作者：Jacquelyn K. Beals, PhD
出處：WebMD醫學新聞
August 25, 2008 — 有常見的多巴胺分解酵素變異同合子的人，顯示在代表情緒處理指標的音響情感驚嚇反射有較大的嫌惡刺激影響。發表於2008年8月10日的Behavioral Neuroscience期刊的一篇新研究，支持「兒茶酚甲基轉移酵素[COMT (基因密碼catechol-O-methyltransferase)] 」基因會增加焦慮異常的可能性。
COMT通常包含一種單一核苷酸多型體，在酵素構造的158號位置處，以methionine (Met)取代 valine (Val)；有兩組Met變異的人，其COMT活性比有兩組Val變異的人少將近三分之一。
稍早的研究認為，Met變異(與較高的皮質多巴胺濃度)提供認知效果的好處，但是情緒調節較差；Val變異則有較差的操作記憶，但是有較佳的情緒穩定。
主要作者、Christian Montag以電子郵件向Medscape Pathology & Lab Medicine表示，有越來越多證據指出，正面情緒與較高的多巴胺濃度有關，缺乏多巴胺可能會有負面情緒。這是很複雜的領域，但是科學家還沒有共通意見。加上複雜性，這需要不同腦部區域的多巴胺濃度。
德國波昂大學心理系的Montag醫師表示，我們的結果指出前額葉皮質的多巴胺高濃度與負面情緒有關，因為Met/Met表示對於多巴胺的代謝少於Val/Met和Val/lVal，高多巴胺和正面情緒的看法與中腦邊緣區有關。
發表的此一研究包括了從基因資料庫獲得的96名健康、平均年紀22歲的德國女性；Val/Val、Val/Met和 Met/Met組各篩檢出32名，研究對象隨機觀察一系列的圖片：12張愉悅的(如動物、嬰兒)、12張中性的(如電源，吹風機)，與12張嫌惡的(如武器、犯罪受害者)，每張圖片6秒。比106-dB白雜訊超出35-ms視為驚嚇，利用左眼下的電極偵測眨眼，在觀看圖片時，以15-25秒的隨機間隔發生聲音。
研究對象的基因類型並不影響觀看愉悅圖片時的驚嚇反應，對於中性圖片，Met/Met者傾向比Val/Val 有更大的驚嚇反應，不過在校正多重比較之後，沒有顯著差異；當觀看嫌惡圖片時，COMT基因類型對於驚嚇反應有顯著影響(F(2, 93) = 6.38; P < .003)；Met/Met 組顯示比有Val者更顯著強烈的驚嚇反應(Val/Val和Val/Met; F(1, 94) = 12.59; P = .001)。
Medscape Pathology & Lab Medicine 收到來自共同作者、Vanderbilt大學心理系神經科學博士候選人Joshua W. Buckholtz的電子郵件 ，他表示，認知表現似乎與皮質多巴胺濃度呈現ㄇ型函數，多巴胺太少導致無法專注在重要的環境刺激，太多會導致對於這類刺激的持續性過度聚焦。
Buckholtz先生表示，我們認為或許這是發生在COMT-Met者一種對於潛在威脅資訊無法改變的過度聚焦，這種過度聚焦或許可以解釋，何以COMT-Met者有較大的風險發生焦慮異常。
作者提出多種假設，其中最可能的是，前額葉皮質的多巴胺濃度升高，會導致對於嫌惡刺激無法改變的專注，無法從威脅刺激轉移注意力，會引起威脅感持續，而造成增加焦慮異常的可能。
是的，如同Montag醫師指出的，Met/Met基因型在人類中常見，但顯然不是每個有此變異的人都發生類似異常，其他基因變異，當然還包括環境對於基因活性的調節都是重要因素，但或許有一天，可以對某種基因型處方適當劑量的某種藥物，他認為這在未來指日可待。
國家健康研究中心、國家心智健康研究中心、基因認知與精神病計畫主任Daniel R. Weinberger醫師以電子郵件向 Medscape Pathology & Lab Medicine提出建議，世界上不同種族間有不同變異， Val/Met 不是COMT唯一的功能性變異；若以對 COMT 變異的瞭解來發展焦慮和恐懼處理異常的臨床治療，也還需要更多研究來實現。
Montag醫師、Buckholtz先生和Weinberger 醫師宣稱沒有相關資金上的往來。
Individuals With COMT Variant Show Exaggerated Reaction to Aversive Stimuli
By Jacquelyn K. Beals, PhD
Medscape Medical News
August 25, 2008 — Individuals homozygous for a common variant of a dopamine catabolic enzyme demonstrate a greater influence of aversive stimuli on the acoustic affective startle reflex — an indicator of emotion processing. A new study, published August 10, 2008, in Behavioral Neuroscience, supports COMT (encoding catechol-O-methyltransferase) as a gene that increases susceptibility to anxiety disorders.
