The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro

It has been suggested that the anticonvulsant effect of lamotrigine resides with it's ability to block voltage gated Na-channels at presynaptic sites, thus stabilizing the presynapse, and, consequently, reducing the release of synaptic transmitters. Neurochemical studies have shown that it can inhibit the veratrine-stimulated release of the excitatory transmitter, glutamate from cortical tissue, but that at slightly higher concentrations it also reduces the release of the inhibitory transmitter, GABA. In the present study we examined the effect of the drug on the release of these transmitters at synapses in the rat entorhinal cortex, using the whole-cell patch clamp technique to record spontaneous excitatory (EPSCs) and inhibitory postsynaptic currents (IPSCs). Lamotrigine reduced the frequency, but not the amplitude of spontaneous EPSCs. This clearly indicated a presynaptic effect to reduce the release of glutamate. However, the same effect was observed when we tested the drug on miniature EPSCs, recorded in the presence of TTX and Cd, showing that blockade of Na-channels or Ca-channels was not a prerequisite for inhibition of glutamate release. In contrast to it's effects on EPSCs, lamotrigine increased both the frequency and amplitude of spontaneous IPSCs, suggesting that the drug was acting presynaptically to enhance GABA release. Again, similar effects were seen with miniature IPSCs recorded in TTX. These opposite effects of lamotrigine on glutamate and GABA release are similar to those we have reported previously with phenytoin, and suggest that reciprocal modulation of the background release of the major excitatory and inhibitory transmitters may be a significant factor in dampening excitability in pathologically hyperexcitable cortical networks.

[1]  R. Maj,et al.  Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. , 1999, The Journal of pharmacology and experimental therapeutics.

[2]  E. Harris,et al.  An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels , 1992, Epilepsy Research.

[3]  E. Reynolds,et al.  Lamotrigine for generalised epilepsies , 1992, The Lancet.

[4]  G. Holmes,et al.  Lamotrigine in Absence and Primary Generalized Epilepsies , 1997, Journal of child neurology.

[5]  M. Brodie,et al.  Antiepileptic Drug Monitoring at the Epilepsy Clinic: A Prospective Evaluation , 1991, Epilepsia.

[6]  D. Heal,et al.  Weak blockade of AMPA receptor-mediated depolarisations in the rat cortical wedge by phenytoin but not lamotrigine or carbamazepine. , 1997, European journal of pharmacology.

[7]  J. DeFelipe,et al.  Deficit of quantal release of GABA in experimental models of temporal lobe epilepsy , 1999, Nature Neuroscience.

[8]  N. Bowery,et al.  Effect of lamotrigine on the electrically-evoked release of endogenous amino acids from slices of dorsal horn of the rat spinal cord , 1995, Neuropharmacology.

[9]  O. Yuge,,et al.  Quantitative measurement of thromboelastography as a function of platelet count. , 1999, Anesthesia and analgesia.

[10]  M. Leach,et al.  Pharmacological Studies on Lamotrigine, A Novel Potential Antiepileptic Drug , 1986, Epilepsia.

[11]  G. Bernardi,et al.  Differential Inhibition by Riluzole, Lamotrigine, and Phenytoin of Sodium and Calcium Currents in Cortical Neurons: Implications for Neuroprotective Strategies , 1997, Experimental Neurology.

[12]  M. Schmutz,et al.  Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters , 1995, Neurology.

[13]  G Bernardi,et al.  An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons , 1999, British journal of pharmacology.

[14]  K. Hsu,et al.  Inhibition of N‐type calcium currents by lamotrigine in rat amygdalar neurones , 1996, Neuroreport.

[15]  M. Leach,et al.  Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neuroglial cultures from rat cortex , 1993, Brain Research.

[16]  H. Möller,et al.  Lamotrigine may limit pathological excitation in the hippocampus by modulating a transient potassium outward current , 1998, Brain Research.

[17]  B. Roth,et al.  Pharmacological Studies on Lamotrigine, A Novel Potential Antiepileptic Drug , 1986, Epilepsia.

[18]  A. Dhillon,et al.  Reciprocal modulation of glutamate and GABA release may underlie the anticonvulsant effect of phenytoin , 1999, Neuroscience.

[19]  H. Higashi,et al.  Mechanisms underlying the enhancement of excitatory synaptic transmission in basolateral amygdala neurons of the kindling rat. , 1998, Journal of neurophysiology.

[20]  Christophe Bernard,et al.  Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy , 1999, The Journal of comparative neurology.

[21]  R. S. Jones,et al.  A comparison of spontaneous EPSCs in layer II and layer IV-V neurons of the rat entorhinal cortex in vitro. , 1996, Journal of neurophysiology.

[22]  A. Richens,et al.  Lamotrigine in primary generalised epilepsy , 1992, The Lancet.

[23]  Roland S. G. Jones Entorhinal-hippocampal connections: a speculative view of their function , 1993, Trends in Neurosciences.

[24]  K. Hsu,et al.  Presynaptic inhibition of excitatory neurotransmission by lamotrigine in the rat amygdalar neurons , 1996, Synapse.

[25]  K. Goa,et al.  Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy. , 1993, Drugs.

[26]  J. M. Crowder,et al.  Common Anticonvulsants Inhibit Ca2+ Uptake and Amino Acid Neurotransmitter Release In Vitro , 1987, Epilepsia.

[27]  H. Frizelle,et al.  The combined effects of halothane and lamotrigine on excitatory postsynaptic potentials and use-dependent block in the rat dentate gyrus in vitro. , 1999 .