Abstract
Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg, IP, for 3 weeks. On abrupt termination of the drug, the animals showed withdrawal hyperactivity which was indicated by increased horizontal locomotion and vertical activity, and diarrhoea. The peak effect was seen 3 days after the withdrawal of diazepam. Effects of various alpha2 agonists, clonidine, guanfacine and B-HT 920, were studied on the diazepam withdrawal phenomena. Clonidine (100 μg/kg, IP) given twice a day at an interval of 12 h prevented both withdrawal-induced hyperactivity and diarrhoea. On the contrary, equimolar doses of guanfacine and B-HT 920 failed to reverse withdrawal-induced hyperactivity but attenuated the effect of diarrhoea. However, higher doses (500 μg/kg, IP) of guanfacine and B-HT 920 given twice a day at 12-h intervals were found to be effective. Pretreatment with yohimbine (1.5 mg/kg, IP) reversed the protective effect of clonidine, indicating the involvement of alpha2 receptors in the action of clonidine.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bousquet P, Guertzenstein PG (1973) Localization of the central cardiovascular action of clonidine. Br J Pharmacol 49:573–579
Cumin R, Bonetti EP, Scherschlicht R, Haefely WE (1982) Use of benzodiazepine antagonist, Ro 15–1788, in studies of physiological dependence on benzodiazepines. Experientia 38:833–834
Dews PB (1953) The measurement of the influence of drugs on voluntary activity in mice. Br J Pharmacol 8:46–48
Dijoseph JF, Taylor JA, Nabi Mir G (1984) Alpha2 receptors in the gastrointestinal system: A new therapeutic approach. Life Sci 35:1031–1042
Fariello RW, Ticku MK (1983) The perspective of GABA replenishment therapy in the epilepsies: a critical evaluation of hopes and concerns. Life Sci 33:1629–1634
Gallager DW, Lakoski JM, Gonsalves SF, Rauch SL (1984) Chronic benzodiazepine treatment decrease post synaptic GABA sensitivity. Nature 308:74–77
Gold MS, Redmond DE, Kleber HD (1978) Clonidine blocks acute opiate-withdrawal symptoms. Lancet ii:599–602
Gonsalves SF, Gallager DW (1985) Spontaneous and Ro 15–1788-induced reversal of subsensitivity of GABA following chronic benzodiazepines. Eur J Pharmacol 110:163–170
Hallstrom C, Lader M (1981) Benzodiazepine withdrawal phenomena. Int Pharmacopsychiatry 16:235–244
Jarrott B, Louis WJ, Summer RJ (1982) (3H)-Guanfacine: A radioligand that selectively labels high affinity alpha2 adrenoceptor sites in homogenates of rat brain. Br J Pharmacol 75:401–408
Kobinger W, Pichler L (1980) Investigation into different types of post- and pre-synaptic alpha adrenoceptors at cardiovascular sites in rats. Eur J Pharmacol 65:393–402
Lamb RJ, Griffiths RR (1985) Effect of repeated Ro 15–1788 administration in benzodiazepine dependent baboons. Eur J Pharmacol 110:257–261
Lukas SE, Griffiths RR (1982) Precipitated withdrawal by a benzodiazepine receptor antagonists (Ro 15–1788) after seven days of diazepam. Science 217:1161–1163
Martin WR, McNicholas LF, Cherian S (1982) Diazepam and pentobarbital dependence in the rat. Life Sci 31:721–730
McNicholas LF, Martin WR, Cherian S (1983) Physical dependence on diazepam and lorazepam in the dog. J Pharmacol Exp Ther 226:783–789
Mottram DR (1983) Pre-junctional alpha2-adrenoceptor activity of B-HT 920. J Pharm Pharmacol 35:652–655
Murphy SM, Owen RT, Tyrer PJ (1984) Withdrawal symptoms after six weeks treatment with diazepam. Lancet ii:1389
Petursson H, Lader MH (1981) Withdrawal from long term benzodiazepine treatment. Br Med J 283:643–645
Pevnick JS, Jasinski DR, Haertzen CA (1978) Abrupt withdrawal from therapeutically administered diazepam. Arch Gen Psychiatry 35:995:998
Ryan G, Boisse NR (1983) Experimental induction of benzodiazepine tolerance and physical dependence. J Pharmacol Exp Ther 226:100–107
Saameli K, Scholtysik G, Waite R (1975) Pharmacology of BS 100–141, a centrally acting antihypertensive drug. Clin Exp Pharmacol Physiol (suppl) 2:207–212
Scholtysik G (1980) Pharmacology of guanfacine. Br J Clin Pharmacol 10:215–245
Scholtysik C, Jerie P, Picard CW (1980) Guanfacine. In: Scriabin A (ed) Pharmacology of antihypertensive drugs. New York, Raven press, pp 79–98
Scholtysik G, Lauener H, Eichenberger E, Burki H, Salzmann R, Muller-Schweinitzer E, Waite R (1975) Pharmacological actions of the antihypertensive agent N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride (BS 100–141). Arzneim Forsch 25:1483–1491
Tyrer P, Rutherford D, Huggett T (1983) Benzodiazepine withdrawal symptoms and propranolol. Lancet i:520–522
Wartenburg AA (1983) Treatment of alcohol withdrawal syndrome. JAMA 9:1271
Williams VC, Varnado GC, Nwangwu PU (1985) Clinical pharmacology of Benzodiazepines. Drugs of Today 2:75–96
Winokur A, Rickels K, Greenblatt DJ, Snyder PJ, Schatz NJ (1980) Withdrawal reaction from long term low dose administration of diazepam. Arch Gen Psychiatry 37:101–105
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kunchandy, J., Kulkarni, S.K. Reversal by alpha-2 agonists of diazepam withdrawal hyperactivity in rats. Psychopharmacology 90, 198–202 (1986). https://doi.org/10.1007/BF00181241
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00181241