Summary
In the present study the actions of γ-hydroxybutyric acid (GHBA) on dopaminergic neurons in the rat substantia nigra (SN) were pharmacologically analysed utilising extracellular single unit recording techniques. Intravenous administration of GHBA was associated with several effects on the neuronal activity of nigral dopamine (DA) neurons. Low doses (<200 mg/kg) of GHBA produced a slight excitation of the neurons, concomitant with a regularised firing rhythm and lack of burst activity. In higher doses GHBA produced an even higher degree of regularisation but, in contrast to low doses, an inhibition of firing rate. Administration of the GABAB-receptor agonist baclofen, in all essential respects, mimicked the effect of GHBA on the firing of nigral DA neurons. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic administration of GHBA were antagonised by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.).
Our observations show that GHBA affects the firing pattern of nigral DA neurons in doses considerably lower than those required to inhibit the firing rate of the neurons. This action, as well as the decreased firing rate observed after high doses of GHBA, are mediated via activation of GABAB-receptors.
Similar content being viewed by others
References
Andén N-E, Stock G (1973) Inhibitory effect of gamma-hydroxybutyric acid and gamma-aminobutyric acid on the dopamine cells in the substantia nigra. Naunyn-Schmiedeberg's Arch Pharmacol 279:89–92
Andén N-E, Wachtel H (1977) Biochemical effects of baclofen (β-parachlorophenyl-GABA) on the dopamine and the noradrenaline in the rat brain. Acta Pharmacol Toxicol 40:310–320
Bean AJ, Roth RH (1991) Extracellular dopamine and neurotensin in rat prefrontal cortex in vivo: effects of medial forebrain bundle stimulation frequency, stimulation pattern and dopamine autoreceptors. J Neurosci 11:2694–2702
Benavides J, Rumigny JF, Bourguignon JJ, Cash C, Wermuth C, Mandel P, Vincendon G, Maitre M (1982) High affinity binding sites for γ-hydroxybutyric acid in rat brain. Life Sci 30:953–961
Bowery NG (1982) Baclofen 10 years on. Trends Pharmacol Sci 3:400–403
Broxterman HJ, Noach EL, van Valkenburg CFM, Wijling A (1981) Cross-tolerance of dopamine metabolism to baclofen, γ-butyrolactone and HA-966 in the striatum and olfactory tubercle of the rat. Life Sci 28:973–981
Chergui K, Charlety PJ, Akaoka H, Brunet J L, Saunier CF, Buda M, Svensson TH, Chouvet G (1991) Participation of NMDA receptors in spontaneous burst firing of dopaminergic mesencephalic neurons. C R Acad Sci 313:139–144
Diana M, Mereu G, Mura A, Fadda F, Passino N, Gessa G (1991) Low doses of γ-hydroxybutyric acid stimulate the firing rate of dopaminergic neurons in unanaesthetised rats. Brain Res 556:208–211
Engberg G, Kling-Petersen T, Nissbrandt H (1993) GABAB-receptors activation alters the firing pattern o dopamine neurons in the rat substantia nigra. Synapse (in press)
Fox S, Krnjevic K, Morris ME, Puil E, Werman R (1978) Action of baclofen on mammalian synaptic transmission. Neurosci 3:495–515
Gariano RF, Groves PM (1988) Burst firing induced in midbrain dopamine neurons by stimulation of the medial prefrontal and anteriorcingulate cortices. Brain Res 462:194–198
Gessa GL, Crabai F, Vargiu L, Spano PF (1968) Selective increase of brain dopamine induced by γ-hydroxybutyrate Study of the mechanism of action. J Neurochem 15:377–381
Giarman N J, Roth RH (1964) Differential estimation of gamma-butyrolactone of gamma-hydroxybutyric acid in rat blood and brain. Science 145:583
Gonon FG (1988) Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry. Neuroscience 24:19–28
Grace AA, Bunney BS (1980) Effects of baclofen on nigral dopaminergic cell activity following acute and chronic haloperidol treatment. Brain Res Bull 5:[Suppl 2] 537–543
Grace AA, Bunney BS (1983) Intracellular and extracellular electrophysiology of nigral dopamine neurons. I. Identification and characterization. Neuroscience 10:301–315
Grace AA, Bunney BS (1984) The control of firing pattern in nigral dopamine neurons burst firing. J Neurosci 4:2877–2890
Grace AA, Onn S-P (1989) Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. J Neurosci 9:3463–3481
