Role of metabotropic glutamate receptors in the depression of GABA-mediated depolarization of frog primary afferent terminals

• Published in: Neuroscience 1997-12, Vol.81 (4), p.1079-1090
• Main Authors: Hackman, J.C, Holohean, A.M, Davidoff, R.A
• Format: Article
• Language: English
• Subjects: Animals; Anura; Biological and medical sciences; Central nervous system; Cycloleucine - analogs & derivatives; Cycloleucine - pharmacology; Electric Stimulation; Electrophysiology; excitatory amino acids; Freshwater; frog; Fundamental and applied biological sciences. Psychology; GABA; gamma-Aminobutyric Acid - pharmacology; gamma-Aminobutyric Acid - physiology; In Vitro Techniques; Isomerism; Membrane Potentials - drug effects; Membrane Potentials - physiology; metabotropic glutamate receptors; N-methyl- d-aspartate; Nerve Endings - drug effects; Nerve Endings - physiology; Neurons, Afferent - drug effects; Neurons, Afferent - physiology; Neuroprotective Agents - pharmacology; Rana pipiens; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - physiology; Signal Transduction - drug effects; spinal cord; Spinal Cord - cytology; Spinal Cord - drug effects; Spinal Nerve Roots - drug effects; Spinal Nerve Roots - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(97)00234-0

Sucrose gap recordings from the dorsal roots of isolated, hemisected frog spinal cords were used to determine the effects of metabotropic l-glutamate receptor activation on primary afferent terminals by (±)-1-amino- trans-1,3-cyclopentane-dicarboxylic acid ( t-ACPD). Dorsal root potentials evoked by ventral root volleys were significantly reduced by t-ACPD (30 μM), as were GABA- and muscimol-induced afferent terminal depolarizations. The effects of t-ACPD on GABA-depolarizations depended upon activation of group I metabotropic glutamate receptors, i.e. the effects were blocked by the group I/II antagonist ( RS)- α-methyl-4-carboxyphenylglycine, but not by the group II antagonist α-methyl-(2 S,3 S,4 S)- α-(carboxycyclopropyl)-glycine or the group III antagonist α-methyl-( S)-2-amino-4-phosphonobutyrate and were mimicked by the group I agonist 3,5-dihydroxyphenylglycine but were not mimicked by the group III agonist ( S)-2-amino-4-phosphonobutyrate. Increasing the intracellular concentration of 3′,5′-cyclic adenosine monophosphate with 8-bromo-cAMP, forskolin, and 3-isobutyl-1-methylxanthine significantly reduced GABA depolarizations, but the protein kinase inhibitors Rp-adenosine 3,5-cyclic monophosphothioate triethylamine and N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide did not alter t-ACPD's depression of GABA depolarizations. The actions of t-ACPD on GABA depolarizations were neither mimicked nor blocked by phorbol-12-myristate 13-acetate, thapsigargin, staurosporine, or arachidonic acid, presumptive indications that the effects of t-ACPD did not involve phosphoinositide hydrolysis, the release of Ca 2+ from intracellular stores, or the formation of arachidonate. t-ACPD's effects on GABA depolarizations were blocked by 20 mM Mg 2+, the broad spectrum l-glutamate antagonist kynurenate, and the selective N-methyl- d-aspartate antagonist D(−)-2-amino-5-phosphonovaleric acid, but not by the non- N-methyl- d-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Low concentrations of N-methyl- d-aspartate (10 μM) mimicked the effect of t-ACPD on GABA responses. These results suggest that t-ACPD's depression of GABA depolarizations involves an indirect, three-stage mechanism that includes activation of Group I metabotropic glutamate receptors on interneurons and/or on afferent terminals, the release of l-glutamate from the latter structures, and the activation of N-methyl- d-aspartate receptors on primary afferent terminals. The depression