Skip to main content
Log in

The GABA/benzodiazepine receptor chloride channel complex during repeated episodes of physical ethanol dependence in the rat

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

The GABA/benzodiazepine (BZ) receptor chloride channel complex was investigated during repeated episodes of ethanol intoxication and withdrawal in the rat; the intragastric intoxication technique was applied and the severity of intoxication, withdrawal and number of seizures were recorded. The following groups were studied after decapitation during withdrawal 10–16 h after the last ethanol feeding: A) isocalorically fed controls not receiving ethanol; B) isocalorical controls subjected to a single ethanol intoxication period; C) animals subjected to 15 intoxication-withdrawal episodes (spontaneous seizures); D) same as C, but without developing seizures. A radio receptor technique was applied in the characterization of the receptor complex comprising specific binding to the BZ-receptor, the chloride channel and the GABA receptor by 3H-diazepam, 35S-TBPS and 3H-muscimol, respectively. The allosteric couplings among the components of the receptor complex were studied by 3H-diazepam and 35S-TBPS binding enhancement tests involving muscimol, ZK 93423 and DMCM. Cortex, hippocampus and cerebellum were the brain regions studied. Except for a reduced specific binding of 3H-diazepam in cerebellum, there were no indications of changes in specific binding to any part of the receptor complex. The allosteric coupling of BZ and GABA receptors as well as chloride channel-BZ receptors were unchanged in all groups. It is notable that no changes at all could be related to number of intoxication-withdrawal episodes or to the development of seizures. Thus, the present study gave no indication that the GABA/benzodiazepine receptor chloride channel complex is directly involved in the augmentation of cerebral nervous system excitability (seizures) during repeated episodes of physical ethanol dependence.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Ballenger JC, Post RM (1978) Kindling as a model for alcoholic withdrawal syndromes. Br J Psychiatry 133:1–14

    Google Scholar 

  • Bosio A, Lucci L, Spano PF, Trabucci M (1982) Cerebral toxic effects of chronic ethanol treatment: actions on GABA and benzodiazepine recognition sites. Toxicol Lett 13:99–104

    Google Scholar 

  • Braestrup C, Nielsen M (1986) Benzodiazepine receptor binding in vivo and efficacy. In: Olsen RW, Venter JC (eds) Benzodiazepine/GABA receptors and chloride channels. Liss, New York, pp 167–184

    Google Scholar 

  • Braestrup C, Nielsen M, Krogsgaard-Larsen P, Falch E (1979) Partial agonists for brain GABA/benzodiazepine receptor complex. Nature 280:331–333

    Google Scholar 

  • Braestrup C, Honoré T, Nielsen M, Petersen EN, Jensen LH (1984) Ligands for benzodiazepine receptors with positive and negative efficacy. Biochem Pharmacol 33:859–862

    Google Scholar 

  • Burnham WM, Niznik HB, Okazaki MM, Kish SJ (1983) Binding of [3H]flunitrazepam and [3H]Ro5–4864 to rude homogenates of amygdala-kindled rat brain: two months post seizures. Brain Res 279:359–362

    Google Scholar 

  • Clemmesen L, Hemmingsen R (1984) Physical dependence on ethanol during multiple intoxication and withdrawal episodes in the rat: evidence of a potentiation. Acta Pharmacol Toxicol 55:345–350

    Google Scholar 

  • Greenberg DA, Cooper EC, Gordon A, Diamond I (1984) Ethanol and the γ-aminobutyric acid-benzodiazepine receptor complex. J Neurochem 42:1002–1068

    Google Scholar 

  • Hemmingsen R, Chapman AG (1980) Cerebral metabolic state during the ethanol withdrawal reaction in the rat. J Neurochem 34:1561–1566

    Google Scholar 

  • Hemmingsen R, Kramp P, Rafaelsen OJ (1979) Delirium tremens and related clinical states. Aetiology, pathophysiology and treatment. Acta Psychiatr Scand 59:337–369

