Skip to main content
SpringerLink
Log in

δ-Aminovaleric acid antagonizes the pharmacological actions of baclofen in the central nervous system

  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Summary

The action of δ-aminovaleric acid (AVA) on the muscle relaxant properties of baclofen, a GABAB receptor agonist, was investigated in two experimental models: (1) the pathologically increased muscle tone of the gastrocnemius muscle in spastic mutant Han-Wistar rats and (2) the Hoffmann (H)-reflex recorded from plantar foot muscles after electrical stimulation of the tibial nerve in barbiturate (60 mg/kg) anaesthetized rats. In both paradigms coadministration of AVA (500 nmol/5 μl) antagonized the muscle relaxant action of intrathecally applied baclofen (0.2–2 nmol), but failed to affect the muscle relaxant effects of intrathecally injected muscimol (2–20 nmol). In contrast, coadministration of bicuculline (1 nmol) did block the muscle relaxant action of muscimol, but failed to alter the effects of baclofen. When administered alone, bicuculline (1 nmol), or AVA (500 nmol–2 μmol) were without intrinsic action in both paradigms. In an additional series of experiments we investigated the action of AVA on a supraspinal effect of baclofen. Coadministration of AVA (12.5 nmol/0.5 μl) in the ventromedial thalamic nucleus antagonized the catalepsy induced by baclofen (ED50 10 pmol/0.5 μl), as indicated by an increase in ED50 of baclofen by a factor of 4.835 and a parallel shift of the probit-log dosage regression line to the right. The parallel shift seems to be consistent with a competitive mechanism of action of AVA. This study presents evidence that AVA antagonizes central pharmacological actions of baclofen at both spinal and supraspinal sites without affecting the actions of a GABAA agonist, muscimol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Allan RD, Dickenson HW (1986) Evidence that antagonism by δ-aminovaleric acid of GABAB receptors in the guinea-pig ileum may be due to an interaction between GABAA and GABAB receptors. Eur J Pharmacol 120: 119–122

    Google Scholar 

  • Bowery NG, Brown DA (1974) Depolarizing actions of γ-aminobutyric acid and related compounds on rat superior cervical ganglia in vitro. Br J Pharmacol 50: 205–218

    Google Scholar 

  • Bowery NG, Doble A, Hill DR, Hudson AL, Shaw JS, Turnbull MJ, Warrington R (1981) Bicuculline-insensitive GABA receptors on peripheral autonomic nerve terminals. Eur J Pharmacol 71: 53–70

    Google Scholar 

  • Bowery NG, Hill DR, Hudson AL (1983) Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes. Br J Pharmacol 78: 191–206

    Google Scholar 

  • Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, Turnbull M (1980) (-)baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature (Lond) 283: 92–94

    Google Scholar 

  • Bowery NG, Price GW, Hudson AL, Hill DR, Wilkin GP, Turnbull MJ (1984) GABA receptor multiplicity. Neuropharmacology 23: 219–231

    Google Scholar 

  • Capland JG, Davies CTM (1964) A simple clinical skin electrode. Lancet 1: 416

    Google Scholar 

  • Curtis DR, Duggan AW, Felix D, Johnston GAR (1971) Bicuculline, an antagonist of GABA and synaptic inhibition in the spinal cord. Brain Res 32: 69–96

    Google Scholar 

  • Curtis DR, Game CJA, Johnston GAR, McCulloch RM (1974) Central effects of β-(p-chlorophenyl)-γ-aminobutyric acid. Brain Res 70: 493–499

    Google Scholar 

  • Curtis DR, Lodge D, Bornstein JC, Peet MJ (1981) Selective effects of (-)baclofen on spinal synaptic transmission in the cat. Exp Brain Res 42: 158–170

    Google Scholar 

  • Curtis DR, Watkins JC (1960) The excitation and depression of spinal neurones by structurally related amino acids. J Neurochem 6: 117–141

    Google Scholar 

  • Davidoff RA (1985) Antispasticity drugs: mechanisms of action. Ann Neurol 17: 107–116

    Google Scholar 

  • Davidoff RA, Sears ES (1974) The effects of lioresal on synaptic activity in the isolated spinal cord. Neurology (Minneap) 24: 957–963

    Google Scholar 

  • Davies J (1981) Selective depression of synaptic excitation in cat spinal neurones by baclofen: an iontophoretic study. Br J Pharmacol 72: 373–384

