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  • The present study manipulated dopaminergic

    2021-07-28

    The present study “manipulated” dopaminergic functioning by examining genetic variation related to the catechol-O-methyltransferase (COMT) gene. The gene transcribes the COMT enzyme involved in degradation of released dopamine in the frontal cortex. COMT cx 4945 is primarily localized to the frontal cortex of the cx 4945 and has a direct effect on prefrontal cortex dopamine levels (Backman et al., 2006). The gene coding for COMT has at least 5 common single-nucleotide polymorphisms (SNPs) that lead to different functionality of the enzyme and have effects on cognition, arousal, pain sensitivity, and stress reactivity in humans and animal models (Chen et al., 2011). The SNP most often associated with cognition has a Val to Met substitution at codon 158 (VAL158Met) and is the focus of this study. This SNP influences the stability of the enzyme in vitro and determines the enzymatic activity in vivo with the Met allele having approximately 1 quarter the enzymatic activity of the Val allele (Chen et al., 2004, Lachman et al., 1996, Lotta et al., 1995). Thus, individuals with the Met/Met genotype compared to Val/Met and Val/Val have greater dopamine availability and perform better on cognitive tasks that are supported by the frontal lobes like working memory and measures of executive functioning (Egan et al., 2001, de Frias et al., 2005). For example, Met homozygotes performed better than Val/Met or Val homozygotes on the N-back test of working memory (Goldberg et al., 2003), the Letter-Number Sequencing Test, and Wisconsin Card Sorting Test (Bruder et al., 2005). In addition, aging magnifies the relationship between COMT genotype and cognitive performance with a greater performance deficit for Val carriers compared to Met homozygotes with increased age (Nagel et al., 2008, Raz et al., 2011). COMT genotype effects in aging were also magnified in frontal cortex activation on a working memory task during functional magnetic resonance imaging [fMRI; (Sambataro et al., 2009)]. Older Val homozygotes had increased working memory-related activation in the dorsolateral prefrontal cortex and functional connectivity compared to Met homozygotes and younger participants (Sambataro et al., 2009). Critically, this study did not include an analysis by sex. Sex also influences COMT effects on cognition. Women have 20%–30% less COMT activity than men (Chen et al., 2004, Fahndrich et al., 1980). Both Raz et al. (2011)O'Hara et al. (2006) found that sex interacted with COMT genotype such that older men who had a Val allele showed greater negative effects on cognition compared to older women (Raz et al., 2011). Thus, it is likely that gonadal steroids and the hormone change at menopause modulate COMT activity. Estrogen directly influences COMT activity by inhibiting COMT gene transcription through 2 estrogen response elements located on the COMT promotor (Jiang et al., 2003, Weinshilboum, 2006, Xie et al., 1999). Thus, the decline in estrogen levels after menopause may result in increased COMT transcription and decreased dopaminergic functioning, and thereby impact cognitive processes like working memory. In addition to its role in catecholamine metabolism, COMT is involved in metabolism of estradiol and estrone. Estradiol is metabolized into catecholestrogens first by cytochrome P450 enzymes. Then catecholestrogens are then inactivated by O-methylation by COMT creating either 2-methoxyestradiol or 4-methoxyestrone (Liehr and Ricci, 1996, Liehr and Roy, 1990). There may be an important feedback relationship between the functioning of the COMT enzyme and the transcription of the COMT gene that involves estradiol and therefore may be a mechanism underlying cognitive changes after menopause. There is 1 prior study that examined the relationship between COMT, estrogen level, and working memory in healthy younger premenopausal women. Jacobs and D'Esposito (2011) showed that hormone variation during the menstrual cycle in premenopausal women interacted with COMT genotype to influence working memory-related brain activation and performance. Performance measured by correct rejection of the lure items on an N-back test of working memory was best for women with a Met/Met genotype in the low estradiol phase of the menstrual cycle and while lowest performance was seen for the Val/Val genotype and the low estradiol phase of the menstrual cycle. The Met/Met group during the high estrogen phase of the cycle had the greatest decrease in prefrontal cortex activation. The group with the hypothesized least amount of dopamine (Val/Val and low estradiol) had the greatest amount of activation. Thus, activation was inversely related to the proposed level of dopamine. The decreased frontal activation as dopamine increased was interpreted as more cognitively “efficient”.