Reversal of GABA-mediated Inhibition of the Electrically and Potassium Chloride Evoked [3H]-GABA Release from Rat Substantia Nigra Slices by DL-3-Hydroxy-3-Phenyl Pentanamide

Sergio E Meza-Toledo; Norman G Bowery

doi:10.1055/s-0031-1296469

Arzneimittelforschung, Inhaltsverzeichnis

Arzneimittelforschung 2008; 58(2): 53-61
DOI: 10.1055/s-0031-1296469

CNS-active Drugs · Hypnotics · Psychotropics · Sedatives

Editio Cantor Verlag Aulendorf (Germany)

Reversal of GABA-mediated Inhibition of the Electrically and Potassium Chloride Evoked [³H]-GABA Release from Rat Substantia Nigra Slices by DL-3-Hydroxy-3-Phenyl Pentanamide

Authors

Sergio E Meza-Toledo

¹Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, México D. F., México
Norman G Bowery

²Department of Pharmacology, The Medical School, The University of Birmingham, Edgbaston, Birmingham, (UK)

Abstract

The phenyl alcohol amides, DL-2-hydroxy-2-phenyl butyramide (CAS 52839-87-9), DL-3-hydroxy-3-phenyl pentanamide (CAS 131802-69-2, DL-HEPP) and DL-4-hydroxy-4-phenyl hexanamide (CAS 67880-30-2) and their fluorine and chlorine analogs, at a concentration of 100 µmol/L, did not displace [³H]-γ-aminobutyric acid ([³H]-GABA, CAS 108158-36-7) from GABA_A receptors and only weakly displaced [³H]-GABA and [³H]-CGP62349 (CAS 186986-97-0), a GABA_B receptor antagonist, from GABA_B receptors in rat brain crude synaptic membranes. The electrically and potassium chloride (15 mmol/L) evoked [³H]-GABA release in the presence of DL-HEPP, GABA and GABA_B receptor ligands from rat brain substantia nigra (SN) slices was studied. R-Baclofen (CAS 69308-37-8) (10 µmol/L), a GABA_B receptor agonist, produced an inhibition of the electrically evoked [³H]-GABA release and this inhibition was blocked by CGP 55845A (CAS 149184-22-5) (10 µmol/L), a GABA_B receptor antagonist, but was not affected by DL-HEPP (100 µmol/L). CGP 55845A (10 µmol/L) did not alter the electrically evoked [³H]-GABA release in the absence of baclofen. The addition of DL-HEPP (100 µmol/L) alone did not affect the electrically-evoked release of [³H]-GABA release control, but it was able to significantly reduce the inhibitory effect of GABA (CAS 56-12-2) (10 µmol/L) on [³H]-GABA release evoked both by electrical and potassium chloride stimulation, in the presence of tiagabine (CAS 115103-54-3) (10 µmol/L), a GABA uptake blocker. In three preliminary experiments, bicuculline (CAS 485-49-4) (10 µmol/L) and picrotoxinin (CAS 17617-45-7) (10 µmol/L), two GABA_A antagonists, inhibited the electrically evoked release of [³H]-GABA from rat SN slices, and DL-HEPP (100 µmol/L) reversed this inhibition. The mechanism of action of DL-HEPP is not known but, it might act as a negative GABA modulator in rat brain slices.

Key words

Anticonvulsants - GABA modulators, negative - DL-3-Hydroxy-3-phenyl pentanamide, influence on GABA binding - Substantia nigra, evoked [³H]-GABA release

