Impact of early-life lead exposure on adult delta-9-tetrahydrocannabinol sensitivity in male and female C57BL6/J mice.

Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (the main psychoactive component of which is delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3rd most widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. Here we establish a link between early life Pb exposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The study seeks to answer whether Pb exposure affects physiological/behavioral THC sensitivity (as measured by the cannabinoid-induced tetrad). It was hypothesized that Pb exposure would decrease THC sensitivity and that sex-dependent effects of Pb-exposure and THC would be observed. Interestingly, results showed that THC sensitivity was increased by Pb exposure, but only in female mice. Future research will fully explore the implications of these findings, namely how these effects impact THC self-administration and the mechanism(s) by which developmental Pb exposure produces these effects.

Systemic Administration of the AMPA Receptor Antagonist, NBQX, Reduces Alcohol Drinking in Male C57BL/6J, But Not Female C57BL/6J or High-Alcohol-Preferring, Mice.

BACKGROUND: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are ionotropic glutamate receptors that have been investigated for their role in modulating alcohol consumption. However, little is known about the role of AMPA receptors in the control of binge-like or free-access alcohol drinking in C57BL/6J or in selectively bred high-alcohol-preferring (HAP) mice. The purpose of this experiment was to assess the role of systemic administration of the AMPA receptor antagonist, 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX), on alcohol consumption using a model of binge-like drinking, drinking in the dark (DID) and free-access 2-bottle choice (2BC) in male and female C57BL/6J and HAP mice. METHODS: C57BL/6J mice were allowed free access to 20% (v/v) alcohol for 2 hours each day beginning 3 hours into the dark cycle for 4 days. On day 5, mice were intraperitoneally injected with one of 4 doses of NBQX (0, 3, 10, or 30 mg/kg; n = 10) 15 minutes before alcohol presentation and were given 4-hour alcohol access (extended DID). HAP mice were given 24-hour free access to 10% (v/v) alcohol and water for 19 days. On day 20, mice were intraperitoneally injected with one of 4 doses of NBQX (0, 3, 10, or 30 mg/kg; n = 9) 15 minutes before alcohol and water presentation. RESULTS: In the first 2 hours of DID, at 30 mg/kg, male, but not female C57BL/6J or HAP, mice drank significantly less alcohol compared with controls and 30 mg/kg NBQX did not alter saccharin intake in the males. Although male HAP mice drank significantly less alcohol than female mice following 10 mg/kg NBQX, neither sex exhibited drinking that differed significantly from controls. NBQX did not reduce locomotor behavior at any dose, sex, or genotype. CONCLUSIONS: These data suggest that AMPA receptors play a key role in modulating binge-like alcohol consumption without altering saccharin consumption or general locomotion and that this effect is specific to sex and genotype.