Increase in Free Choice Oral Ethanol Self‐Administration in Catechol‐O‐Methyltransferase Gene‐Disrupted Male Mice

Abstract

The effect of catechol-O -methyltransferase ( Comt ) gene disruption on the voluntary oral consumption of water, ethanol (2.5-20%, v/v) and cocaine (0.1-0.8 mg/ml) was studied in the free-choice, two-bottle paradigm in male and female mice. Solutions containing ethanol or cocaine, or tap water were available ad libitum from drinking burettes for 4 weeks. Catechol-O -methyltransferase-deficient male mice consumed significantly more ethanol than their wild-type male littermates. In contrast, female mice did not show genotype differences in the consumption of ethanol solutions. During the cocaine experiment, male mice developed either a side preference or an aversion that obscured cocaine consumption. This pattern of drinking was not dependent on Comt genotype. In female mice, Comt genotype was not associated with cocaine consumption. In conclusion, disruption of Comt gene influenced ethanol consumption in a gender-dependent manner in mice, supporting the hypothesis that low catechol-O -methyltransferase activity is one of the predisposing factors for high alcohol consumption in males.Catechol-O -methyltransferase catalyses the metabolism of catecholamines and other catechols both in the brain and in the peripheral tissues. In striatum, uptake by the dopamine transporter removes dopamine from the synaptic cleft [1][2][3]. However, in brain areas with a low dopamine transporter density (e.g. in the prefrontal cortex), the role of catechol-O -methyltransferase in the control of dopaminergic transmission is more crucial [4][5][6]. Recently, it was shown that in catechol-O -methyltransferase ( Comt ) gene-disrupted mice, elimination of dopamine in prefrontal cortex was two times slower than in wild-type animals, whereas dopamine clearance in the striatum was normal [7]. Prefrontal cortex is involved in certain aspects of cognition [8,9]. It sends projections and modulates dopaminergic transmission in subcortical areas and even dopamine synthesis in the midbrain [10]. These pathways are critically important not only in reward and emotions but also in the development of addiction [11].The common functional Val108/158Met polymorphism is known to control human catechol-O -methyltransferase activity. The Met allele results in a heat-labile enzyme with reduced enzyme activity [12,13]. Comt Val108/158Met polymorphism has been proposed to affect cognitive functions [14,15], but its role in alcoholism remains unclear. Some studies have shown an association between the high catechol-O -methyltransferase activity and alcoholism in males [16]. In contrast, there are reports claiming an association between the low enzyme activity and high alcohol consumption in non-alcoholic males [17] as well as in individuals with type 1 and type 2 alcoholism [18,19]. Several reports also indicate that catechol-O -methyltransferase polymorphism is not linked to alcoholism [20].Previous studies with catechol-O -methyltransferase-deficient mice have shown that the gene disruption has only minor effects on striatal dopamine levels under no...

Alcohol dependence as a chronic pain disorder

“…Some studies suggest that the met158 allele contributes to the development of both late-onset and early-onset alcoholism (Tiihonen et al, 1999; Wang et al, 2001) whereas others fail to find an association between COMT variation and alcohol dependence (Foroud et al, 2007; Ishiguro et al, 1999; Samochowiec et al, 2006). Male COMT −/− mice were found to drink more alcohol than wildtype mice (Tammimäki et al, 2008); however, it cannot be concluded yet whether this reflects stronger or weaker reinforcing effects.…”

Tolcapone Suppresses Ethanol Intake in Alcohol‐Preferring Rats Performing a Novel Cued Access Protocol

“…Moreover, interactions between allelic variations in COMT and Tolcapone treatment are observed in a number of cognitive behaviors (Farrell et al, 2012). An association is also observed between allelic variations in COMT and alcohol drinking behavior (Tammimäki et al, 2008; Hendershot et al, 2012) as well as the propensity to relapse (Wojnar et al, 2009; but see Köhnke et al, 2003; Foroud et al, 2007).…”

Genes and Alcohol Consumption

“…Studies consistently show that ethanol self-administration in operant and 2BC tests is decreased in D 1 - and D 2 - receptor deficient mice (Delis et al, 2013; El-Ghundi et al, 1998; Palmer, Low, Grandy, & Phillips, 2003; Phillips et al, 1998; Risinger, Freeman, Rubinstein, Low, & Grandy, 2000; Thanos, Rivera, et al, 2005); however, deletion of the D 2 long receptor increased DID (Bulwa et al, 2011) (Table 3). Overexpression of D 2 transiently increased intake in D 2 receptor knockout mice and decreased intake in wild-type mice (Thanos, Rivera, et al, 2005). Effects of D 3 and D 4 dopamine receptor deletion are less well studied, but there is a report of substantially decreased alcohol consumption in 2BC and DID tests in D 3 knockout mice (Leggio et al, 2014).…”