Chronic Developmental Lead Exposure increases μ-Opiate Receptor Levels in the Adolescent Rat Brain

Abstract

Opioid use and abuse has reached epidemic proportion in the United States resulting in a significant numbers of deaths due to overdose. While environmental factors are implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Human and preclinical studies have suggested an association between childhood lead (Pb 2+ ) intoxication and proclivity to substance abuse and delinquent behavior. 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 Pb 2+ exposure on µ-opioid receptor (MOR) levels in the rat brain using [ 3 H]-D-Ala2-MePhe4-Gly-ol5 enkephalin ([ 3 H]-DAMGO) quantitative receptor autoradiography.Our results indicate that chronic developmental Pb 2+ exposure increases the levels of [ 3 H]-DAMGO specific binding to MOR in several limbic regions of the brain in male and female rats during the pre-adolescence (PN14) and early-adolescence (PN28) period. These changes were less pronounced in late-adolescence (PN50) and adult (PN120) animals. Our findings are important because the pre-adolescence and early adolescence period is a time in which there is higher engagement in reward and drug seeking behaviors in humans.In summary, we show that chronic exposure to Pb 2+ an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period with important implications to opioid drug use and abuse.

Chronic early-life lead exposure sensitizes adolescent rats to cocaine: Role of the dopaminergic system

“…Dopamine receptors can form heteromers with opioid receptors, D2 dopamine receptors, and NMDA receptors, among others (reviewed in Derouiche and Massotte, 2019), and they can be involved in substance use disorder. Our data shows that Pb 2+ exposure alters D1R levels in several brain regions implicated in substance abuse and previous studies from our group show that Pb 2+ exposure affects other neurotransmission systems, which could translate at the behavioral level (Guilarte and McGlothan, 2003;Neal et al, 2010Neal et al, , 2011Stansfield et al, 2015;Albores-Garcia et al, 2021). Additionally, other studies have shown the role of environmental toxin exposures on drug sensitivity.…”

“…The Pb 2+ exposure paradigm used in this study did not change the body weight gain of Pb 2+ -exposed rats at PN28, PN50, or PN120 (Albores-Garcia et al, 2021). BLL were significantly higher in both exposed groups in male and female rats, at all evaluated ages (Albores-Garcia et al, 2021).…”

“…There are other neurotransmitter systems involved in SZ that have been previously shown to be affected by Pb 2+ exposure, and dopaminergic signaling could be modulated by these other systems. For example, opioid receptors are highly implicated in reward and therefore a key signaling system in drug abuse mechanisms (Mulder et al, 1984;Spanagel et al, 1992;Shippenberg and Rea, 1997;Karkhanis et al, 2017), as well as a potential target of Pb 2+ exposure (Albores-Garcia et al, 2021), particularly in early developmental stages. Dopamine receptors can form heteromers with opioid receptors, D2 dopamine receptors, and NMDA receptors, among others (reviewed in Derouiche and Massotte, 2019), and they can be involved in substance use disorder.…”

“…However, our results suggest a putative role of dopaminergic disturbances in Pb 2+ -exposed animals that needs to be further explored in order to explain the observed behavioral outcomes. In addition, this work is part of a long-standing project with data suggesting that exposure to environmental toxins during critical stages of brain development may contribute to the etiology of mental disorders (Abazyan et al, 2014;Stansfield et al, 2015), such as SZ and an increased susceptibility to substance use disorder (Albores-Garcia et al, 2021).…”

“…In the United States, the use of psychostimulant drugs is still a significant public health concern, as it is estimated that around 1.6 million Americans have drug abuse problems (Center for Behavioral Health Statistics and Quality, 2016). Recent studies from our laboratory show that chronic developmental Pb 2+ exposure increases µ-opiate receptor levels in brain regions implicated with addiction circuits (Albores-Garcia et al, 2021) which could sensitize the animals to the effects of opioids, and other drugs. However, the consequences of these changes in the animal behavior and the underlying mechanisms behind SZ and substance abuse comorbidity, as well as the potential role of Pb 2+ exposure as a risk factor for both pathologies have not been completely elucidated or investigated.…”