Harich Silke, Gross Gerhard, Bespalov Anton
Neuroscience Discovery Research, Abbott, 67061 Ludwigshafen, Germany.
Psychopharmacology (Berl). 2007 Jul;192(4):511-9. doi: 10.1007/s00213-007-0742-y. Epub 2007 Feb 23.
Glutamatergic mechanisms are implicated in psychiatric disorders such as schizophrenia. Modulation of glutamatergic neurotransmission via stimulation of the metabotropic glutamate 2/3 receptors (mGluR2/3) has been shown to reverse a number of behavioral effects of NMDA receptor antagonists thus indicating potential antipsychotic activity of mGluR2/3 agonists.
The present study aimed to evaluate the effects of LY-354740 (mGluR2/3 agonist) and LY-487379 (mGluR2 potentiator) on social novelty discrimination in male Wistar rats that were treated with PCP (10 mg/kg, s.c.) on postnatal days 7, 9, and 11.
During each test session (twice a week, postnatal days 70-100), an adult experimental rat was presented with a juvenile, untreated rat (4 weeks old) for a period of 30 min. At the end of this period, a second (novel) juvenile rat was introduced for 5 min.
Adult rats spent more time exploring the novel than the familiar juvenile. This capacity for social novelty discrimination was impaired in rats that received neonatal PCP treatment and the impaired discrimination could be reversed by acute treatment with antipsychotic drugs such as clozapine (0.3-3 mg/kg) and the glycine transporter GlyT1 inhibitor SSR-504734 (1-10 mg/kg). Acute pretreatment with LY-354740 (1-10 mg/kg) or LY-487379 (3-30 mg/kg) facilitated social discrimination in rats with PCP administration history without having appreciable effects in controls and without affecting total time spent in social interaction.
These results suggest that targeting glutamatergic functions may reverse long-term developmental cognitive deficits produced by PCP.
谷氨酸能机制与精神分裂症等精神疾病有关。通过刺激代谢型谷氨酸2/3受体（mGluR2/3）来调节谷氨酸能神经传递已被证明可逆转NMDA受体拮抗剂的多种行为效应，从而表明mGluR2/3激动剂具有潜在的抗精神病活性。
本研究旨在评估LY-354740（mGluR2/3激动剂）和LY-487379（mGluR2增强剂）对出生后第7、9和11天接受氯胺酮（10mg/kg，皮下注射）处理的雄性Wistar大鼠社会新奇辨别能力的影响。
在每个测试阶段（每周两次，出生后第70 - 100天），将一只成年实验大鼠与一只未经处理的幼年大鼠（4周龄）放在一起30分钟。在此时间段结束时，引入第二只（新奇的）幼年大鼠5分钟。
成年大鼠花在探索新奇幼年大鼠上的时间比熟悉的幼年大鼠更多。接受新生期氯胺酮处理的大鼠这种社会新奇辨别能力受损，而这种受损的辨别能力可通过抗精神病药物如氯氮平（0.3 - 3mg/kg）和甘氨酸转运体GlyT1抑制剂SSR - 504734（1 - 10mg/kg）的急性处理得到逆转。LY - 354740（1 - 10mg/kg）或LY - 487379（3 - 30mg/kg）的急性预处理促进了有氯胺酮给药史大鼠的社会辨别能力，对对照组没有明显影响，且不影响社交互动总时长。
这些结果表明，针对谷氨酸能功能可能逆转氯胺酮产生的长期发育性认知缺陷。
