Reversal by alpha-2 agonists of diazepam withdrawal hyperactivity in rats

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 alpha 2 agonists, clonidine, guanfacine and B-HT 920, were studied on the diazepam withdrawal phenomena. Clonidine (100 micrograms/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 micrograms/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 alpha 2 receptors in the action of clonidine.

Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in diazepam-dependent rats

“…The slow time course of withdrawal reaction may be explained in terms of slow elimination of an accumulated active metabolite of parent drug (N-desmethyldiazepam) resulting in the gradual loss of pharmacological activity (Ryan and Boisse 1983). Similar results were seen by Kunchandy and Kulkarni (1986).…”

Modulatory effect of alpha2 adrenoceptor agonists on Ro 5-4864-induced convulsions in rats and mice

“…1984;Kunchandy etal. 1984;Kunchandy and Kulkarni 1986). A similar profile of potency is found in the present study also.…”

“…This discrepancy in action correlates with their potency as well as pharmacokinetic parameters. In in vivo studies, clonidine is reported to be the most potent alpha2 adrenoeeptor agonists even though guanfacine and B-HT 920 are more specific in alphaz receptor binding (Kobinger and Pichler 1980;Scholtysik 1980;Buccafusco et al 1984;Kunchandy et al 1985;Kunchandy and Kulkarni 1986). In in vitro studies, ICI 106270 has been shown to have a specificity and potency equal to clonidine, but it was less potent when administered intravenously, indicating less penetration through the blood-brain barrier due to low lipophilicity.…”

Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence

“…File neurochemical mechanisms might underlie different components of the withdrawal syndrome. For example, clonidine reversed withdrawal-induced hyperactivity (Kunchandy and Kulkarni 1986), but was ineffective against the anxiogenic response detected in the elevated plus-maze (Baldwin et al 1989).…”