Zhou Y, Bendor J T, Yuferov V, Schlussman S D, Ho A, Kreek M J
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10021, USA.
Neuroscience. 2005;134(4):1391-7. doi: 10.1016/j.neuroscience.2005.05.032.
In humans, stress is recognized as a major factor contributing to relapse to drug abuse in abstinent individuals; drugs of abuse themselves or withdrawal from such drugs act as stressors. In the animals, evidence suggests that centrally released arginine vasopressin in both amygdala and hypothalamus plays an important role in stress-related anxiogenic behaviors. The stress responsive hypothalamic-pituitary-adrenal axis is under tonic inhibition via endogenous opioids, and cocaine withdrawal stimulates hypothalamic-pituitary-adrenal activity. The present studies were undertaken to determine whether: (1) 14-day (chronic) "binge" pattern cocaine administration (45 mg/kg/day) or its withdrawal for 3 h (acute), 1 day (subacute) or 10 days (chronic) alters arginine vasopressin mRNA levels in amygdala or hypothalamus; (2) the opioid receptor antagonist naloxone (1mg/kg) alters arginine vasopressin mRNA or hypothalamic-pituitary-adrenal hormonal responses in acute cocaine withdrawal; and (3) there are associated changes of mu opioid receptor or proopiomelanocortin mRNA levels. In amygdala, arginine vasopressin mRNA levels were unchanged after chronic "binge" cocaine, but were increased during acute cocaine withdrawal. Naloxone completely blocked this increase. Neither chronic cocaine nor its acute withdrawal altered amygdalar mu opioid receptor mRNA levels. The increase in amygdalar arginine vasopressin mRNA levels was still observed after subacute withdrawal, but not after chronic withdrawal. Although hypothalamic-pituitary-adrenal tolerance developed with chronic "binge" cocaine, there were modestly elevated plasma adrenocorticotropin hormone levels during acute withdrawal. While naloxone produced modest adrenocorticotropin hormone elevations in cocaine-naïve rats, naloxone failed to elicit an adrenocorticotropin hormone response in cocaine-withdrawn rats. In hypothalamus, neither chronic cocaine nor acute withdrawal altered arginine vasopressin, proopiomelanocortin or mu opioid receptor mRNA levels. These results show that: (1) opioid receptors mediate increased amygdalar arginine vasopressin gene expression during acute cocaine withdrawal, and (2) cocaine withdrawal renders the hypothalamic-pituitary-adrenal axis insensitive to naloxone. Our findings suggest a potential role for amygdalar arginine vasopressin in the aversive consequences of early cocaine withdrawal.
在人类中，压力被认为是导致戒毒个体复吸药物滥用的主要因素；滥用药物本身或停用此类药物会成为压力源。在动物中，有证据表明杏仁核和下丘脑中央释放的精氨酸加压素在与压力相关的焦虑行为中起重要作用。应激反应性下丘脑-垂体-肾上腺轴受到内源性阿片类物质的紧张性抑制，而可卡因戒断会刺激下丘脑-垂体-肾上腺活动。本研究旨在确定：（1）14天（慢性）“ binge”模式可卡因给药（45 mg / kg /天）或其戒断3小时（急性）、1天（亚急性）或10天（慢性）是否会改变杏仁核或下丘脑中精氨酸加压素mRNA水平；（2）阿片受体拮抗剂纳洛酮（1mg / kg）是否会改变急性可卡因戒断时精氨酸加压素mRNA或下丘脑-垂体-肾上腺激素反应；以及（3）μ阿片受体或阿片促黑激素皮质素原mRNA水平是否存在相关变化。在杏仁核中，慢性“ binge”可卡因后精氨酸加压素mRNA水平未改变，但在急性可卡因戒断期间升高。纳洛酮完全阻断了这种升高。慢性可卡因及其急性戒断均未改变杏仁核μ阿片受体mRNA水平。亚急性戒断后仍观察到杏仁核精氨酸加压素mRNA水平升高，但慢性戒断后未观察到。尽管慢性“ binge”可卡因会导致下丘脑-垂体-肾上腺耐受，但急性戒断期间血浆促肾上腺皮质激素水平适度升高。虽然纳洛酮在未接触过可卡因的大鼠中会使促肾上腺皮质激素水平适度升高，但纳洛酮在已戒断可卡因的大鼠中未能引发促肾上腺皮质激素反应。在下丘脑中，慢性可卡因和急性戒断均未改变精氨酸加压素、阿片促黑激素皮质素原或μ阿片受体mRNA水平。这些结果表明：（1）阿片受体介导急性可卡因戒断期间杏仁核精氨酸加压素基因表达增加，（2）可卡因戒断使下丘脑-垂体-肾上腺轴对纳洛酮不敏感。我们的研究结果表明杏仁核精氨酸加压素在早期可卡因戒断的不良后果中可能起作用。