    Google Scholar 

  • Hemmingsen R, Braestrup C, Nielsen M, Barry DI (1982) The benzodiazepine/GABA receptor complex during severe ethanol intoxication and withdrawal in the rat. Acta Psychiatr Scand 65:120–126

    Google Scholar 

  • Hollander M, Wolfe DA (1973) Nonparametric statistical methods. Wiley, New York

    Google Scholar 

  • Iadarola MJ, Gale K (1982) Substantia nigra: site of anticonvulsant activity mediated by γ-amino-butyric acid. Science 218:1237–1240

    Google Scholar 

  • Kramp PX, Rafaelsen OJ (1978) Delirium tremens: a double blind comparison of diazepam and barbital treatment. Acta Psychiatr Scand 58:174–190

    Google Scholar 

  • McNamara JO, Peper AM, Patrone V (1980) Repeated seizures induce long-term increase in hippocampal benzodiazepine receptors. Proc Natl Acad Sci USA 77:3029–3032

    Google Scholar 

  • Majchrowicz E (1975) Induction of physical dependence upon ethanol and the associated behavioral changes in the rat. Psychopharmacology 43:245–254

    Google Scholar 

  • Nielsen M, Honoré T, Braestrup C (1985) Radiation inactivation of brain [35S]-t-butylbicyclophosphorothionate binding sites reveals complicated molecular arrangements of the GABA/benzodiazepine receptor chloride channel complex. Biochem Pharmacol 34:3633–3642

    Google Scholar 

  • Niznik HB, Kish SJ, Burnham WM (1983) Decreased benzodiazepine receptor binding in amygdala-kindled rat brains. Life Sci 33:425–430

    Google Scholar 

  • Olsen RW (1982) Drug interactions at the GABA receptor-ionophore complex. Annu Rev Pharmacol Toxicol 22:245–277

    Google Scholar 

  • Rondouin G, Lerner-Natoli M, Chandieu I, Chickeportiche R, Baldy-Moulinier M (1985) GABA transport in kindling-induced hyperexcitability state. J Cereb Blood Flow Metab [Suppl 1] 5:371–372

    Google Scholar 

  • Schoemaker H, Smith TL, Yamamura HI (1983) Effect of chronic ethanol consumption on central and peripheral type benzodiazepine binding sites in the mouse brain. Brain Res 258:347–350

    Google Scholar 

  • Shin C, Pedersen HB, McNamara O (1985) γ-aminobutyric acid and benzodiazepine receptors in the kindling model of epilepsy: a quantitative radiohistochemical study. J Neurosci 5:2696–2701

    Google Scholar 

  • Tallman JF, Thomas JW, Gallager DW (1978) GABA-ergic modulation of benzodiazepine binding site sensitivity. Nature 274:383–385

    Google Scholar 

  • Tamborska E, Marangos PJ (1986) Brain benzodiazepine binding sites in ethanol dependent and withdrawal states. Life Sci 38:465–472

    Google Scholar 

  • Ticku MK, Burch T (1980) Alterations in γ-aminobutyric acid receptor sensitivity following acute and chronic ethanol treatments. J Neurochem 34:417–423

    Google Scholar 

  • Tietz EI, Gomez F, Berman RF (1985) Amygdala kindled seizure stage is related to altered benzodiazepine binding site density. Life Sci 36:183–190

    Google Scholar 

  • Volicer L, Biagioni TM (1982) Effect of ethanol administration and withdrawal on GABA receptor binding in rat cerebral cortex. Subst Alcohol Actions Misuse 3:31–39

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ulrichsen, J., Clemmesen, L., Barry, D. et al. The GABA/benzodiazepine receptor chloride channel complex during repeated episodes of physical ethanol dependence in the rat. Psychopharmacology 96, 227–231 (1988). https://doi.org/10.1007/BF00177565

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00177565

Key words

Navigation