Duke Angela N, Platt Donna M, Cook James M, Huang Shengming, Yin Wenyuan, Mattingly Bruce A, Rowlett James K
New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA.
Psychopharmacology (Berl). 2006 Aug;187(3):321-30. doi: 10.1007/s00213-006-0431-2. Epub 2006 Jun 17.
Benzodiazepine agonists characteristically increase food intake in humans and non-human subjects, and the underlying mechanisms of this effect are not understood completely.
Compounds with selectivity for GABAA receptor subtypes were used to evaluate the role of GABAA receptors containing alpha1 and alpha5 subunits (alpha1GABAA and alpha5GABAA receptors, respectively) in benzodiazepine-induced increases in sucrose pellet consumption.
Adult male squirrel monkeys (N=4-6), maintained under free-feeding conditions, were administered with intramuscular injections of the nonselective benzodiazepines diazepam and alprazolam, the alpha1GABAA-preferring compounds zolpidem and zaleplon, or the alpha5GABAA-preferring agonist QH-ii-066 before daily 10-min periods when sucrose pellets were available. In a separate experiment, observable behavioral effects (e.g., ataxia and procumbent posture) were quantified after administration of alprazolam, zaleplon, and QH-ii-066. To further assess the roles of GABAA receptor subtypes, zolpidem-induced increases in pellet consumption were re-evaluated after pretreatment with nonselective antagonist flumazenil, the alpha1GABAA-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (BCCT), or QH-ii-066.
Alprazolam, diazepam, zolpidem, and zaleplon but not QH-ii-066 significantly increased sucrose pellet consumption. In addition, all agonists decreased locomotion and environment-directed behavior as well as engendered ataxia and procumbent posture. For all compounds except QH-ii-066, these behaviors occurred at doses similar to those that increased pellet consumption. Flumazenil and BCCT, but not QH-ii-066, antagonized zolpidem-induced increases in pellet consumption in a surmountable fashion.
These results suggest that the alpha1GABAA receptor subtype plays a key role in benzodiazepine-induced increases in consumption of palatable food, whereas the alpha5GABAA receptor subtype may not be involved in this effect.
苯二氮䓬类激动剂通常会增加人类和非人类受试者的食物摄入量，而这种效应的潜在机制尚未完全明确。
使用对GABAA受体亚型具有选择性的化合物，来评估含有α1和α5亚基的GABAA受体（分别为α1GABAA和α5GABAA受体）在苯二氮䓬类药物引起的蔗糖颗粒消耗量增加中所起的作用。
在自由进食条件下饲养的成年雄性松鼠猴（N = 4 - 6），在每天有10分钟可获取蔗糖颗粒的时间段之前，通过肌肉注射给予非选择性苯二氮䓬类药物地西泮和阿普唑仑、优先作用于α1GABAA的化合物唑吡坦和扎来普隆，或优先作用于α5GABAA的激动剂QH-ii-066。在另一项实验中，对给予阿普唑仑、扎来普隆和QH-ii-066后的可观察到的行为效应（如共济失调和俯卧姿势）进行量化。为了进一步评估GABAA受体亚型的作用，在用非选择性拮抗剂氟马西尼、优先作用于α1GABAA的拮抗剂β-咔啉-3-羧酸叔丁酯（BCCT）或QH-ii-066预处理后，重新评估唑吡坦引起的颗粒消耗量增加情况。
阿普唑仑、地西泮、唑吡坦和扎来普隆显著增加了蔗糖颗粒的消耗量，但QH-ii-066没有。此外，所有激动剂都减少了运动和环境导向行为，并导致共济失调和俯卧姿势。除QH-ii-066外，所有化合物的这些行为都发生在与增加颗粒消耗量相似的剂量下。氟马西尼和BCCT，但不是QH-ii-066，以可克服的方式拮抗了唑吡坦引起的颗粒消耗量增加。
这些结果表明，α1GABAA受体亚型在苯二氮䓬类药物引起的美味食物消耗量增加中起关键作用，而α5GABAA受体亚型可能不参与此效应。
