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  • Sex has been shown to mediate the relationship

    2019-09-07

    Sex has been shown to mediate the relationship between allelic differences in COMT and behavior (Harrison & Tunbridge, 2008). The COMT promoter region contains 2 estrogen response elements (Xie, Ho, & Ramsden, 1999) that can inhibit the formation of COMT (Jiang, Xie, Ramsden, & Ho, 2003). With regard to alcohol drinking, Tammimäki et al. (2008) showed that manipulating COMT affected consumption in male but not female mice. In the absence of COMT manipulations, sex specific effects on alcohol behaviors have also been reported. For instance, female rodents show overall higher ethanol intakes than males (Lancaster and Spiegel, 1992, Morales et al., 2014, Tammimäki et al., 2008). We have previously shown that COMT modulation reduces drinking in male P rats (McCane et al., 2014) but the effects of tolcapone on the drinking behaviors of female P rats is unknown. Therefore, the current study assessed the effects of tolcapone in both male and female P and Wistar rats. Working under the hypothesis that differences in COMT are associated with aberrant ethanol seeking and intake, the current project sought to investigate the influence of alterations in COMT activity and expression on alcohol seeking and drinking. While sex-linked differences in COMT protein expression (Schendzielorz, Rysa, Reenila, Raasmaja, & Mannisto, 2011) and effects of tolcapone are documented (Tunbridge, Farrell, Harrison, & Mackay, 2013), it is currently unknown if COMT expression differs between male and female Wistar and P rats. Thus it is unclear whether pharmacotherapies targeting COMT will be efficacious in both sexes. Therefore, an additional aim of the current project was to quantify sex and strain differences in COMT using western blot analyses to determine whether these differences in COMT expression might be associated with variances in the effects of tolcapone.
    Materials and methods
    Results
    Discussion In our previous study, we observed that tolcapone treatment resulted in a reduction in cued reward consumption in male P but not Wistar rats (McCane et al., 2014). Additionally, we observed null effects of tolcapone on free choice drinking for both P and Wistar rats (McCane et al., 2014). Importantly, both these findings were observed in male rats and females were not tested. Here we report that tolcapone reduces “earned” reinforcer consumption in male P but not Wistar rats with no effect on females of either strain. In other words, consummatory behavior was consistently modulated by tolcapone under conditions of cued, limited access, but not in a free choice condition (IAP; McCane et al., 2014). Therefore, we hypothesize that the behavioral effects of this parthenolide are not mediated by a general suppression of consummatory behavior but rather an attenuation of the salience of reward-paired cues. Moreover, since both sex and strain differences in COMT expression were detected in the PFC, we further hypothesize that COMT-mediated differences in cortical catecholamine levels contribute to the efficacy of tolcapone. Our previous findings showed that tolcapone attenuated cued ethanol consumption in Wistars, but only in high drinkers (McCane et al., 2014). However, in the current study, tolcapone had no effect in female rats of either strain, both of which drank more than their male counterparts. It is not likely that alcohol history alone can explain the differences in tolcapone\'s efficacy. In our previous study (McCane et al., 2014) we observed that during the IAP, male P rats drank levels of ethanol comparable to what females in the same paradigm consume in the current experiments. Additionally, we have previously observed that tolcapone was more efficacious in high drinkers, compared to low drinkers (McCane et al., 2014). As such, one might hypothesize that in females tolcapone would be more efficacious, which was not the case, indicating sex-mediated differences in COMT, independent of level of intake. Our findings are consistent with results obtained from Tammimäki et al. (2008), where COMT gene disruption resulted in sex-mediated differences in ethanol intake in mice. Specifically, male mice with COMT gene disruptions consumed more ethanol than wild type mice and, while females consumed more ethanol than males, there was no effect of COMT gene disruption on their ethanol intake (Tammimäki et al., 2008). Interactions between sex and COMT genotype have also been observed in behavioral responses to pharmacological challenges. Male and female mice showed different responses to amphetamine-induced locomotor activity where male mice homozygous for COMT deletion showed enhanced activity, an effect not observed in female homozygotes or wild type animals (Huotari, García-Horsman, Karayiorgou, Gogos, & Männistö, 2004). Moreover, sex differences in pharmacological therapies for AUD have been reported where naltrexone in combination with topiramate reduced responding for ethanol in male rats to a greater extent than in female rats (Moore & Lynch, 2015). Consistent with these findings, in the current experiments, female behavior was not sensitive to pharmacological manipulations of COMT. However, it is possible that a higher dose is required in females. Additionally, in mice, sex/COMT genotype interactions were observed in a behavioral measure of impulsivity (Papaleo, Erickson, Liu, Chen, & Weinberger, 2012), a phenotype associated with addiction disorders (Perry & Carroll, 2008). Lastly, sex differences in COMT inhibition on catecholamine metabolism have been observed in rats (Laatikainen, Sharp, Harrison, & Tunbridge, 2013). Estrogen decreases COMT activity as well as gene and protein expression (Cohn and Axelrod, 1971, Jiang et al., 2003). Sex specific compensatory mechanisms may therefore account for interactions between sex, COMT, and behavior (Harrison & Tunbridge, 2008). The present experiments add to a growing body of literature which suggest that COMT genotype has sexually dimorphic effects on behavior (Harrison & Tunbridge, 2008).