimated amount of toluene in tissues. A physiologically based pharmacokinetic (PBPK) model was used to estimate concentration of toluene in arterial blood (CaTOL) from published studies in rats and humans exposed acutely to toluene vapor. Data for rats were selected from studies of avoidance behavior using both rate of responding and measures of successful responding. Data for humans were from studies of choice reaction time (CRT). Behavioral measures were converted to proportion of baseline to place them on a common scale across experiments. A meta-analysis was done to fit dose-effect curves using CaTOL and the rescaled effects. Results demonstrated that effects were an orderly function of CaTOL and were not influenced by concentration or duration of exposure, except as exposure influenced CaTOL. In rats, response rates first increased, reached a peak, and then declined as CaTOL increased. Successful avoidance in rats and CRT in humans always declined as CaTOL increased. In rats, response rates were increased by 10% at CaTOL approximately 13 ml/L. In humans, reaction times increased by 10% at CaTOL approximately 3 ml/L. Cross-species comparisons were made with the following caveats: PBPK uncertainties, few human data, and poor task comparability.

Gender-dependent behavioral and sensory effects of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) in rats.

Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with behavioral and cognitive deficits in humans and animal models. Perinatal exposure to PCBs has also been associated with sensory deficits in animal models. These effects were hypothesized to be mediated in part by ortho-substituted PCBs, which do not or weakly bind to the aryl hydrocarbon (Ah) receptor. The present studies were designed to determine whether perinatal exposure to Aroclor 1254, a commercial mixture of > 99% ortho-substituted PCBs, would affect cognitive and sensory function in Long-Evans rats. Adult male and female offspring of female rats fed Aroclor 1254 (Lot #124-191; doses of 0, 1, or 6 mg/kg/day; gestational day 6 through postnatal day 21; n = eight/group) were trained to perform a signal detection task capable of assessing sensory thresholds. Training included autoshaping and operant conditioning. Thresholds for detecting a 1-s light stimulus were determined under background illuminations ranging from 2 lux to complete darkness. Female rats exposed to Aroclor 1254 autoshaped more rapidly than control females, at a rate akin to control males. Control females had lower thresholds than control males at all levels of background illumination. These differences were abolished by Aroclor 1254, which reduced thresholds in males and increased thresholds in females. These data extend previous findings of gender-specific effects of PCBs on neurobehavioral development to measures of acquisition and sensory function.

A physiologically based pharmacokinetic model for trichloroethylene in the male long-evans rat.

A physiologically based pharmacokinetic (PBPK) model for trichloroethylene (TCE) in the male Long-Evans (LE) rat was needed to aid in evaluation of neurotoxicity data collected in this rodent stock. The purpose of this study was to develop such a model with the greatest possible specificity for the LE rat. The PBPK model consisted of 5 compartments: brain, fat, slowly perfused tissue, rapidly perfused viscera, and liver. Partition coefficients (blood, fat, muscle, brain, liver) were determined for LE rats. The volumes of the brain, liver, and fat compartments were estimated for each rat, with tissue-specific regression equations developed from measurements made in LE rats. Vapor uptake data from LE rats were used for estimation of Vmaxc. As blood flow values for LE rats were not available, values from Sprague-Dawley (SD) and Fischer-344 (F344) rats were used in separate simulations. The resulting values of Vmaxc were used to simulate tissue (blood, liver, brain, fat) TCE concentrations, which were measured during (5, 20, 60 min) and after (60 min of TCE followed by 60 min of air) flow-through inhalation exposures of LE rats to 200, 2000, or 4000 ppm TCE. Simulation of the experimental data was improved by use of F-344 blood-flow values and the corresponding Vmaxc (8.68 mg/h/kg) compared to use of SD flows and the associated Vmaxc (7.34 mg/h/kg). Sensitivity analysis was used to determine those input parameters with the greatest influence on TCE tissue concentrations. Alveolar ventilation consistently (across exposure concentration, exposure duration, and target tissue) had the greatest impact on TCE tissue concentration. The PBPK model described here is being used to explore the relationship between measures of internal dose of TCE and neurotoxic outcome.

Effects of unilateral removal of basal forebrain cholinergic neurons on cued target detection in rats.

Corticopetal cholinergic neurons in the basal forebrain (BF) were removed unilaterally from rats by infusing the cholinergic immunotoxin 192 IgG-saporin into the substantia innominata. After 2 weeks, the rats with right-hemisphere infusions showed signs of visuospatial neglect for targets in the left visual field in a cued visual target detection task based upon human covert orienting procedures. No behavioral effects were evident 4-6 weeks post-infusion. Ten to 22 weeks post-infusion all rats responded more quickly and less accurately to targets in the visual field contralateral to the infusion than to targets ipsilateral to the infusion: further, accuracy for contralateral targets decreased with increasing time between trial initiation and target presentation (target delay), whereas accuracy for ipsilateral targets increased with target delay. Cues did not affect responding to targets in the contralateral visual field more than to targets in the ipsilateral field. The changes in performance could not be attributed to sensory or mnemonic impairment or to response bias. The temporal characteristics of response accuracy and latency suggest the competitive interaction of two time-dependent processes: an attentional process which relies upon cholinergic input from the BF, and a response preparation process which is normally inhibited by the attentional process. These results suggest a role for corticopetal cholinergic pathways in maintaining attention to salient stimuli by inhibiting subcortical motor circuits.

