Glutamate and dopamine in nucleus accumbens core and shell: sequence learning versus performance.

This study sought to determine whether neurochemical changes associated with chronic postweaning lead (Pb) exposure, namely, enhanced dopamine (DA) activity and/or blockade of NMDA function in nucleus accumbens (NAC), underlie the learning impairments also associated with this Pb regimen, and whether core or shell subregions of nucleus accumbens would be more important to such effects. If so, then mimicking these neurochemical changes in normal (control) rats should reproduce these Pb-induced learning impairments. For this purpose, the effects of DA (20-80 microg), the non-competitive NMDA antagonist MK-801 (1.0-2.5 microg) or DA+MK-801 (40+1.0, 80+2.5 microg) were infused in core or shell of nucleus accumbens in normal rats and effects on a multiple schedule of repeated learning (RL) and performance (P) evaluated. In core, MK-801 mimicked the effects of Pb exposure, selectively reducing RL accuracy with no corresponding changes in P accuracy, an effect derived from an increased frequency of perseverative errors. DA produced non-specific changes, reducing accuracy levels in RL and P components. Accuracy and rate effects of DA could be reversed by concurrent administration of the higher MK-801 dose. In shell, MK-801, primarily the lower dose, reduced accuracy in both the RL and P components, while DA did not produce any systematic effects. Collectively, these results point to a greater importance of core as compared to shell in the mediation of learning of spatial sequences, and suggest that inhibition of glutamatergic NMDA function may play a critical role in the selective learning impairments associated with chronic low level Pb exposure.

Lead exposure and dorsomedial striatum mediation of fixed interval schedule-controlled behavior.

Prior studies demonstrate a critical role for mesolimbic dopamine systems, particularly nucleus accumbens, in the mediation of fixed interval (FI) schedule-controlled behavior and an enhancement of nucleus accumbens dopamine activity as a mechanism of chronic postweaning lead (Pb)-induced increases in Fl response rates. Since dorsomedial striatum, like nucleus accumbens, receives limbic input, it could also conceivably contribute to Pb-related effects on FI performance. Therefore, changes in FI schedule-controlled behavior were examined following administration of dopamine or the non-specific irreversible dopamine antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) into dorsomedial striatum of rats exposed from weaning to 0, 50 or 500 ppm Pb acetate drinking solutions. The 500 ppm exposure increased baseline FI response rates relative to both 0 and 50 ppm. Intra-dorsomedial striatum EEDQ and dopamine had no effects when examined across all animals. However, both compounds produced rate-dependent effects, i.e. increases or decreases in rate in different subjects, depending upon baseline Fl overall rates. The rate-increasing effects of intra-dorsomedial striatum dopamine actually mimicked Pb effects, increasing Fl overall and run rates and shortening postreinforcement pause times. Further, Pb exposure modulated effects of dopamine and EEDQ in dorsomedial striatum. While these collective findings conceivably suggest dorsomedial striatum as another potential site through which postweaning Pb exposure influences FI performance, this possibility is not supported by other studies that show that chronic postweaning Pb alters dopamine binding sites and evoked dopamine release in nucleus accumbens but not in dorsomedial striatum even over a year exposure period. Thus, while both regions may play a role in mediating Fl performance under normal conditions, it appears that alterations in nucleus accumbens dopamine activity may be sufficient to induce chronic postweaning Pb-induced increases in FI response rates.

Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson's disease?

The absence of any compelling basis for a heritable basis of idiopathic Parkinson's disease (PD) has focused attention on environmental exposures as causative agents. While the herbicide paraquat has repeatedly been implicated, its impact on dopamine systems following systemic exposures is equivocal. The restricted focus on paraquat also ignores the extensive geographical overlap of its use with other agrichemicals known to adversely impact dopamine systems, including ethylenebisdithiocarbamate fungicides such as maneb. The present study sought to determine whether combined exposures to paraquat and maneb would produce additive effects and support a multiple-hit environmental contribution to PD. C57BL/6 mice were exposed to either paraquat (5-10 mg/kg) or maneb (15-30 mg/kg) i.p. alone or in combination once a week for 4 weeks. Sustained decreases in motor activity immediately following injections were consistently observed only with combined exposures, with activity levels returning to control values 24 h later. Concurrently, levels of dopamine and metabolites and dopamine turnover were increased immediately post-injection only by combined exposures, and returned to control levels or below within 48 h. Reductions in tyrosine hydroxylase immunoreactivity, measured 3 days after the last injection, resulted only from combined exposure and were detected in dorsal striatum, but not in the nucleus accumbens. The fact that combined exposures resulted in potentiated effects that appear to target nigrostriatal dopamine systems suggests that these combinations may be important environmental risk factors for Parkinsonism. These findings also raise questions about the adequacy of current risk assessment guidelines for these chemicals which are based on effect levels derived from exposures to single agents.

