O'Neill Heidi C, Rieger Kate, Kem William R, Stevens Karen E
Department of Psychiatry C268-71, University of Colorado Health Sciences Center, 4200 East 9th Avenue,Denver, CO 80262, USA.
Psychopharmacology (Berl). 2003 Sep;169(3-4):332-9. doi: 10.1007/s00213-003-1482-2. Epub 2003 May 21.
Impaired auditory gating is common in schizophrenic patients. Evidence suggests that this deficit is related to a reduced number of alpha(7) nicotinic receptors and therefore treatment with alpha(7) nicotinic agonists may improve this condition. 3-(2,4)-Dimethoxybenzylidine anabaseine (DMXB; also known as GTS-21) is such an agonist and has shown efficacy in mice both orally and intraperitoneally.
Rats reared in social isolation post weaning have demonstrated a deficit in auditory gating similar to that seen in schizophrenia patients. The current study determined the effects of DMXB on auditory gating in awake, freely moving rats, comparing a group born and raised in-house and reared in isolation post-weaning (isolation reared) with a group shipped from the supplier as adults and housed in groups prior to surgery (controls).
Ten unmedicated, baseline recordings were obtained following surgical implantation of a recording electrode. All control group rats and the isolation-reared rats that showed deficient gating at baseline were treated with 1.0, 3.33, 10 or 33 mg/kg DMXB, IP, to determine the drug's impact on auditory gating.
Isolation-reared rats had significantly improved auditory gating at the 3.33, 10 and 33 mg/kg doses, while control rats had a significant impairment in their auditory gating at the 33 mg/kg dose.
DMXB improved the auditory gating deficit seen in isolation-reared rats. As previously observed in another model, the change was produced through a decrease in the test amplitude in isolation-reared animals. Control animals had a significant reduction in conditioning amplitude at the high dose, which produced the loss of auditory gating. The results in the isolation-reared rats are in concert with previous studies which found similar improvement in auditory gating following administration of DMXB to DBA mice, the only differences being in the duration of the effect.
听觉门控受损在精神分裂症患者中很常见。有证据表明，这种缺陷与α7烟碱型受体数量减少有关，因此用α7烟碱型激动剂治疗可能会改善这种状况。3-(2,4)-二甲氧基苄叉假木贼碱（DMXB；也称为GTS-21）就是这样一种激动剂，已在小鼠口服和腹腔注射实验中显示出疗效。
断奶后在社会隔离环境中饲养的大鼠表现出与精神分裂症患者类似的听觉门控缺陷。本研究确定了DMXB对清醒、自由活动大鼠听觉门控的影响，将一组在内部出生并饲养、断奶后隔离饲养（隔离饲养组）的大鼠与一组成年后从供应商处运来并在手术前群居饲养的大鼠（对照组）进行比较。
在手术植入记录电极后，获得10次未用药的基线记录。所有对照组大鼠和在基线时表现出门控缺陷的隔离饲养大鼠接受1.0、3.33、10或33mg/kg DMXB腹腔注射，以确定药物对听觉门控的影响。
隔离饲养组大鼠在3.33、10和33mg/kg剂量下听觉门控有显著改善，而对照组大鼠在33mg/kg剂量下听觉门控有显著损伤。
DMXB改善了隔离饲养大鼠的听觉门控缺陷。正如之前在另一个模型中观察到的，这种变化是通过隔离饲养动物测试振幅的降低产生的。高剂量时，对照动物的条件振幅显著降低，导致听觉门控丧失。隔离饲养大鼠的结果与之前的研究一致，之前的研究发现给DBA小鼠施用DMXB后听觉门控有类似改善，唯一的差异在于效果持续时间。