Volltext

Referenzen

References
1 Carvajal G, Russek M, Tapia R, Massieu G. Anticonvulsive action of substances designed as inhibitors of γ-amino-butyric acid–α-ketoglutaric acid transaminase. Biochem Pharmacol. 1964; 13: 1059-1069
2 Carvajal G, Massieu G. Gama-hidroxi-gama-etil-gama-fenil-butiramida (HEPB), nuevo agente anticonvulsionante agonista del GABA. In: Velasco-Suárez M, Escobedo-Rios F. eds. Neurobiología, Symposium Internacional. México: Progreso; 1979. p. 103-115
3 Meza-Toledo SE, Zenteno-García MT, Juárez-Carvajal E, Martínez-Muñoz D, Carvajal-Sandoval G. A New Homologous Series of Anticonvulsants: Phenyl Alcohol Amides. Syntheses and Pharmacological Evaluation. Arzneimittel-Forschung (Drug Research). 1990; 40: 1289-1291
4 Pérez de la Mora M, Tapia R. Anticonvulsant effect of 5-ethyl, 5-phenyl, 2-pyrrolidinone and its possible relationship to γ-aminobutyric acid-dependent inhibitory mechanisms. Biochem Pharmacol. 1973; 22: 2635-2639
5 Tapia R, Drucker-Colín RR, Meza-Ruiz G, Durán L, Levi G. Neurophysiological and neurochemical studies on the action of the anticonvulsant γ-hydroxy, γ-ethyl, γ-phenyl butyramide. Epilepsia. 1979; 20: 135-145
6 Solís H, Jurado JL, Fernández-Guardiola A. La acción de la butiramida sobre el desarrollo del kindling y el kindling amigdalino ya establecido en el gato. In: Velasco-Suárez M, Escobedo-Rios F. eds Neurobiología, Symposium International. México: Progreso; 1979. p. 83-94
7 Soilís H, Galindo-Morales JA, Bravo J, López E. Efecto de la DL-4-hidroxi, 4-etil, 4-fenil butiramida (HEPB) y de su homólogo propionamida (HEPP) sobre la excitabilidad neuronal. Arch Neurocien (Méx). 1996; 1: 99-103
8 Brailowsky S, Montiel T, Hernández E, Marescaux C, Vergnes M. Effects of 3-hydroxy, 3-ethyl, 3-phenylpropionamide (HEPP) on rat models of generalized and focal epilepsy. Epilepsy Res. 1992; 11: 167-172
9 Pineda AG, Gutiérrez VM, Flores AM, Pacheco MF. Estudio comparativo entre los efectos de la DL-4-hidroxi, 4-etil, 4-fenil butiramida (HEPB) y fenobarbital sobre la memoria espacial dependiente del hipocampo. Arch Neurocien (Méx). 1996; 1: 189-192
10 Carvajal-Sandoval G, Juárez-Carvajal E, Cruz-Peinado C, Meza-Toledo SE. Synthesis and Pharmacological Evaluation of a New Homologous Series of (±)-p-Fluoro-phenyl Alcohol Amide Anticonvulsants. Arzneimittel-Forschung (Drug Research). 1998; 48: 349-352
11 Meza-Toledo SE, Juárez-Carvajal E, Carvajal-Sandoval G. Synthesis of a New Homologous Series of p-Chlorophenyl Alcohol Amides, their Anticonvulsant Activity and their Testing as Potential GABA_B Receptor Antagonists. Arzneimittel-Forschung (Drug Research). 1998; 48: 797-801
12 Meza-Toledo SE, Martinez-Muñoz D, Carvajal-Sandoval G. Inhibition of R-[³H]-Baclofen Binding to Rat Brain Synaptic Membranes by a Homologous Series of Phenyl Alcohol Amides Anticonvulsants and Their Evaluation as GABA_B Receptor Blockers. Arzneimittel-Forschung (Drug Research). 1998; 48: 1051-1057
13 Bittiger H, Bellouin C, Froestl W, Heid J, Schmutz M, Stampf P. [³H] CGP 62349: A New Potent GABA_B Receptor Antagonist Radioligand. Pharmacol Rev Commun. 1996; 8: 97-98
14 Arbilla S, Kamal L, Langer SZ. Presynaptic GABA autoreceptors on GABAergic nerve endings of the rat substantia nigra. Eur J Pharmacol. 1979; 57: 211-217
15 Floran B, Silva I, Nava C, Aceves J. Presynaptic modulation of the release of GABA by GABA_A receptors in pars compacta and by GABA_B receptors in pars reticulata of the rat substantia nigra. Eur. J. Pharmacol. 1988; 150: 277-286
16 Giralt MT, Bonanno G, Raiteri M. GABA terminal autoreceptors in the pars compacta and in the pars reticulata of the rat substantia nigra are GABA_B . Eur. J. Pharmacol. 1990; 175: 137-144
17 Meza-Toledo SE, Bowery NG. Baclofen inhibits electrically evoked GABA release from rat substantia nigra slices without evidence for autoreceptors. Br. J. Pharmacol. 2000; 131: 46
18 Bittiger H, Froestl W, Mickel SJ, Olpe HR. GABA_B receptor antagonists: from synthesis to therapeutic applications. TIPS. 1993; 14: 391-394
19 Bowery NG, Hill DR, Hudson AL. Characteristics of GABA_B receptor binding sites on rat whole brain synaptic membranes. Br J Pharmacol. 1983; 78: 191-206
20 Hill DR, Bowery NG. [³H]-baclofen and [³H]-GABA bind to bicuculline- insensitive GABA_B sites in rat brain. Nature. 1981; 290: 149-152
21 Bruton R, Qume M. [³H]-GABA binding to GABA_A and GABA_B sites on rat brain crude synaptic membranes. In: Keen M. ed. Receptor Binding Techniques. Totowa, USA: Humana Press; 1999. p. 27-35
22 Raiteri M, Angelini F, Levi G. A simple apparatus for studying the release of neurotransmitters from synaptosomes. Eur J Pharmacol. 1974; 25: 411-414
23 Macdonald RL, Olsen RW. GABA_A receptor channels. Annu Rev Neurosci. 1994; 17: 569-602
24 Liu Z, Vergnes M, Depaulis A, Marescaux C. Involvement of intrathalamic GABA_B neurotransmission in the control of absence seizures in the rat. Neuroscience. 1992; 48: 87-93
25 Iadarola MJ, Gale K. Substantia nigra: site of anticonvulsant activity mediated by gamma-aminobutyric acid. Science. 1982; 218: 1237-1240
26 Bowery NG, Hudson AL, Price GW. GABA_A and GABA_B receptor site distribution in the rat central nervous system. Neuroscience. 1987; 20: 365-383
27 Chu DCM, Albin RL, Young AB, Penney JB. Distribution and kinetics of GABA_B binding sites in rat central nervous system: a quantitative autoradiographic study. Neuroscience. 1990; 34: 341-357
28 Nicholson LF, Faull RL, Waldvogel HJ, Dragunow M. The regional, cellular and subcellular localization of GABAA/benzodiazepine receptors in the substantia nigra of the rat. Neuroscience. 1992; 50: 355-370
29 Ng TKY, Yung KKL. Distinct cellular distribution of GABABR1 and GABAAα1 receptor immunoreactivity in the rat substantia nigra. Neuroscience. 2000; 99: 65-76
30 Bowery NG. GABA_B receptor pharmacology. Annu Rev Pharmacol Toxicol. 1993; 33: 109-147
31 Waldmeier PC, Wicki P, Feldtrauer JJ, Baumann PA. Release of endogenous GABA from the substantia nigra is not controlled by GABA autoreceptors. Naunyn-Schmiedeberg’s Arch Pharmacol. 1989; 340: 372-378
32 Chávez JL, Martínez MD. Mecanismo de acción del anticonvulsionante DL-3-hidroxi, 3-etil, 3-fenil propionamida (HEPP). Arch Neurocien (Méx). 1996; 1: 173-177