Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats
Introduction
Alcohol use disorder (AUD) is a chronic relapsing disorder that is characterized by compulsive alcohol use (Koob and Le Moal, 1997), which places an enormous burden on society. In addition to its psychological and societal toll, AUD was estimated to cost the United States' economy USD$249 billion in 2010 alone (Sacks et al., 2015). Current behavioral and pharmacological treatments have limited efficacy, and there is an urgent need for new and more effective treatments (Koob, 2010). Alcohol use disorder has high comorbidity with several psychiatric disorders, including generalized anxiety disorder and depression. Thus, the development of treatments for AUD that may also address psychiatric comorbidities is critically important.
The enzyme glyoxalase 1 (GLO1) is the rate-limiting enzyme in the glyoxalase system, a metabolic pathway that detoxifies α-oxoaldehydes, particularly methylglyoxal (Mannervik, 2008; Thornalley, 1990, Thornalley, 1993, Thornalley, 2003b). Methylglyoxal (MG) is naturally produced by several mechanisms, including by the degradation of glycolytic intermediates, dihydroxyacetone phosphate, and glyceraldehyde-3-phosphate (Thornalley, 1993). In conjunction with GLO2, GLO1 enzymatically converts MG into d-lactate (Thornalley, 2003a). Methylglyoxal is a competitive partial agonist at γ-aminobutyric acid A (GABAA) receptors, and physiological levels of MG have been implicated in several processes that involved GABAA signaling. For example, voluntary binge-like alcohol drinking was recently shown to be modulated by Glo1 gene expression (McMurray et al., 2017b). The overexpression of Glo1 increased drinking, and the genetic knockdown of Glo1 and pharmacological inhibition of the enzyme (GLO1) that is encoded by Glo1 decreased alcohol drinking in nondependent mice in the drinking-in-the-dark (DID) paradigm (McMurray et al., 2017b). Interestingly, a role for Glo1 in two other behavioral domains that are often comorbid with alcoholism has also been demonstrated. The genetic and pharmacological manipulation of Glo1 affects anxiety-like behavior (Distler et al., 2012; McMurray et al., 2016; Williams et al., 2009) and depression-related behavior (McMurray et al., 2017b). This raises the possibility that GLO1 inhibitors may be useful for the treatment of AUD and other common comorbid conditions. However, the effect of small-molecule inhibitors of GLO1 on alcohol self-administration in animal models of alcohol dependence remains to be demonstrated.
The present study tested the effect of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) on alcohol self-administration in alcohol-dependent and nondependent rats. We used the chronic intermittent ethanol (CIE) model combined with operant self-administration, a model that has been shown to have robust predictive validity for alcoholism and construct validity for the neurobiological mechanisms of alcohol dependence (Heilig and Koob, 2007; Koob, 2009). Rats that are made dependent by CIE exhibit clinically relevant blood alcohol levels (BALs; 150–250 mg/100 ml), an increase in alcohol drinking when tested during early and protracted abstinence, and compulsive-like alcohol drinking (e.g., responding despite adverse consequences; Kimbrough et al., 2017b; Leao et al., 2015; O'Dell et al., 2004; Roberts et al., 1996; Schulteis et al., 1995; Vendruscolo et al., 2012). Alcohol dependence that is induced by alcohol vapor results in withdrawal symptoms during both acute withdrawal and protracted abstinence (de Guglielmo et al., 2017; Kallupi et al., 2014; Macey et al., 1996; Vendruscolo and Roberts, 2014), anxiety-like behavior (Valdez et al., 2002), irritability-like behavior (Kimbrough et al., 2017a), and the development of mechanical hyperalgesia (Edwards et al., 2012). We hypothesized that if GLO1 is a relevant target for the treatment of AUD, then pBBG treatment will reduce alcohol self-administration in both dependent and nondependent rats.
