Timofeeva Olga A, Levin Edward D
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Pharmacol Biochem Behav. 2008 Sep;90(3):372-81. doi: 10.1016/j.pbb.2008.03.011. Epub 2008 Mar 27.
Alpha2-adrenoreceptor (alpha(2)-AR) antagonists have been shown to improve, while alpha(2)-AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) alpha(2)-AR agonists attenuate the cognitive impairments. The effect with alpha(2)-AR antagonists remains unclear.
We investigated the effects of the alpha(2)-AR antagonist idazoxan on memory function in rats treated/not treated with NMDAR antagonist dizocilpine or a combination of dizocilpine and nicotine to clarify noradrenergic/cholinergic regulation of memory function.
Female Sprague-Dawley rats (n=12) were trained for food reward on the radial maze. Working and reference memory errors and response latency were assessed after injections of idazoxan (0.5, 1.0 mg/kg), dizocilpine (0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or in combination.
Dizocilpine potently impaired memory. Nicotine (0.4 mg/kg) reversed this impairment. Idazoxan at the doses tested did not affect performance when given alone or with dizocilpine, but it did block the nicotine reversal of the dizocilpine-induced memory impairment. Three rats after 10-12 drug treatments developed limbic seizures. Our findings suggest that combination of drugs which block alpha(2)-AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.
已表明α2 - 肾上腺素能受体（α(2)-AR）拮抗剂可改善认知功能，而α(2)-AR激动剂会损害具有功能正常的N - 甲基 - D - 天冬氨酸受体（NMDAR）的受试者的认知功能。在NMDAR受抑制的受试者（精神分裂症模型）中，α(2)-AR激动剂可减轻认知障碍。α(2)-AR拮抗剂的作用仍不清楚。
我们研究了α(2)-AR拮抗剂伊达唑胺对用NMDAR拮抗剂地佐环平或地佐环平与尼古丁联合处理/未处理的大鼠记忆功能的影响，以阐明去甲肾上腺素能/胆碱能对记忆功能的调节。
对雌性Sprague - Dawley大鼠（n = 12）进行放射状迷宫食物奖励训练。在注射伊达唑胺（0.5、1.0 mg/kg）、地佐环平（0.05 mg/kg）、尼古丁（0.2、0.4 mg/kg）或溶剂，单独或联合注射后，评估工作记忆和参考记忆错误以及反应潜伏期。
地佐环平严重损害记忆。尼古丁（0.4 mg/kg）可逆转这种损害。单独给予或与地佐环平联合给予时，所测试剂量的伊达唑胺不影响行为表现，但它确实阻断了尼古丁对由地佐环平引起的记忆损害的逆转作用。10 - 12次药物处理后，三只大鼠出现边缘性癫痫发作。我们的研究结果表明，在精神分裂症患者中，将阻断α(2)-AR的药物与烟碱激动剂联合使用可能会阻止烟碱激动剂的治疗效果，并增加重复给药时惊厥活动的风险。
