Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine
| Autor: | Ajna Hamidovic, Abraham A. Palmer, Andrea Dlugos, Harriet de Wit |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Genotype medicine.medical_treatment Neuropsychological Tests Profile of mood states Catechol O-Methyltransferase behavioral disciplines and activities Article Young Adult Internal medicine Genetics medicine Humans Attention Psychiatry Amphetamine Biological Psychiatry Genetics (clinical) Catechol-O-methyl transferase Working memory Cognition Stimulant Psychiatry and Mental health Affect Endocrinology Frontal lobe Amino Acid Substitution Area Under Curve Digit symbol substitution test Female Psychology medicine.drug |
| Popis: | Catechol-O-methyltransferase (COMT) is an enzyme which metabolizes catecholamines and catechol-estrogens in both the CNS and periphery. The discovery of a common functional genetic variant at codon 158 (val158met) (Lachman et al.,1996; Lotta et al.,1995) led to the observation that individuals who were homozygous for the val allele performed more poorly than other genotypic groups on tasks of executive function (Egan et al., 2001). The differences in performance have been attributed to localized function of COMT in the prefrontal system. Further these differences appear to contribute to individual differences in responses to stimulant drugs, such as d-amphetamine (Mattay et al, 2003). However, given the complex modulation and functional heterogeneity of frontal lobe systems, further evaluation of COMT val158met-related phenotypes is needed. Here, we examined additional measures of cognition, including lapses in attention and general measures of visuo-spatial-motor speed of processing, as well as self-reports of mood, both without a drug and in response to acute administration of d-amphetamine. Dopamine (DA) is removed from the synapse in most parts of the brain by the dopamine transporter, but in the frontal cortex, the DA is cleared mainly by the catabolic enzyme COMT (Karoum et al., 1994). The substitution of methionine (met) for valine (val) at codon 158 in the COMT gene (COMT) leads to a lower enzymatic activity so that met/met carriers have higher synaptic levels of DA in the frontal cortex, which appears to improve their performance on measures of executive function and working memory (Mattay et al., 2003; Egan et al., 2001; Turnbridge et al., 2006). Both environmental factors and pharmacologic manipulations modify the effects of COMT val158met genotype on cognition. For example, years of education – one possible marker of socioeconomic status – interacts with the COMT val158met genotype such that met/met carriers' cognitive scores improve markedly with increasing years of education, whereas the scores of val/val individuals are only marginally influenced by years of education (Enoch et al., 2009). Interestingly, in one study (Mattay et al., 2003) the psychostimulant d-amphetamine, which increases synaptic DA levels, worsened executive function and working memory of met/met carriers, whereas it improved performance among val/val carriers. This was explained as an inverted “U” functional response curve so that performance is improved by modest increases in synaptic DA levels, but impaired when levels exceed a certain optimal level. The goal of the present study was to further characterize the function of COMT val158met by analyzing 1. Whether genotypic groups differ in drug free condition on measures of motor processing and attention, and 2. Whether genotypic groups differ on their responses to these measures following administration of d-amphetamine. We used two measures of cognition - the Digit Symbol Substitution Test (DSST; Wechsler, 1958), which provides a non-specific measure of visuo-spatial and motor speed-of-processing, and Deviation from the Mode (DevMod), a new measure of lapses in attention (de Wit 2009), derived from a simple reaction time task. We used a task measuring lapses in attention to obtain important information about moment-to-moment fluctuations in task performance. In addition to these measures of cognitive function, we also evaluated mood states using Profile of Mood States (McNair et al., 1971) and personality, using Multidimensional Personality Questionnaire (Tellegen, 1982). We hypothesized that the val/val carriers would perform more poorly than met/met carriers on lapses in attention and visuo-spatial-motor speed of processing tasks in the absence of pharmacologic manipulation, consistent with what has been reported on other measures of cognition. In addition, we hypothesized that val/val carriers would exhibit a greater improvement in performance after d-amphetamine than met/met carriers. We did not expect that these genotypic groups would differ in the mood-altering effects of d-amphetamine because these effects are not believed to be mediated in brain regions where COMT plays a major role (Volkow, 1997). Studies of this kind, investigating the relationships between genotype and responses to drugs, will help to explain inter-individual variability in responses to drugs, including drugs such as stimulants that are used in clinical settings. These studies will also help to identify the separate brain processes that mediate the cognitive and mood-altering effects of drugs. |
| Databáze: | OpenAIRE |
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