Section snippets
Animals
Adult male Wistar rats (n = 12; Charles River, Raleigh, NC, USA), weighing 225–275 g at the beginning of the experiments, were housed in groups of two per cage in a temperature-controlled (22 °C) vivarium on a 12 h/12 h light/dark cycle (lights on at 8:00 PM) with ad libitum access to food and water. All of the behavioral tests were conducted during the dark phase of the light/dark cycle. All of the procedures adhered to the National Institutes of Health Guide for the Care and Use of Laboratory
Systemic pBBG reduces alcohol self-administration in nondependent and dependent rats
pBBG significantly reduced alcohol self-administration in nondependent rats. This effect was confirmed by the one-way ANOVA, which revealed a significant effect of treatment (F2,11 = 9.53, p < 0.01). The Newman Keuls post hoc test showed that pBBG significantly reduced alcohol self-administration at the dose of 25 mg/kg (p < 0.01; Fig. 2A, a). The effect was dose-dependent, in which a significant difference was detected between the 7.5 and 25 mg/kg doses (p < 0.05; Fig. 2A, a). Water
Discussion
The present study demonstrated a role for GLO1 in the regulation of alcohol consumption in dependent rats and extended previous findings by showing a key role for GLO1 in modulating alcohol drinking in nondependent animals. A key novel finding was that pBBG, a small-molecule inhibitor of GLO1, reduced alcohol self-administration in dependent rats and was more effective in the dependent state than in the pre-dependent state. Treatment with pBBG (7.5 and 25 mg/kg) significantly reduced alcohol
Authors contributions
GdG, AAP, and OG were responsible for the study concept and design. GdG, DEC, and ABL contributed to the acquisition of animal data. GdG and OG drafted the manuscript. All authors critically reviewed the content and approved the final version for publication.
Funding and disclosure
This study was supported by National Institutes of Health grants AA006420, AA020608, AA022977 (OG), and AA025515 (ABL). The authors declare no conflict of interest.
Acknowledgements
The authors thank Michael Arends for proofreading the manuscript.
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2023, NeuropharmacologyCitation Excerpt :The current gold standard animal model for the induction of alcohol dependence in rats is the model of chronic intermittent ethanol vapor (CIE). The CIE model represents a very efficient way to produce alcohol dependence (Becker and Lopez, 2004; de Guglielmo et al., 2016; Gilpin et al., 2008, 2009; Leao et al., 2015; Lopez and Becker, 2014; Richardson et al., 2008), and over the years it has been helpful to elucidate the neuronal mechanisms underlying alcohol dependence (de Guglielmo et al., 2016, 2018, 2019; Funk et al., 2006; Healey et al., 2008; Kallupi et al., 2014; Kimbrough et al., 2017; Kononoff et al., 2018; Leao et al., 2015; Nealey et al., 2011; Smith et al., 2011; Valdez et al., 2002; Varodayan et al., 2017; Vendruscolo et al., 2012, 2015; Walker, 2012; Walker and Koob, 2008; Walker et al., 2011). We recently characterized a novel animal model animal for the induction and maintenance of alcohol dependence in outbred rats using chronic intermittent alcohol vapor self-administration (EVSA model (de Guglielmo et al., 2017)) by using a novel apparatus that allow rats to self-administer alcohol vapor in their home cage.
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2022, Redox BiologyCitation Excerpt :Pretreatment with a GLO1 inhibitor also alleviated pilocarpine-induced seizures, whereas Glo1 overexpression exacerbated seizures and decreased the MG concentration in the brain. Likewise, GLO1 inhibitors reduced alcohol consumption [82,83] and handling-induced convulsion after alcohol injection [84], whereas Glo1 overexpression exacerbated these effects. In addition, alcohol consumption was reduced in Glo1 hemizygous-knockdown mice [82].
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2022, Physiology and BehaviorCitation Excerpt :This pathway is involved in apoptosis, metabolism, and reactive oxygen species [38]. Recent studies have manipulated Glo1 to examine its effects on alcohol intake in several behavioral assays including drinking in the dark [44] in mice, self-administration in rats [40] and locomotor impairment in mice [45]. In all three studies decreased Glo1 resulted in reduced alcohol intake.