Chronic developmental lead exposure increases μ-opiate receptor levels in the adolescent rat brain

Abstract

Childhood lead (Pb²⁺) intoxication is a global public health problem best known for producing deficits in learning and poor school performance. Human and preclinical studies have suggested an association between childhood Pb²⁺ intoxication and proclivity to substance abuse and delinquent behavior. While environmental factors have been implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb²⁺ exposure (1500 ppm in the diet) on μ-opioid receptor (MOR) levels in the rat brain using [³H]-d-Ala2-MePhe4-Gly-ol5 enkephalin ([³H]-DAMGO) quantitative receptor autoradiography at different developmental stages (juvenile, early-adolescent, late adolescent and adult) in male and female rats. Our results indicate that chronic developmental Pb²⁺ exposure increases the levels of [³H]-DAMGO specific binding to MOR in juvenile and early adolescent Pb²⁺-exposed male and female rat brain with no changes in late-adolescent (PN50) and minor changes in Pb²⁺-exposed adult male rats (PN120). Specifically, at PN14, Pb²⁺-exposed males had an increase in MOR binding in the lateral posthalamic nuclei (LPTN), and Pb²⁺-exposed females had increased MOR binding in LPTN, medial thalamus, and hypothalamus. At PN28, Pb²⁺-exposed males had increased MOR levels in the striatum, stria medullaris of the thalamus, LPTN, medial thalamus, and basolateral amygdala, while Pb²⁺-exposed females showed an increase in nucleus accumbens core, LPTN, and medial thalamus. No changes were detected in any brain region of male and female rats at PN50, and at PN120 there was a decrease in MOR binding of Pb²⁺-exposed males in the medial thalamus. Our findings demonstrate age and gender specific effects of MOR levels in the rat brain as a result of chronic developmental Pb²⁺ exposure. These results indicate that the major changes in brain MOR levels were during pre-adolescence and early adolescence, a developmental period in which there is higher engagement in reward and drug-seeking behaviors in humans. In summary, we show that chronic exposure to Pb²⁺, an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period, these findings have important implications for opioid drug use and abuse.

Keywords: Adolescence; Brain; Mu-opioid receptor; Pb(2+) exposure; Rat.