Continuous exposure to FG 7142: behavioural sensitisation is not accompanied by changes in benzodiazepine/GABA receptor coupling

Abstract

Chronic intermittent high-dose treatment with N-methyl-β-carboline-3-carboxamide (FG 7142) leads to kindling accompanied by reduction in γ-aminobutyric acid (GABA) receptor function, whereas chronic continuous administration may result in behavioural effects in the opposite direction from those of acute FG 7142. In the present study, we have investigated the effects of continuous administration of low doses of FG 7142 on the response to an acute challenge dose of FG 7142 in an ethologically based model of anxiety. Rats treated continuously for 14 days with FG 7142 delivered by osmotic minipump at a rate of 1.2-1.5 mg/kg/day showed sensitisation to the anxiogenic effects of a challenge dose of FG 7142 (6 mg/kg), as measured in the elevated plus-maze. This was not accompanied by any change in benzodiazepine/GABA receptor coupling, as assessed by the 'GABA shift'. These results indicate that continuous low-dose treatment with FG 7142 can elicit sensitisation to the behavioural effects of FG 7142, but that this is unlikely to be mediated by changes in benzodiazepine/GABA receptor coupling.

Keywords

FG 7142 chronic treatment sensitisation elevated plus-maze benzodiazepine/GABA receptor coupling rat

References

Adamec R. (1991) Acute and lasting effects of FG 7142 on defence and approach-attack behaviour in cats—implications for models of anxiety which use response suppression. J Psychopharmacol 5: 29-55

Adamec R. (1993) Lasting effects of FG 7142 on anxiety, aggression and limbic physiology in the cat. J Psychopharmacol 7: 232-248

Brett R.R. (1992) Chronic diazepam treatment: effect on the GABA A receptor complex. PhD Thesis, University of Strathclyde

Brett R.R. , Pratt J.A. (1990) Chronic handling modifies the anxiolytic effect of diazepam in the elevated plus-maze. Eur J Pharmacol 178: 135-138

Bruhwyler J. , Chleide E. , Houbeau G. , Mercier M. (1991) Stimulant effect of the β-carboline FG 7142 in the open-field test. Eur J Pharmacol 200: 183-185

Corda M.G. , Giorgi O. , Biggio G. (1986) Behavioural and biochemical evidence for a long-lasting decrease in GABAergic function elicited by chronic administration of FG 7142 . Brain Res 384: 60-67

Corda M.G. , Longoni B. , Giorgi O. , Fernandez A. , Biggio G. (1988) Chronic treatment with FG 7142 reduces the function of the GABAA receptor-coupled chloride ionophore in rats. Neurosci Res Commun 3: 167-174

File S.E. (1985) Tolerance to the behavioral actions of benzodiazepines . Neurosci Biobehav Rev 9: 113-121

File S.E. , Pellow S. , Braestrup C. (1985) Effects of the beta-carboline, FG 7142, in the social interaction test of anxiety and the holeboard: correlations between behavior and plasma concentrations. Pharmacol Biochem Behav 22: 941-944

10.

Gallager D.W. , Marley R.J. , Hernandez T.D. (1991) Biochemical and electrophysiological mechanisms underlying benzodiazepine tolerance and dependence. In Pratt J (ed.), The biological bases of drug tolerance and dependence. Academic Press, London , pp. 49-70

11.

Handley S.L. , McBlane J.W. (1993) An assessment of the elevated X-maze for studying anxiety and anxiety modulating drugs. J Pharmacol Toxicol Methods 29: 129-138

12.

Jevanjee F. , Little H.J. , Martin I.L. , Nicholass J.M. , Nutt D.J. (1985) Is FG 7142 mediated kindling due to changes in efficacy at the benzodiazepine/GABA receptor complex? Br J Pharmacol 84: 188P

13.

Laurie D.J. (1990) Neuroanatomical studies on the acute and chronic effects of benzodiazepine receptor ligands. PhD Thesis, University of Strathclyde

14.

Laurie D.J. , Gray A.M. , Pratt J.A. (1990) Influence of mammillary body lesions on the effects of diazepam and FG 7142 in the elevated plus-maze test for anxiety. Neurosci Lett 38(Suppl): S105

15.

Lewin E. , Peris J. , Bleck V. , Zahniser N.R. , Harris R.A. (1989) Chemical kindling decreases GABA-activated chloride channels of mouse brain. Eur J Pharmacol 160: 101-106

16.

Lister R.G. (1990) Ethologically-based animal models of anxiety disorders . Pharmacol Ther 46: 321-340

17.

Little H.J. , Nutt D.J. , Taylor S.C. (1984) Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling. Br J Pharmacol 83: 951-958

18.

Little H.J. , Nutt D.J. , Taylor S.C. (1987) Kindling and withdrawal changes at the benzodiazepine receptor. J Psychopharmacol 1: 35-46

19.

Marley R.J. , Heninger C. , Hernandez T.D. , Gallager D.W. (1991) Chronic administration of β-carboline-3-carboxylic acid methylamide by continuous intraventricular infusion increases GABAergic function. Neuropharmacology 30: 245-251

20.

Pritchard G.A. , Galpern W.R. , Lumpkin M. , Miller L.G. (1991) Chronic benzodiazepine administration. VIII. Receptor upregulation produced by chronic exposure to the inverse agonist FG-7142. J Pharmacol Exp Ther 258: 280-285

21.

Schneider H.H. , Stephens D.N. (1988) Co-existence of kindling induced by the β-carboline, FG 7142, and tolerance to diazepam following chronic treatment in mice. Eur J Pharmacol 154: 35-45.

22.

Thiébot M-H. , Soubrié P. , Sanger D. (1988) Anxiogenic properties of β-CCE and FG 7142: a review of promises and pitfalls. Psychopharmacology 94: 452-463