Leading to Drug Addiction

VIRGOLINI, MB

Conferencia; NeuroToxicity Society and International NeuroToxicology Association Meeting; 2017

NTS and INA

Developmental exposure to environmental neurotoxicants induces differential reactivity to challenging events later in life, including drug addiction. We have demonstrated that low level lead (Pb) exposure (220 ppm in drinking water) during gestation and lactation enhances the motivational responses to ethanol (Etoh) in periadolescent male pups in both, a voluntary Etoh consumption test and oral self-administration task. In search of the neurobiological basis that may account for these differences, the focus of these studies was on central Etoh metabolism and the enzymes involved in brain acetaldehyde (ACD) modulation. In the brain, catalase (CAT) mediates central Etoh oxidation to ACD, whereas ALDH favors ACD oxidation to acetate. At this respect, we report here that both, pharmacological CAT activation or brain ALDH inhibition was able to increase Etoh intake in both, control and Pb-exposed animals, while CAT blockade reduced the drug consumption selectively in the Pb group. Moreover, an intra VTA shRNA antiCAT vector microinfusion reduced Etoh intake only in the Pb group. At the neurochemical level, on the last session of the Etoh intake test, blood CAT activity and midbrain CAT expression were increased as result of Pb exposure, difference that disappeared with pharmacological CAT inhibition and resurged with CAT activation. On the opposite, brain ALDH2 activity and expression were reduced in the Pb-exposed group, a fact that may have prevented the expected ALDH2 activity inhibition after pharmacological blockade. These results contrast with peripheral ACD accumulation induced by systemic ALDH inhibition (a therapeutic approach employed in clinical practice to dissuade Etoh consumption) that resulted in a decrease in Etoh intake predominantly in the Pb-exposed animals. Overall, these results indicate that Etoh metabolizing enzymes are modulated by developmental Pb exposure with resultant central ACD accumulation, suggesting a prevalence of the reinforcing effects of brain ACD against the aversive peripheral ACD accumulation. Supported by: FONCyT, SECyT and CONICET (Argentina)