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.

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.

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.

Low-level lead exposure selectively enhances dopamine overflow in nucleus accumbens: an in vivo electrochemistry time course assessment.

Exposures to even very low levels of lead (Pb) alter behavioral and neurochemical functions. The current study was based on the hypothesis that excess synaptic dopamine (DA) availability may contribute to such disturbances and that the mesolimbic DA projection is more sensitive than the nigrostriatal system to Pb-induced DA-based alterations. In vivo electrochemical measurements of potassium chloride-evoked DA overflow and clearance were compared in dorsal striatum (STR) (nigrostriatal system) and nucleus accumbens (NAC)(mesolimbic system) of male rats after 11 weeks or 11 months of postweaning exposure to 0, 50, or 150 ppm Pb acetate drinking solutions. Pb increased evoked DA overflow selectively in NAC, with biphasic effects at 11 weeks, including increases greater than 400% at 50 ppm and concentration-related effects up to 265% of control at 11 months. Considered relative to 11-week control levels, continued exposure tended to attenuate the magnitude of Pb-related increases in DA overflow in NAC. Pb decreased clearance time in both brain regions, with these effects markedly augmented across time. These changes in DA function were observed at blood Pb values of only 15-16 micrograms/dl, underscoring their environmental relevance. The current findings support the hypothesis of excess DA availability as a mechanism of Pb-induced behavioral alterations and of a particular vulnerability of mesolimbic DA systems (NAC) to such effects. They also suggest that different mechanisms underlie Pb-related changes in amplitude and clearance and confirm previous reports of regional differences of DA systems in response to Pb exposure.

Lead-induced changes in dopamine D1 sensitivity: modulation by drug discrimination training.

Prior studies have reported that Pb exposure results in enhanced sensitivity to both D1 and D2 dopamine agonists as indicated by left shifts of the dose-effect functions for the discrimination of these agonists from saline in drug discrimination procedures (Cory-Slechta and Widzowski, 1991). To further determine mechanisms of such Pb-induced changes in dopamine system functions, this study evaluated the potential contribution to Pb-induced D1 supersensitivity of:i) synergistic D1-D2 receptor interactions, and ii) the effects of the chronic D1 agonist administration inherent in the drug discrimination procedures themselves. As in Cory-Slechta and Widzowski (1991), rats exposed from weaning to 50 or 150 ppm Pb acetate in drinking water and trained using standard operant drug discrimination procedures to discriminate 6.0 mg/kg of the partial D1 agonist SKF38393 from saline showed greater sensitivity to SKF38393 (left-shifted dose effect curves) than did the 0 ppm group. To determine the role of D1/D2 interactions in this supersensitivity, SKF38393 dose-effect curves of the groups were compared in the presence and absence of a dose of 0.04 mg/kg of the D2 antagonist haloperidol. The impact of the chronic administration of the D1 agonist utilized in drug discrimination training was determined by comparing the dose-effect curves of the groups before and after a 24 day period of discontinuation of drug discrimination training. D1/D2 interactions do not appear to contribute to Pb-induced enhancement of sensitivity to the D1 agonist SKF38393, as it was maintained even in the presence of the D2 antagonist haloperidol. Discontinuation of drug discrimination training resulted in sensitization in control but not Pb-treated rats, a pattern indicative of Pb-induced D1 subsensitivity. These data raise questions about the depletion of dopamine (DA) availability as a mechanism of Pb-induced alterations in DA system function and suggest that Pb-induced D1 supersensitivity may represent altered effects of chronic D1 administration imposed on DA systems modified by Pb exposure per se.

Measles spread in medical settings: an important focus of disease transmission?

During the period September 1981 to August 1985, we investigated every reported case of measles in Oklahoma to confirm the diagnosis, to determine the source, and to identify contacts to prevent spread of the disease. During this time, 33 serologically and/or epidemiologically confirmed cases were investigated. Nine (27%) persons acquired measles in a medical office or clinic waiting area. Eight of these recalled direct face-to-face contact with a source. An additional six (18%) cases were associated with exposure to these medically acquired cases, for a total of 45% that were the direct or indirect result of exposures in medical waiting rooms. The medical waiting room is a location where a reservoir of susceptible individuals may congregate, allowing for potential exposures to measles and other infectious diseases. Because many persons in these settings are too young to have received routine measles vaccination, other measures to decrease exposures in this setting may be necessary to achieve the goal of measles elimination in the United States.

Pertussis epidemic in Oklahoma. Difficulties in preventing transmission.

From Jan 1 to Dec 31, 1983, 351 cases of pertussis were reported in Oklahoma. Overall, 59% of the cases were among children 3 months to 6 years of age, the target age group for pertussis vaccination; only 42% of the patients in this age group were appropriately immunized for age with diphtheria and tetanus toxoids and pertussis vaccine (DTP). A survey of 185 households in the neighborhoods of three cases found that only 65% of 57 children 3 months to 6 years of age were appropriately immunized for their age. Aggressive control of the outbreak was attempted in Oklahoma County with recommendations for widespread vaccination against pertussis. However, the effort failed to immunize 82% of the 931 children in the initial target group. Nonetheless, analysis of the reported cases suggested that less than one fourth of the cases were potentially preventable by a single additional dose of DTP, ie, in individuals 3 months to 6 years of age with a history of at least one prior dose of DTP who were not appropriately immunized for age. The optimal solution to outbreak control is outbreak prevention by ensuring that the maximal number of children younger than 7 years of age receive routine age-appropriate DTP vaccination.

School-based measles outbreaks: correlation of age at immunization with risk of disease.

During the Spring of 1978, students with a history of previous measles vaccination accounted for over three-forths of 203 cases of measles in a metropolitan county. Seventy cases occurred in two schools where 99% of the students were vaccinated. We analyzed countywide data to determine past patterns of measles vaccination, including outbreak control and vaccination update clinics. We also examined records of children from the two schools to assess the relationship between disease incidence and age at vaccination. When susceptibility was determined by trained health workers rather than by parents, fewer doses of measles vaccine were estimated to be needed. The majority of cases occurred among children 5 to 9 years old. Attack rates were higher for children vaccinated at 12 months of age or younger than for those vaccinated at 13 months of age or older. There were no significant differences in attack rates among children vaccinated at 13 months of age or older. These findings support recommendations for delaying routine measles vaccination until after 12 months of age and suggest that, during outbreaks, all children vaccinated prior to 13 months of age be revaccinated.