Preferential Vulnerability of Nucleus Accumbens Dopamine Binding Sites to Low‐Level Lead Exposure: Time Course of Effects and Interactions with Chronic Dopamine Agonist Treatments

Abstract

This study examined the hypotheses that low‐level lead (Pb) exposure would increase dopamine (DA) binding sites, would do so preferentially in nucleus accumbens, and that such effects would be modified by concurrent DA agonist treatment. D1‐like and D2‐like binding sites and the dopamine transporter (DT) were measured autoradiographically in caudate‐putamen and nucleus accumbens of rats exposed from weaning to 0, 50, or 150 ppm Pb acetate drinking solutions with or without concurrent chronic intermittent intraperitoneal injections of the D1‐like agonist SKF 82958 or the DA agonist apomorphine after 2 weeks (no injections), 8 months, or 12 months of Pb exposure. Pb selectively decreased DA binding in nucleus accumbens. Decreases in D2‐like and DT sites were sustained across the 12‐month exposure, whereas D1‐like sites evidenced recovery at 12 months. Chronic intermittent DA agonist treatments reversed these effects of Pb in nucleus accumbens, restoring receptor and DT binding levels to normal, despite decreasing binding sites of non‐Pb‐treated rats. These studies implicate increased DA availability as a mechanism of Pb‐induced DA system changes. They also raise the possibility that Pb exposure could serve as a predisposing factor in neurodegenerative diseases associated with DA system dysfunction or could alter the course of DA‐based therapeutic treatments.

Developmental lead exposure attenuates methamphetamine dose-effect self-administration performance and progressive ratio responding in the male rat

“…Because these changes are associated with the reinforcement properties of methamphetamine, and inasmuch as lead exposure is known to antagonize mesolimbic dopamine systems (cf. CorySlechta, 1995;Pokora et al, 1996), it is reasonable to assert that the attenuation of methamphetamine reinforcement in the present studies derived at least partly from the effects of developmental lead exposure on dopamine function. Importantly, it would appear that such effects are long-lasting and potentially permanent (cf.…”

“…As noted, developmental lead exposure results in behavioral changes across different psychoactive drugs. Because methamphetamine operates in part to interfere with the dopamine transporter and therein enhance dopamine transmission (Ranaldi and Poeggel, 2002), and because lead has a lasting impact at this site (Pokora et al, 1996), it would seem reasonable to examine lead/methamphetamine interactions. Accordingly, the purpose of the present project was to inform on the effects of perinatal lead exposure on methamphetamine dose-effect performance (Experiment 1), and to determine potential differences in progressive ratio responding which is believed to provide an index of motivation to seek the drug (Experiment 2).…”

Inorganic Lead Exposure in the Rat Activates Striatal cFOS Expression at Lower Blood Levels and Inhibits Amphetamine-Induced cFOS Expression at Higher Blood Levels

“…A pronounced decrease in D 2 -like binding sites was also observed in the nucleus accumbens at the 150 ppm level of exposure for all time points measured. Pokora et al (1996) concluded in this study that the nucleus accumbens was preferentially affected by lead relative to the striatum.…”

“…In particular, it involved a much more extensive developmental exposure that included both the prenatal and postnatal periods. Pokora et al (1996) used a postweaning exposure protocol similar to the one used in the present study to examine the time course of the effects of lead on DA D 1 -like and D 2 -like receptor binding in the striatum and nucleus accumbens. In the striatum, lead exposure at the 150 ppm level caused only a small and transient decrease in D 1 -like binding after 8 months of lead treatment (no longer significant after 12 months), but no effect at the earlier 2-week time point.…”

CNS effects of developmental Pb exposure are enhanced by combined maternal and offspring stress

“…Thus, both Pb and stress target low SES populations. Secondly, both Pb and stress act on brain mesocorticolimbic and hippocampal dopamine and glutamate systems (Diorio et al 1993;Lowy et al 1993;Piazza et al 1996;Pokora et al 1996;Cory-Slechta et al 1998;Rouge-Pont et al 1998;Cory-Slechta et al 1999;Barrot et al 2000;Moghaddam 2002), which may in fact explain their common consequences, including cognitive dysfunction and attention deficits (Dohrenwend, 1973;Bellinger et al, 1994;Schwartz, 1994;Anderson and Armstead, 1995a;Cory-Slechta, 1995;Needleman et al, 1996;Dietrich et al, 2001;Bradley and Corwyn, 2002). Third, the mesocorticolimbic dopamine system, a key target of Pb effects on behavior (Cory-Slechta 1995;Cory-Slechta et al 1996;Cory-Slechta et al 1997a;Cory-Slechta et al 1997b;CorySlechta et al 1998;Cory-Slechta et al 2002;Abbott et al 2003) has extensive interactions with the hypothalamic-pituitary-adrenal (HPA) axis, the system that coordinates the body's physiological response to stress (Vazquez 1998).…”