Evaluation of techniques for assessing neurobehavioral development in children.

A battery of tests has been designed to explore functional disabilities in children 10-12 years of age arising from adverse conditions during early development. At these ages, it becomes possible to use more complex and challenging tests than those typically used at earlier ages. Although the battery was prompted originally by questions arising from methylmercury exposure, it was also designed for applicability to neurotoxicant exposures arising from pesticides, solvents, persistent organic pollutants such as PCBs and dioxins, other metals, and nutrient excesses and deficiencies as well. The test battery includes the following categories: (1) neuropsychological tests with established psychometric properties not widely exploited in studies of developmental neurotoxicity; (2) electrophysiological and behavioral tests of sensory functioning spanning a broader range of indices than those used generally in studies of neuropsychological development; and (3) adaptations of performance tasks used previously only in animals. The battery was developed in Rochester, New York, and then field-tested on a group of 61 children in the Republic of the Seychelles, where the Ministry of Health had established the Child Development Center. Our findings suggest a number of tests and procedures with the potential for inclusion in test batteries aimed at the exploration of adverse neurodevelopmental effects.

Lead-induced decrements in waiting behavior: involvement of D2-like dopamine receptors.

Some behavioral changes produced by chronic postweaning lead (Pb) exposure have been linked to mesolimbic dopamine (DA) system alterations. This study sought to determine the role of DA systems in Pb-induced changes in a fixed ratio (FR) waiting-for-reward paradigm. Rats exposed chronically from weaning to 0, 50, or 150 ppm Pb acetate drinking solutions earned free reinforcers for waiting after completion of an FR, with increasing time between successive free reinforcers. Responses during the waiting period reset the FR requirement. Once performance stabilized, the effects of acute IP administration of the D1 agonist SKF82958, the D2 agonist quinpirole, the D1 antagonist SCH23390, and the D2 antagonist eticlopride were determined. Pb itself increased FR response rates and decreased mean waiting time, a pattern of behavior that increased the number of earned reinforcers, but doubled the number of responses/reinforcer. None of the DA compounds mimicked Pb effects when administered to controls. Only DA agonists altered waiting behavior and responses per reinforcer. Quinpirole, in particular, appeared to reverse Pb effects on the FR wait baseline by increasing waiting time and decreasing FR resets to control levels. These findings point to a particular role for D2 DA function in Pb's detrimental effects on waiting.

Learning versus performance impairments following regional administration of MK-801 into nucleus accumbens and dorsomedial striatum.

To further ascertain the relative contributions of nucleus accumbens (NAC) and dorsomedial striatum (DS) to cognitive behaviors, the comparative effects in rats of MK-801 microinjections into these regions on a multiple schedule of repeated learning (RL) and performance (P) were examined. The RL component required learning of a new three-member response sequence during each experimental session, while the P component required rote performance of a pre-learned response, thus permitting a more precise delineation of treatment-related cognitive vs. non-cognitive changes. MK-801 decreased overall accuracy in both the RL and P components of the schedule in both brain regions, indicating that in neither NAC nor DS are NMDA receptors exclusively involved in mediating acquisition processes. Decreases in overall accuracy were primarily due to increased perseverative errors which may have been the result of excessively accelerated responding, a type of motoric alteration. MK-801 administered into NAC also resulted in an additional increase in skipping errors at the 2.5 micrograms dose, a finding which could be consistent with disrupted learning resulting from an inability to encode spatial relationships. Collectively these findings suggest that NAC and DS mediate some behavioral functions in common, but that additional cognitive-related spatial processes are mediated by NAC.

The effects of postweaning low-level Pb exposure on sustained attention: a study of target densities, stimulus presentation rate, and stimulus predictability.

It has been suggested that behavioral effects associated with low-level lead (Pb) exposure are related to alterations in attentional processes. These "attention deficits" remain undefined, and few studies have directly addressed the effects of Pb on specific measures of attention. The current study assessed the impact of Pb on sustained attention, as one of the 3 primary clinical symptom domains of attention deficit disorder. Groups of rats were exposed from weaning (21 days of age) to either 0, 50, or 150 ppm Pb acetate in drinking water producing blood Pb levels of <5, 16.0, and 28.0 microg/dl, respectively. Rats were trained to discriminate a pulsing (target) from a non-pulsing (distracter) light. Parametric manipulations of target probability (10%-80%) and inter-stimulus interval (1 s-6 s, and variable) were imposed to evaluate whether effects of Pb were dependent upon attention demand. Sensitivity of the paradigm to changes in CNS function was validated by examining the effects of d-amphetamine (0.0-2.0 mg/kg) in a separate group of rats. Exposure to 50 ppm increased errors of omission only during sessions with long and variable inter-stimulus intervals. The 150 ppm group showed a small increase in errors of commission during sessions with a long inter-stimulus interval. No other Pb-related effects were observed. The absence of any pronounced Pb effects in this study on this sustained attention task could indicate that: 1) any Pb-induced attention deficits are modified by reinforcement and time-out contingencies; 2) Pb disrupts other aspects of attention such as inability to tolerate delays or impulsivity; and 3) Pb-related deficits are due to other behavioral dysfunctions.