    Google Scholar 

  • Davies J, Watkins JC (1974) The action of β-phenyl-GABA derivatives on neurones of the cat cerebral cortex. Brain Res 70: 501–505

    Google Scholar 

  • DiChiara G, Morelli M, Porceddu ML, Gessa GL (1979) Role of thalamic γ-aminobutyrate in motor functions: catalepsy and ipsiversive turning after intrathalamic muscimol. Neuroscience 4: 1453–1465

    Google Scholar 

  • Dralle D, Müller H, Zierski J, Klug N (1985) Intrathecal baclofen for spasticity. Lancet 2: 1003

    Google Scholar 

  • Fox S, Krnjević K, Morris ME, Puil E, Werman R (1978) Action of baclofen on mammalian synaptic transmission. Neuroscience 3: 495–515

    Google Scholar 

  • Giotti A, Luzzi S, Spagnesi LS, Zilletti L (1983a) GABAA and GABAB receptor-mediated effects in guinea-pig ileum. Br J Pharmacol 78: 469–478

    Google Scholar 

  • Giotti A, Luzzi S, Spagnesi LS, Zilletti L (1983b) Homotaurine: a GABAB antagonist in guinea-pig ileum. Br J Pharmacol 79: 855–862

    Google Scholar 

  • Hill DR, Bowery NG (1981) 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain. Nature (Lond) 290: 149–152

    Google Scholar 

  • Johnston GAR, Beart PM, Curtis DR, Gama CJA, McCulloch RM, McLachlau RM (1972) Bicuculline methochloride as a GABA antagonist. Nature (Lond) 240: 219–220

    Google Scholar 

  • Kerr DIB, Ong J (1984) Evidence that ethylenediamine acts in the isolated ileum of the guinea-pig by releasing endogenous GABA. Br J Pharmacol 83: 169–177

    Google Scholar 

  • Klockgether T, Schwarz M, Turski L, Sontag K-H (1986) The rat ventromedial thalamic nucleus and motor control: role of N-methyl-D-aspartate-mediated excitation, GABAergic inhibition, and muscarinic transmission. J Neurosci 6: 1702–1711

    Google Scholar 

  • König JFR, Klippel RA (1963) The rat brain. A stereotaxic atlas of the forebrain and lower parts of the brain stem. Williams and Wilkins, Baltimore

    Google Scholar 

  • Kroin JS, Penn RD, Beissinger RL, Arzbacher RC (1984) Reduced spinal reflexes following intrathecal baclofen in the rabbit. Exp Brain Res 54: 191–194

    Google Scholar 

  • Lanthorn TH, Cotman CW (1981) Baclofen selectively inhibits excitatory synaptic transmission in the hippocampus. Brain Res 225: 171–178

    Google Scholar 

  • Levy RA, Proudfit HK (1979) Analgesia produced by microinjection of baclofen and morphine at brain stem sites. Eur J Pharmacol 57: 43–55

    Google Scholar 

  • Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96: 99–113

    Google Scholar 

  • Magladery JW, McDougal DB (1950) Electrophysiological studies of nerve and reflex activity in normal man. I. Identification of certain reflexes in the electromyogram and the conduction velocity of peripheral nerve fibres. Bull Johns Hopkins Hosp 86: 265–290

    Google Scholar 

  • Meinck HM (1976) Occurrence of the H reflex and the F wave in the rat. Electroenc Clin Neurophys 41: 530–533

    Google Scholar 

  • Müller H, Zierski J, Dralle D, Börner U, Hoffmann O (1987) The effect of intrathecal baclofen on electrical muscle activity in spasticity. J Neurol 234: 348–352

    Google Scholar 

  • Muhyaddin M, Roberts PJ, Woodruff GN (1982) Presynaptic γ-aminobutyric acid receptors in the rat anococcygeus muscle and their antagonism by 5-amino-valeric acid. Br J Pharmacol 77: 163–168

    Google Scholar 

  • Muhyaddin M, Roberts PJ, Woodruff GN (1983) Presynaptic GABAB receptors and the regulation of (3H)noradrenaline release from rat anococcygeus muscle. Eur J Pharmacol 92: 9–14

