Long‐term inhibition of ethanol intake by the administration of an aldehyde dehydrogenase‐2 (ALDH2)‐coding lentiviral vector into the ventral tegmental area of rats

Abstract

Previous studies suggest that acetaldehyde generated from ethanol in the brain is reinforcing. The present studies tested the feasibility of achieving a long-term reduction of chronic and post-deprivation binge ethanol drinking by a single administration into the brain ventral tegmental area (VTA) of a lentiviral vector that codes for aldehyde dehydrogenase-2 (ALDH2), which degrades acetaldehyde. The ALDH2 gene coding vector or a control lentiviral vector were microinjected into the VTA of rats bred for their alcohol preference. In the chronic alcohol administration model, naïve animals administered the control vector and subsequently offered 10% ethanol and water ingested 8-9 g ethanol/kg body weight/day. The single administration of the ALDH2-coding vector prior to allowing ethanol availability reduced ethanol drinking by 85-90% (P < 0.001) for the 45 days tested. In the post-deprivation binge-drinking model, animals that had previously consumed ethanol chronically for 81 days were administered the lentiviral vector and were thereafter deprived of ethanol for three 7-day periods, each interrupted by a single 60-minute ethanol re-access after the last day of each deprivation period. Upon ethanol re-access, control vector-treated animals consumed intoxicating 'binge' amounts of ethanol, reaching intakes of 2.7 g ethanol/kg body weight in 60 minutes. The administration of the ALDH2-coding vector reduced re-access binge drinking by 75-80% (P < 0.001). This study shows that endowing the ventral tegmental with an increased ability to degrade acetaldehyde greatly reduces chronic alcohol consumption and post-deprivation binge drinking for prolonged periods and supports the hypothesis that brain-generated acetaldehyde promotes alcohol drinking.

(R)-Salsolinol, a product of ethanol metabolism, stereospecifically induces behavioral sensitization and leads to excessive alcohol intake

“…A syringe pump (model 55-5920, Harvard Apparatus, South Natick, MA, USA) delivered 1.0 μl of vehicle (aCSF) or of (R)-SAL or (S)-SAL) in 100 seconds (0.6 μl/minute) and injectors remained in place for 30 seconds after the injection procedure was completed in order to prevent backflow through the cannula. A note on laterality: Our previous studies (Karahanian et al 2011(Karahanian et al , 2015Quintanilla et al 2012;Tampier et al 2013) suggest that at a higher brain level, differences in (right − left) input appear integrated as one. Thus, clear physiological effects are observed when only one side is injected.…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…In this system, treatment with an ADH inhibitor 4-methylpyrazole prevented gut leakiness, whereas treatment with cyanamide, an ALDH2 inhibitor, increased the rate of leakiness (permeability) in cultured Caco-2 cells and animal models. Last, some reports suggested that acetaldehyde produced and accumulated in the brain is involved in alcohol-seeking behavior, likely contributing to alcohol addiction (Deitrich, 2011;Karahanian et al, 2011Karahanian et al, , 2015Rodd-Henricks et al, 2002).…”

Racemic Salsolinol and its Enantiomers Act as Agonists of the μ-Opioid Receptor by Activating the Gi Protein-Adenylate Cyclase Pathway

“…Nevertheless, a number of studies have shown that acetaldehyde, the primary metabolite of ethanol in the brain, is self-administered intracranially by rats at micromolar concentrations showing strong motivational and reinforcing effects (Rodd et al, 2005). Indeed, ethanol metabolism to acetaldehyde in the brain is required to exert ethanol’s reinforcing actions (Karahanian et al, 2011, 2015; Quintanilla et al, 2012; Israel et al, 2015; Peana et al, 2016). …”