Motalli Rita, D'Antuono Margherita, Louvel Jacques, Kurcewicz Irene, D'Arcangelo Giovanna, Tancredi Virginia, Manfredi Mario, Pumain René, Avoli Massimo
Montreal Neurological Institute and Department of Neurology, McGill University, Montreal, Quebec, Canada.
J Pharmacol Exp Ther. 2002 Dec;303(3):1102-13. doi: 10.1124/jpet.102.040782.
The GABA(B) receptor agonist baclofen enhances the epileptiform activity induced by 4-aminopyridine (4AP) in juvenile rat hippocampal slices. In this study, we used a similar experimental approach (i.e., field potential, intracellular, and [K+]o recordings in the CA3 area of slices obtained from 15-23-day-old rats) to establish whether antagonizing GABA(B) receptors could exert opposite (presumably anticonvulsant) effects. Bath application of 4AP (50 microM) induced spontaneous interictal and ictal discharges along with synchronous GABA receptor-mediated potentials. All types of 4AP-induced synchronous activity occurred more frequently during application of the GABA(B) receptor antagonist p3-amino-propyl,p-diethoxymethylphosphonic acid (CGP 35348) (0.1-1 mM; EC50 = 0.25 mM). Moreover, CGP 35348 augmented the frequency and, to a lesser extent, the duration of the asynchronous synaptic activity recorded intracellularly from CA3 pyramids (n = 19). In medium containing 4AP + ionotropic glutamatergic antagonists (which abolished interictal and ictal activity), CGP 35348 prolonged both GABA-receptor-mediated field potentials and the accompanying intracellular long-lasting depolarizations without modifying their rate (n = 12). The transient elevations in [K+]o associated with GABA receptor-mediated potentials in 4AP-containing medium (n = 7 slices) became larger during CGP 35348 application. Similar findings were obtained when CGP 35348 was applied to medium containing 4AP + ionotropic glutamatergic antagonists (n = 6). Thus, the effect of CGP 35348 on 4AP-induced epileptiform activity is not anticonvulsant and to some extent similar to what was reported in this model during GABA(B) receptor activation. We propose that the facilitation of ictal activity by CGP 35348 is mainly caused by the blockade of presynaptic GABA(B) receptor, leading to an increase in GABA release and subsequent larger [K+]o elevations.
γ-氨基丁酸B（GABA(B)）受体激动剂巴氯芬可增强4-氨基吡啶（4AP）在幼年大鼠海马切片中诱导的癫痫样活动。在本研究中，我们采用了类似的实验方法（即对从15至23日龄大鼠获取的切片的CA3区进行场电位、细胞内和细胞外[K+]记录）来确定拮抗GABA(B)受体是否会产生相反的（可能是抗惊厥的）作用。浴加4AP（50微摩尔）可诱导自发性发作间期和发作期放电以及同步的GABA受体介导的电位。在应用GABA(B)受体拮抗剂p-3-氨基丙基，p-二乙氧基甲基膦酸（CGP 35348）（0.1至1毫摩尔；半数有效浓度[EC50]=0.25毫摩尔）期间，所有类型的4AP诱导的同步活动发生得更为频繁。此外，CGP 35348增加了从CA3锥体细胞细胞内记录的异步突触活动的频率，并在较小程度上增加了其持续时间（n=19）。在含有4AP+离子型谷氨酸能拮抗剂（可消除发作间期和发作期活动）的培养基中，CGP 35348延长了GABA受体介导的场电位以及伴随的细胞内长时间去极化，而不改变其速率（n=12）。在含有4AP的培养基中，与GABA受体介导的电位相关的细胞外[K+]的短暂升高（n=7个切片）在应用CGP 35348期间变得更大。当将CGP 35348应用于含有4AP+离子型谷氨酸能拮抗剂的培养基中时，也获得了类似的结果（n=6）。因此，CGP 35348对4AP诱导的癫痫样活动的作用不是抗惊厥的，并且在某种程度上类似于在该模型中GABA(B)受体激活期间所报道的情况。我们提出，CGP 35348对发作期活动的促进作用主要是由突触前GABA(B)受体的阻断引起的，导致GABA释放增加以及随后更大的细胞外[K+]升高。
