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Volume 17, Number 3, Issue of February 1, 1997 pp. 983-995
Copyright ©1997 Society for NeuroscienceEpileptogenesis In Vivo Enhances the Sensitivity of Inhibitory Presynaptic Metabotropic Glutamate Receptors in Basolateral Amygdala Neurons In Vitro
Received July 8, 1996; revised Nov. 13, 1996; accepted Nov. 15, 1996.
Volker Neugebauer, N. Bradley Keele, and Patricia Shinnick-Gallagher Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas 77555-1031
Modulation of excitatory synaptic transmission by presynaptic metabotropic glutamate receptors (mGluRs) was examined in brain slices from control rats and rats with amygdala-kindled seizures. Using whole-cell voltage-clamp and current-clamp recordings, this study shows for the first time that in control and kindled basolateral amygdala neurons, two pharmacologically distinct presynaptic mGluRs mediate depression of synaptic transmission. Moreover, in kindled neurons, agonists at either group II- or group III-like mGluRs exhibit a 28- to 30-fold increase in potency and suppress synaptically evoked bursting. The group II mGluR agonist (2S,3S,4S)-2-(carboxycyclopropyl)glycine (L-CCG) dose-dependently depressed monosynaptic EPSCs evoked by stimulation in the lateral amygdala with EC50 values of 36 nM (control) and 1.2 nM (kindled neurons). The group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) was less potent, with EC50 values of 297 nM (control) and 10.8 nM (kindled neurons). The effects of L-CCG and L-AP4 were fully reversible. Neither L-CCG (0.0001-10 µM) nor L-AP4 (0.001-50 µM) caused membrane currents or changes in the current-voltage relationship. The novel mGluR antagonists (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)-glycine (MCCG; 100 µM) and (S)-2-methyl-2-amino-4-phos-phonobutyrate (MAP4; 100 µM) selectively reversed the inhibition by L-CCG and L-AP4 to 81.3 ± 12% and 65.3 ± 6.6% of predrug, respectively. MCCG and MAP4 (100-300 µM) themselves did not significantly affect synaptic transmission. The exquisite sensitivity of agonists in the kindling model of epilepsy and the lack of evidence for endogenous receptor activation suggest that presynaptic group II- and group III-like mGluRs might be useful targets for suppression of excessive synaptic activation in neurological disorders such as epilepsy.
Key words: excitatory amino acids; metabotropic glutamate receptors; presynaptic; basolateral amygdala; synaptic transmission; neuromodulation; kindling; epilepsy; limbic seizures; anticonvulsant; L-CCG; L-AP4; MCCG; MAP4
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