COMT frequently contains a single nucleotide polymorphism that replaces valine (Val) with methionine (Met) at position 158 in the enzyme structure. Individuals with 2 copies of the Met variant have approximately one third less COMT activity than those with 2 copies of the Val variant.
Earlier studies suggested that the Met variant (and higher cortical dopamine concentrations) provides the advantage of cognitive efficiency, but poor regulation of emotions. The Val variant confers poorer working memory but greater emotional stability.
"[T]here is growing evidence that positive emotionality might be associated with a higher dopamine level, and potentially negative emotionality with a lack of dopamine," said lead author Christian Montag, DiplPsych, in an email to Medscape Pathology and Lab Medicine. "This is a very complicated area, though, where scientists do not have a common opinion. Adding to the complexity, it depends on the dopamine level in the different brain areas.
"Our results would [indicate] that potentially high dopamine levels in the prefrontal cortex go along with negative emotionality, because the Met/Met carriers catabolize less dopamine than carriers of the Val/Met and Val/lVal group," said Dr. Montag, who is from the Department of Psychology, University of Bonn, Germany. "The notion of high dopamine and positive emotionality could relate to the mesolimbic system," he added.
The present study enrolled 96 healthy women of German origin, average age 22 years, from a genetic data bank. Thirty-two patients were selected for each genotypic group: Val/Val, Val/Met, and Met/Met. Subjects observed a randomized series of pictures: 12 pleasant (eg, animals, babies), 12 neutral (eg, electrical outlet, hairdryer), and 12 aversive (eg, weapons, crime victims) for 6 seconds each. The startle response was elicited by a 35-ms burst of 106-dB white noise, and eye blinks were detected by electrodes under the left eye. The sound burst was delivered at random 15- to 25-second intervals during the picture viewing sessions.
Subjects' genotypes did not affect the startle response when viewing pleasant pictures. For neutral pictures, Met/Met individuals tended toward a greater startle response compared with patients with the Val allele, but this was not significant after "correction for multiple comparisons." When the patients viewed aversive pictures, the COMT genotype had a significant effect on the startle response (F(2, 93) = 6.38; P < .003). Met/Met homozygotes showed a significantly stronger startle response than Val carriers (Val/Val and Val/Met; F(1, 94) = 12.59; P = .001).
Medscape Pathology and Lab Medicine received email comments from coauthor Joshua W. Buckholtz, MS, a doctoral candidate in neuroscience, Department of Psychology, Vanderbilt University, Nashville, Tennessee. "[C]ognitive performance seems to follow an 'inverted-U' function with respect to cortical dopamine levels — too little [dopamine] results in an inability to focus on important environmental stimuli, and too much results in a perseverative overfocus on such stimuli," he said.
"We think that perhaps this is what is happening in the COMT-Met subjects: an inflexible overfocus on potentially threatening information, said Mr. Buckholtz. "This overfocus may explain why COMT-Met individuals are at greater risk for developing anxiety disorders."
The authors propose several hypotheses, among them the possibility that "elevated dopamine in the prefrontal cortex could result in an inflexible attentional focus on aversive stimuli." This inability to shift attention from threatening stimuli might cause the perception of threat to persist and underlie the increased susceptibility to anxiety disorders.
Yet, as Dr. Montag pointed out, "The Met/Met genotype...can be found very often in the population, [but] it is clear that not everyone who carries this variant develops such a disorder. Other gene variants, and of course the modulation of gene activity through the environment, are crucial factors." Although it might be possible someday to prescribe the right dose of the right drug for a certain genotype, he sees this date as being far in the future.
Daniel R. Weinberger, MD, director, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, commented to Medscape Pathology and Lab Medicine via email: "There is considerable variation across world populations, and Val/Met is not the only functional variation in COMT." In terms of using the understanding of COMT variants to develop clinical treatment of anxiety and fear processing disorders, "[M]uch more work will be necessary to get to this," said Dr. Weinberger.
Dr. Montag, Mr. Buckholtz, and Dr. Weinberger have disclosed no relevant financial relationships.
Behav Neurosci. 2008;122(4):901–909.
[ 本帖最後由 goodcat1111 於 2008-9-4 23:52 編輯 ] |
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