Brody Suzanne A, Geyer Mark A, Large Charles H
Department of Psychiatry and Neurosciences, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093-0804, USA.
Psychopharmacology (Berl). 2003 Sep;169(3-4):240-6. doi: 10.1007/s00213-003-1421-2. Epub 2003 Apr 16.
Lamotrigine, a broad-spectrum anticonvulsant known to block brain sodium channels, is effective in the treatment of persons with bipolar disorder, perhaps by virtue of its ability to reduce glutamate release. Furthermore, lamotrigine decreases the perceptual abnormalities produced by the N-methyl- d-aspartate (NMDA) antagonist ketamine in humans, similar to the effects of the atypical antipsychotic clozapine. Acutely manic bipolar patients, like persons with schizophrenia, Tourette's, and obsessive compulsive disorder, exhibit decreases in sensorimotor gating, as measured by prepulse inhibition of the startle response (PPI).
We assessed the ability of lamotrigine to reduce the PPI-disruptive effects of ketamine and the dopaminergic agent amphetamine in two inbred mouse strains, C57BL/6J and 129SvPasIco.
Mice were tested in a standard PPI paradigm after administration of lamotrigine (0, 6.7, 13, or 27 mg/kg) or a combination of lamotrigine (27 mg/kg) and either d-amphetamine (10 mg/kg) or ketamine (100 mg/kg).
In the 129SvPasIco mice, lamotrigine reversed the ketamine-induced PPI deficit, without altering PPI in control mice. In C57BL/6J mice, however, 27 mg/kg lamotrigine generally increased PPI in both control and ketamine-treated mice. Lamotrigine did not ameliorate the amphetamine-induced PPI deficit in either strain.
In conclusion, lamotrigine can increase PPI on its own and prevent ketamine-induced, but not amphetamine-induced, disruptions of PPI. These results suggest that lamotrigine may exert its effects on PPI through the glutamatergic system.
拉莫三嗪是一种已知可阻断脑钠通道的广谱抗惊厥药，对双相情感障碍患者有效，可能是因其具有减少谷氨酸释放的能力。此外，拉莫三嗪可减轻N-甲基-D-天冬氨酸（NMDA）拮抗剂氯胺酮在人体产生的感知异常，这与非典型抗精神病药物氯氮平的作用相似。急性躁狂双相患者，与精神分裂症、妥瑞氏症和强迫症患者一样，通过惊吓反应的前脉冲抑制（PPI）测量显示感觉运动门控降低。
我们评估了拉莫三嗪在两种近交小鼠品系C57BL/6J和129SvPasIco中减轻氯胺酮和多巴胺能药物苯丙胺对PPI的破坏作用的能力。
给小鼠施用拉莫三嗪（0、6.7、13或27mg/kg）或拉莫三嗪（27mg/kg）与d-苯丙胺（10mg/kg）或氯胺酮（100mg/kg）的组合后，在标准PPI范式中对小鼠进行测试。
在129SvPasIco小鼠中，拉莫三嗪逆转了氯胺酮诱导的PPI缺陷，而不改变对照小鼠的PPI。然而，在C57BL/6J小鼠中，27mg/kg拉莫三嗪通常会增加对照小鼠和氯胺酮处理小鼠的PPI。拉莫三嗪在两种品系中均未改善苯丙胺诱导的PPI缺陷。
总之，拉莫三嗪可自身增加PPI，并预防氯胺酮诱导而非苯丙胺诱导的PPI破坏。这些结果表明，拉莫三嗪可能通过谷氨酸能系统对PPI发挥作用。
