根據(jù)7月27日發(fā)表在《The Journal of Neuroscience》上的一項(xiàng)新的動物研究，消除位于大腦獎賞中心的細(xì)胞中的一個蛋白質(zhì),，可阻斷焦慮和減輕尼古丁的獎賞效應(yīng)，這一發(fā)現(xiàn)可能有助于研究人員更好地了解尼古丁如何影響大腦,。
尼古丁通過結(jié)合腦細(xì)胞表面的稱之為煙堿受體的蛋白質(zhì)而起作用,。在新研究中，由Salk生物研究所的Tresa McGranahan,、StePHen Heinemann博士,、T. K. Booker博士領(lǐng)導(dǎo)的研究人員發(fā)現(xiàn)，從產(chǎn)生多巴胺的腦細(xì)胞中去除一種特殊類型的煙堿受體,，可使小鼠不太可能找到尼古丁,。多巴胺是一種響應(yīng)獎勵的化學(xué)物質(zhì)。小鼠并未顯示出尼古丁治療后常見的焦慮樣行為的減少,。吸煙者常報告的焦慮緩解是持續(xù)吸煙或復(fù)發(fā)的關(guān)鍵因素,。
“這些發(fā)現(xiàn)表明了被認(rèn)為在煙草成癮的發(fā)展中起到了關(guān)鍵作用的尼古丁獎勵和減輕焦慮的性質(zhì)與一組腦細(xì)胞的活動有關(guān)，”Scripps研究所藥物成癮專家 Paul Kenny博士說,，而他未加入該研究,。
以往的研究表明,，阻斷腹側(cè)被蓋區(qū)（VTA）的alPHa4煙堿受體,，可削弱尼古丁的獎勵的性質(zhì)，VTA是一個重要的大腦區(qū)域,，與動機(jī),、情感和成癮有關(guān)。由于alPHa4受體存在于腹側(cè)被蓋區(qū)的若干類細(xì)胞上,，目前還不清楚尼古丁是如何產(chǎn)生愉悅感的,。
為了研究大腦中對尼古丁反應(yīng)的重要通路，研究人員開發(fā)了一種無法產(chǎn)生alpha4受體的基因突變小鼠,，但僅限于多巴胺腦細(xì)胞,。與正常小鼠相比，這些細(xì)胞中缺乏alpha4受體的小鼠可花費(fèi)更少的時間獲得尼古丁,。這表明alpha4受體對于尼古丁的獎賞效應(yīng)是必需的,。尼古丁也沒能減少突變小鼠的焦慮行為，而它通常在健康小鼠可起作用,。
McGranahan說：“確認(rèn)對尼古丁成癮的兩個主要特征-獎勵和焦慮是必需的煙堿受體的種類,，將可能有助于我們更好地理解導(dǎo)致尼古丁依賴的途徑，以及對全球十億吸煙者潛在的治療方法”,。與煙草使用相關(guān)的疾病仍然是全球的主要?dú)⑹?，每年造?00多萬人死亡。
這一發(fā)現(xiàn)可引導(dǎo)研究人員更好地理解煙草成癮的機(jī)制,，并協(xié)助開發(fā)新的藥物來治療煙癮,，并可緩解焦慮癥，Kenny補(bǔ)充說。
這項(xiàng)研究獲得了國家神經(jīng)疾病與中風(fēng)研究所,、美國國家酒精濫用和酒精中毒研究所,，國家藥物濫用研究所的支持。(生物谷 Bioon.com)
doi:10.1523/?JNEUROSCI.0937-11.2011
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α4β2 Nicotinic Acetylcholine Receptors on Dopaminergic Neurons Mediate Nicotine Reward and Anxiety Relief
Tresa M. McGranahan, Natalie E. Patzlaff, Sharon R. Grady, Stephen F. Heinemann, and T. K. Booker
Nicotine is the primary psychoactive substance in tobacco, and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the α4β2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal as well as nicotine-induced behaviors. Although α4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addiction, mental illness, and movement control in humans. We developed a unique model system to examine the role of α4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the α4 subunit from dopaminergic neurons in mice. The loss α4 mRNA and α4β2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of α4β2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. α4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. α4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze, and elimination of α4β2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of α4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression; however, nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine-related behaviors.
