Inflammation Produced by Alcohol Synergizes with Methamphetamine to Cause Dopaminergic Deficits

Abstract

Alcohol and methamphetamine (Meth) are often co‐abused, in that ~77% of Meth addicts also display an alcohol use disorder. However, the neurochemical consequences of this comorbid drug taking behavior are unknown. We tested the hypothesis that serial exposure to ethanol (EtOH) and Meth produces greater neurotoxicity compared to either drug alone. Sprague Dawley rats were allowed drinking access to a 2 bottle choice of 10% EtOH and water, every other day for 4 weeks, followed by one day of binge Meth (10 mg/kg × 4 injections). Over 4 weeks, both EtOH intake (g/kg) and preference (% total volume) increased (p<0.05). EtOH drinking alone caused inflammation, evidenced by significant increases in lipopolysaccharide (LPS) in serum and increased LPS and cyclooxygenase‐2 (COX‐2) in the striatum 24 hours after the last day of EtOH compared to water drinking (*p<0.05 vs. Water). 7 days after Meth or saline injections, striatal dopamine (DA) was depleted by 50% in Meth‐treated rats and by 95% in EtOH+Meth treated rats (*p<0.05 vs. Water+Saline). The DA transporter, DAT, followed a similar trend. Importantly, EtOH alone did not affect DA or DAT concentrations in the brain. Additionally, the amount of EtOH imbibed significantly correlated with the extent of Meth‐induced DA depletions (r2=0.89; p<0.001). The significantly enhanced DA depletions produced by the serial exposure to EtOH drinking and Meth (Meth alone vs. EtOH+Meth; p<0.05) were blocked by the COX inhibitor, ketoprofen (5 mg/kg) administered twice daily on the intermittent withdrawal days during the EtOH drinking period. To determine whether the loss of DA was paralleled by changes in the substantia nigra pars compacta (SNpc), cell bodies were stained for tyrosine hydroxylase (TH). Immunofluorescence showed a significant loss of TH‐positive cells in the SNpc. To ascertain if the loss of DA at the cell body and terminal levels resulted in Parkinsonian‐like motor deficits, motor function was tested 7 days after the last drug exposure. Rotarod test results showed that neither EtOH alone nor Meth alone affected motor behavior, but the serial exposure to the drugs significantly decreased the latency to fall off the rod. These results show the inflammation during EtOH drinking increases the sensitivity to Meth neurotoxicity in the striatum. Future studies will examine if inflammation mediates the loss of TH and motor function, and the extent to which glutamate‐mediated excitotoxicity plays a role in this DAergic loss.Support or Funding InformationNIH DA007606This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.