Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
Biol Psychiatry. 2011 Apr 1;69(7):633-41. doi: 10.1016/j.biopsych.2010.07.009.
Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine.
We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats.
The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886).
These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.
最近的研究结果表明，脂肪酸酰胺水解酶（FAAH）抑制剂可拮抗尼古丁在大鼠中的奖赏作用。FAAH 的抑制作用会增加大脑中几种内源性物质的水平，包括内源性大麻素大麻素酰胺和非大麻素脂肪酸乙醇酰胺油酸乙醇酰胺（OEA）和棕榈酸乙醇酰胺，它们是 α 型过氧化物酶体增殖物激活受体（PPAR-α）的配体。在这里，我们评估了直接作用的 PPAR-α 激动剂是否可以调节尼古丁的与奖赏相关的作用。
我们结合行为、神经化学和电生理学方法来评估 PPAR-α 激动剂 [[4-氯-6-[(2,3-二甲基苯基)氨基]-2-嘧啶基]硫代]乙酸（WY14643）和甲基油酸乙醇酰胺（methOEA；OEA 的长效形式）对以下方面的影响：1）大鼠和松鼠猴中的尼古丁自我给药；2）大鼠和猴子中的尼古丁寻求行为的恢复；3）大鼠中的尼古丁辨别；4）麻醉大鼠中腹侧被盖区多巴胺神经元的尼古丁诱导的电生理活性；5）自由活动大鼠伏隔核壳中尼古丁诱导的多巴胺水平升高。
PPAR-α 激动剂剂量依赖性地减少了大鼠和猴子中的尼古丁自我给药和尼古丁诱导的恢复，但不改变食物或可卡因强化操作性行为或尼古丁的内感受作用。PPAR-α 激动剂还剂量依赖性地降低了尼古丁诱导的腹侧被盖区多巴胺神经元兴奋和大鼠伏隔核壳中尼古丁诱导的多巴胺水平升高。WY14643 和 methOEA 拮抗尼古丁的行为、电生理和神经化学作用的能力被 PPAR-α 拮抗剂 1-[(4-氯苯基)甲基]-3-[(1,1-二甲基乙基)硫]-α,α-二甲基-5-(1-甲基乙基)-1H-吲哚-2-丙酸（MK886）逆转。
这些发现表明，PPAR-α 可能为戒烟药物提供了一个有价值的新靶点。
