Neurochem. Int. Vol. 11, No. 1, pp. 49-53, 1987 0197-0186/87 $3.00+0.00 Printed in Great Britain. All rights reserved © 1987 Pergamon Journals Ltd DISCONTINUATION EFFECTS OF OXAZEPAM AND DIAZEPAM TREATMENT ON BRAIN GABA METABOLISM IN RATS MIR AHAMED HOSSAIN, ISHWAR S. SINGH, TAPAS K. MAKAR, SUBHENDU GOSWAMI and JAGAT J. GHOSI-I* Department of Biochemistry, University College of Science, Calcutta University, 35 Ballygunge Circular Road, Calcutta 700 019, India (Received 26 November 1986; accepted 2 February 1987) Abstract--The effects of oxazepam and diazepam (both at 10 mg/kg, i.p.) during continuous treatment for 15 days and following discontinuation after 5 days onwards on cerebral glutamic acid decarboxylase (GAD) and GABA-aminotransferase (GABA-T) have been studied. It has been found that during continuous treatment as well as following discontinuation after 5 days, a significant increase in GAD activity is observed in case of diazepam but not in case of oxazepam. On the other hand, a marked decrease in GABA-T activity is observed during continuous treatment up to 15 days with both diazepam and oxazepam but during discontinuation phase, the decreased GABA-T activity tends to increase and attain normal value much earlier in case of oxazepam than diazepam. This differential effect of oxazepam and diazepam on y-aminobutyric acid (GABA) metabolism, following discontinuation of treatment, may possibly contribute to the difference in withdrawal effects associated with the two benzodiazepines. The after effects of the discontinuation of benzo- diazepine (BDZ) drugs following continued use have been reported to elicit characteristic withdrawal reac- tions (Pevnic et al., 1978; Mendelson, 1978; Ayed, 1979; Winokur et al., 1980). However, the so-called withdrawal effects are also reported to differ with different group of BDZ drugs, both short and long acting ones (Hollister, 1981; Lawrence et al., 1983). Several investigators have implicated the role of ),-aminobutyric acid (GABA) in the mechanism of BDZ withdrawal and associated processes. BDZ drugs have been reported to block GABA-antagonist induced convulsion, to enhance GABA binding to synaptic membrane and to potentiate inhibitory ac- tion of GABA (Costa et al., 1975, 1979). On the other hand, GABA as well as GABA agonists increase the binding of BDZ (Briley et al., 1978; Tallman et al., 1978). Cowen and Nutt (1982) hypothesized that during repeated use of BDZ, adaptive changes in the GABAergic neurotransmission occurs and an acute reduction in GABA function following withdrawal of BDZs may possibly account for the hyperexcitability *Address correspondence to: Professor J. J. Ghosh, Centenary Professor of Biochemistry, Department of Biochemistry, University College of Science, 35 BaUygunge Circular Road, Calcutta 700 019, India. 49 NC,I. II/I--D and withdrawal effects. However, despite many stud- ies relating GABA and BDZ action, studies at the level of GABA metabolism during continuous use as well as following discontinuation of different BDZ drugs have attracted relatively little attention. In the present experiment two representative BDZ drugs with distinct pharmacokinetic properties, oxazepam and diazepam, have been used to study their effect on GABA metabolising enzymes, glutamic acid decar- boxylase (GAD, EC 4.1.1.15) and on GABA- aminotransferase (GABA-T, EC 2.6.1.19) during continuous treatment and following abrupt discon- tinuation. EXPERIMENTAL PROCEDURES Materials GABA, Na-L-Glutamic acid, ~t-oxoglutarate, pyri- doxalphosphate, 3-methyl 2-benzothiozolone 2-hydrazone (MBTH) were obtained from Sigma. Drugs Diazepam (Hoffman La Roche, Switzerland) Oxazepam (John Wyeth, U.K.). Animals Adult male albino rats of Charles Foster strain and weighing about 120-140 g were used for the study. The rats were housed at 25_+ I°C, (12h light and dark cycle) and maintained on food and water ad libitum. Oxazcpam and Diazepam in 30% polyethylene glycol vehicle was adminis- tered intraperitoneally at the dose of 10mg/kg body wt.