Hechler V, Gobaille S, Maitre M (1992) Selective distribution of γ-hydroxybutyrate receptors in the rat forebrain and midbrain as revealed by quantitative autoradiography. Brain Res 572:345–348
Manley LD, Kuczenski R, Segal D, Young SJ, Groves PM (1992) Effects of frequency and pattern of medial forebrain bundle stimulation on caudate dialysate dopamine and serotonin. J Neurochem 58:1491–1498
Maitre M, Rumigny JF, Cash CD, Mandel P (1983) Subcellular distribution of γ-hydroxybutyrate binding sites in rat brain. Principal localization in the synaptosomal fraction. Biochem Biophys Res Commun 110:262–265
Olpe H-R, Koella WP (1979) Inhibition of nigral and neocortical cells by γ-hydroxybutyrate A microiontophoretic investigation. Eur J Pharmacol 53:359–364
Olpe H-R, Karlsson G, Pozza MF, Brugger F, Steinmann M, Van Riezen H, Fagg G, Hall RG, Froestl W, Bittiger H (1990) CGP 35348 a centrally active blocker of GABAB-receptors. Eur J Pharmacol 187:27–38
Romo, R, Schultz W (1990) Dopamine neurons of the monkey midbrain Contingencies of responses to active touch during self-initiated arm movements. J Neurophysiol 63:592–606
Roth RH, Giarman NJ (1970) Natural occurrence of gamma-hydroxybutyric acid in mammalian brain. Biochem Pharmacol 21:2111–2121
Roth RH, Walters JR, Aghajanian GK (1973) Effect of impulse flow on the release and synthesis of dopamine in the rat striatum. In Snyder SH, Usdin E (eds). Frontiers in catecholamine research, Pergamon, Oxford, pp 567–574
Roth RH, Doherty JD, Walters JR (1980) Gamma-hydroxybutyrate a role in the regulation of central dopaminergic neurons? Brain Res 18:556–560
Sanghera MK, Trulson ME, German DC (1984) Electrophysiological properties of mouse dopamine neurons in vivo and in vitro studies. Neuroscience 12:793–801
Schultz W, Romo R (1990) Dopamine neurons of the monkey midbrain Contingencies of responses to stimuli eliciting immediate behavioral reactions. J Neurophysiol 63:607–624
Serra M, Sanna E, Foddi C, Concas A, Biggio G (1991) Failure of γ-hydroxybutyrate to alter the function of the GABAA receptor complex in the rat cerebral cortex. Psychopharmacol 104:351–355
Stock G, Magnusson T, Andén N-E (1973) Increase in brain dopamine after axotomy or treatment with gammahydroxybutyric acid due to elimination of the nerve impulse flow. Naunyn-Schmiedeberg's Arch Pharmacol 278:347–361
Svensson TH, Tung CS (1989) Local cooling of the pre-frontal cortex induces pacemaker-like firing of dopamine neurons in the rat ventral tegmental area in vivo. Acta Physiol Scand 136:135–136
Tunnicliff G (1992) Significance of γ-hydroxybutyric acid in the brain. Gen Pharmacol 23:1027–1034
Vayer P, Mandel P, Maitre M (1985) Conversion of γ-hydroxybutyrate to γ-aminobutyrate in vitro. J Neurochem 45:810–814
Vayer P, Mandel P, Maitre M (1987) Gamma-hydroxybutyrate, a possible neurotransmitter. Life Sci 41:1547–1557
Vayer P, Ehrhardt J-D, Gobaille S, Mandel P, Maitre M (1988) Gamma hydroxybutyrate distribution and turnover rates in discrete brain regions of the rat. Neurochem Int 12:53–59
Waldmeier PC (1991) The GABAB-antagonist, CGP 35348, antagonises the effects of baclofen, γ-butyrolactone and HA 966 on rat striatal dopamine synthesis. Naunyn-Schmiedeberg's Arch Pharmacol 343:173–178
Walters JR, Roth RH (1972) Effect of gamma-hydroxybutyrate on dopamine and dopamine metabolites in the rat striatum. Biochem Pharmacol 21:2111–2121
Werner G, Mountcastle VB (1963) The variability of central neural activity in a sensory system and its implication for the central reflection of sensory events. J Neurophysiol 26:958–977
Wojcik WJ, Travagli RA, Costa E, Bertolini M (1990) Baclofen inhibits with high affinity an Irtype-like voltage-dependent calcium channel in cerebellar granule cell cultures. Neuropharmacology 29:696–672
Wojcik WJ, Holopainen I (1992) Role of central GABAB-receptors in physiology and pharmacology. Neuropsychopharmacology 6: 201–214
Author information
Authors and Affiliations
Additional information
Correspondence to: G. Engberg at the above address
Rights and permissions
About this article
Cite this article
Engberg, G., Nissbrandt, H. γ-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors. Naunyn-Schmiedeberg's Arch Pharmacol 348, 491–497 (1993). https://doi.org/10.1007/BF00173208
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00173208