Studies on the correlation between blood cholinesterase inhibition and 'target tissue' inhibition in pesticide-treated rats.

Inhibition of cholinesterase activity in the blood has been proposed as an index of ChE activity in tissues targeted by ChE-inhibiting pesticides, including the muscle end-plate region and the central nervous system (CNS). While opinions vary regarding the utility of blood ChE activity in predicting ChE activity in the target tissues, there appear to be no comprehensive studies designed to assess this possible correlation in a time- and dose-dependent manner. We undertook this type of study by administering a single dose of an organophosphate, chlorpyrifos (0, 30, 60 or 125 mg/kg in corn oil, s.c.) to rats and then sacrificing animals at 1, 4, 7, 21 or 35 days after dosing. Whole blood, plasma, erythrocytes, frontal cortex, hippocampus, striatum, hypothalamus and diaphragm tissue were collected and assayed for ChE activity. Collapsed across dosages, optimal correlations of blood ChE activity with brain or muscle activity occurred 7-21 days after dosing (when ChE inhibition was maximal and most stable). At all times after dosing, there was a high correlation among ChE activity in the hippocampus, striatum and frontal cortex. Generally, ChE activity in whole blood and erythrocytes correlated better with the activity in brain and muscle than did activity in the plasma (whole blood > or = erythrocytes >> plasma). Similar relationships were also observed in a more abbreviated study using a direct acting organophosphate, paraoxon. ChE activity was determined in blood components, brain and muscle at the time of maximal inhibition (4 h after injection) and during recovery (24 hrs after injection) using two dosage levels (0.17 or 0.34 mg/kg, s.c.). Taken together, these data indicate that the level of ChE activity in the blood may accurately reflect activity in other tissues, but that this correlation is tissue- and time-specific.

Effects of trimethyltin on repeated acquisition (learning) in the radial-arm maze.

Trimethyltin (TMT) was used as a positive control neurotoxicant to evaluate a repeated acquisition procedure for the 8-arm radial maze. Ten male Long-Evans rats were trained to collect a single food pellet at the end of each baited arm on each trial of a daily 12-trial test session. Four of the eight arms were baited on all trials of a given session. The set of four baited arms was changed each day: thus the rats were required to learn a new set of baited arms in each session. In trained rats, error frequencies (entries into unbaited arms) declined from about 4 on Trial 1 to less than 1 on Trials 4-12 in each session: this within-session error reduction thus defined an acquisition baseline which was evaluated for its sensitivity to TMT. Learning was impaired after 7 mg/kg (iv) TMT, as shown by a slower decline in within-session error frequencies in all treated rats. Errors and response times were elevated for 5 weeks after TMT but returned to control levels thereafter. Histological examination of hippocampi showed damage in all treated rats 18 weeks after treatment; however, no significant relationship between degree of damage and behavioral effect was observed. Analysis of errors showed that TMT more strongly impaired the rats' ability to avoid arms in the current unbaited set than those baited arms already entered on a given trial (i.e., working memory). These dissociations between behavior and hippocampal morphology in terms of time course, magnitude of effect across animals, and error type suggest that performance of this task does not depend upon hippocampal integrity, as do other tasks involving spatial working memory. Recovery of function in this kind of task may shed light on processes of neural plasticity after exposure to neurotoxic compounds.

Serial spatial reversal learning in rats: comparison of instrumental and automaintenance procedures.

Serial reversals of a spatial discrimination were trained in rats under automaintenance conditions, in which food reward occurred regardless of responding. This automaintained reversal learning was compared to instrumental reversal learning in other rats trained under a similar procedure which required responding for reward. In the automaintenance (AU) procedure, rats received food after every retraction of a "positive" response lever (S+); retraction of a second, "neutral" lever (So) was not paired with food delivery. Responses to the S+ were elicited at fairly constant rates during daily 100-trial conditioning sessions. Responses to the So occurred early in each session but rapidly diminished across trials. When the valences of the levers were reversed, responding shifted to the new S+ and diminished on the new So. Criterion for reversal was defined as a discrimination ratio (DR) of at least 90% responding to the S+ in two consecutive 10-trial blocks. With repeated reversals, acquisition of criterion performance occurred with increasing rapidity, reaching an asymptote below that required for the original discrimination. A second group of rats was trained on a similar instrumental schedule, in which at least one response to the S+ was required for food delivery. Response rates in this instrumental (IN) group were approximately double those of the AU group. However, ratios of S+ to So response rates were similar to those of the AU group, and the serial reversal curves generated were qualitatively similar. Thus rats can show improvement across serial reversals of a spatial discrimination based entirely on pairings of stimulus events (automaintenance), in a manner similar to that observed in instrumental procedures, in which reward is contingent upon correct responding.