    Google Scholar 

  • Nakahiro M, Saito K, Yamada I, Yoshida H (1985) Antagonistic effect of δ-aminovaleric acid on bicuculline insensitive γ-aminobutyric acidB (GABAB) sites in the rat's brain. Neurosci Lett 57: 263–266

    Google Scholar 

  • Newberry NR, Nicoll RA (1984) Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. Nature (Lond) 308: 450–452

    Google Scholar 

  • Olpe HR, Koella WP, Wolf P, Haas HL (1977) The action of baclofen on neurones of the substantia nigra and of the ventral tegmental area. Brain Res 134: 577–580

    Google Scholar 

  • Ong J, Kerr DIB (1983) GABAA-and GABAB-receptor-mediated modification of intestinal motility. Eur J Pharmacol 86: 9–17

    Google Scholar 

  • Penn RD, Kroin JS (1984) Intrathecal baclofen alleviates spinal cord spasticity. Lancet 1: 1078

    Google Scholar 

  • Penn RD, Kroin JS (1985) Continuous intrathecal baclofen for severe spasticity. Lancet 2: 125–127

    Google Scholar 

  • Pierau FK, Zimmermann P (1973) Action of a GABA-derivative on postsynaptic potentials and membrane properties of cats' spinal motoneurones. Brain Res 54: 376–380

    Google Scholar 

  • Pittermann W, Sontag KH, Wand P, Rapp K, Deerberg F (1976) Spontaneous occurrence of spastic paresis in Han-Wistar rats. Neurosci Lett 2: 45–49

    Google Scholar 

  • Price GW, Wilkin GP, Turnbull MJ, Bowery NG (1984) Are baclofen-sensitive GABAB receptors present on primary afferent terminals of the spinal cord? Nature (Lond) 307: 71–74

    Google Scholar 

  • Purpura DP, Girado M, Smith TG, Callan DA, Grundfest H (1959) Structure-activity determinants of pharmacological effects of amino acids and related compounds on central synapses. J Neurochem 3: 238–268

    Google Scholar 

  • Schwarz M, Löscher W, Turski L, Sontag K-H (1985) Disturbed GABAergic transmission in mutant Han-Wistar rats: further evidence for basal ganglia dysfunction. Brain Res 347: 258–267

    Google Scholar 

  • Wilkin GP, Hudson AL, Hill DR, Bowery NG (1981) Autoradiographic localization of GABAB receptor in rat cerebellum. Nature (Lond) 294: 584–587

    Google Scholar 

  • Wilson PR, Yaksh TL (1978) Baclofen is antinociceptive in the spinal intrathecal space of animals. Eur J Pharmacol 51: 323–330

    Google Scholar 

  • Wüllner U, Klockgether T, Schwarz M, Sontag K-H (1987) Behavioural actions of baclofen in the rat ventromedial thalamic nucleus: antagonism by δ-aminovalerate. Brain Res 422: 129–136

    Google Scholar 

  • Yaksh TL, Rudy TA (1976) Chronic catheterization of the spinal subarachnoid space. Physiol Behav 17: 1031–1036

    Google Scholar 

  • Young RR, Delwaide PJ (1981) Drug therapy: spasticity. N Engl J Med 304: 28–33, 96–99

    Google Scholar 

Download references

Author information

Author notes

  1. M. Schwarz

    Present address: Dept. of Neurology and Clinical Neurophysiology, Alfried Krupp Hospital, Alfried-Krupp-Str. 21, D-4300, Essen, F.R.G.

  2. T. Klockgether

    Present address: Dept. of Neurology, University of Tübingen, Liebermeisterstr. 18-20, D-7400, Tübingen, F.R.G.

  3. L. Turski

    Present address: Dept. of Neuropharmacology, Schering AG, Müllerstr. 170-178, D-1000, Berlin 65, F.R.G.

Authors and Affiliations

  1. Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Strasse 3, D-3400, Göttingen, Federal Republic of Germany

    M. Schwarz, T. Klockgether, U. Wüllner, L. Turski & K. -H. Sontag

Authors
  1. M. Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Klockgether
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. U. Wüllner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Turski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. -H. Sontag
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schwarz, M., Klockgether, T., Wüllner, U. et al. δ-Aminovaleric acid antagonizes the pharmacological actions of baclofen in the central nervous system. Exp Brain Res 70, 618–626 (1988). https://doi.org/10.1007/BF00247610

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00247610

Key words

Search

Navigation