Nucleus accumbens dopaminergic medication of fixed interval schedule-controlled behavior and its modulation by low-level lead exposure.

To examine the assertion that changes in nucleus accumbens (NAC) dopamine (DA) activity serve as a mechanism of lead (Pb)-induced disruption of fixed interval (FI) schedule-controlled behavior, the effects of intra-NAC administration of the irreversible DA antagonist EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihyroquinoline) and of dopamine itself on FI performance were compared in rats that had been chronically exposed to 0, 50 or 500 ppm Pb acetate in drinking water from weaning. Pb exposure per se (500 ppm), as in past studies, increased FI response rates, primarily by shortening interresponse times. Although DA, which produced rate-dependent effects, increased FI rates at low doses in the 0 and 50 ppm groups, it did so by decreasing postreinforcement pause times. All DA doses decreased rates in the 500 ppm group. In contrast, the DA antagonist EEDQ suppressed FI response rates, effects that were not strongly rate dependent, by increasing both postreinforcement pause values and mean interresponse times. Pb exposure (500 ppm) delayed the recovery of response rates to control levels at the highest EEDQ dose, raising the possibility of a delay in receptor production rate. Collectively, these data suggest that NAC DA activity may be an important modulator of FI response rates. Enhanced NAC DA activity may contribute to Pb-associated increases in FI rates and may underlie the differential response of control and 500 ppm Pb-treated groups to intra-NAC DA administration. The different processes by which DA and Pb increase FI rates, however, suggests that additional mechanisms are operative in the case of Pb.

Lead, attention, and impulsive behavior: changes in a fixed-ratio waiting-for-reward paradigm.

Similar to the effects observed in children diagnosed with attention deficit hyperactivity disorder (ADHD), experimental animals exposed to lead (Pb) exhibit behaviors attributed to "impulsivity" and "inability to inhibit inappropriate responding." Such behaviors have led some to suggest that Pb exposure is associated with attention deficit. Based on the hypothesis that attention deficits are related to an ineffectiveness of delayed reinforcement, this study examined the effects of chronic postweaning Pb exposure on an FR waiting-for-reward paradigm. Rats were exposed chronically from weaning to 0, 50, or 150 ppm Pb acetate in water and following 40 days of exposure, trained on a fixed-ratio (FR) wait behavioral baseline. A total of 50 lever press responses (FR 50) produced food delivery. After earning an FR pellet, "free" pellets could be obtained by waiting; emission of another lever press reinitiated the FR requirement. "Free" pellets were delivered at increasing intervals (2 s, 4 s, 6 s, etc.). Pb exposure increased response rates on the FR schedule and decreased the mean longest waiting time, but also resulted in a higher number of responses per reinforcer than exhibited by controls. These Pb-induced differences are consistent with an inability to manage delays of reinforcement.

Effects of chronic haloperidol on reaction time and errors in a sustained attention task: partial reversal by anticholinergics and by amphetamine.

The attentional and motor-disruptive effects of low doses of haloperidol were studied in a sustained attention task performed by rats. Five separate groups (n = 7 or 8) of rats were trained to react to a 0.125-sec visual stimulus by executing a nose-poke response within 3 sec of stimulus presentation. Each group of rats received its own dose (0.0, 0.02, 0.04, 0.08 or 0.12 mg/kg) of haloperidol daily for 3 months, and from the 1st week onward dose-effects on reaction time were quite stable across time. Haloperidol treatment disrupted the sustained attention task performance by decreasing the number of behavior-initiated stimulus presentations, decreasing the number of reinforcers earned, increasing the proportion of errors of omission and increasing reaction time to the target stimulus. Testing of challenge drugs began after 23 days of haloperidol treatment. Scopolamine (0.1 and 0.2 mg/kg), benztropine (1.0, 3.0 and 6.0 mg/kg) and d-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg) ameliorated haloperidol-induced reaction time slowing, whereas only benztropine and amphetamine lessened haloperidol-induced errors of omission. The 2.0-mg/kg dose of amphetamine by itself produced a significant increase in errors of omission without affecting reaction time. Haloperidol effectively normalized this amphetamine-induced disruption in attention. The results are consistent with a dopaminergic involvement in the expression of both attention and motor processes.