GABA shunt enzymes and the relationship with morphine abstinence

Selective inhibition of tbe rate-limiting step in tbe degradation of tbe inhibitory neurotransmitter Y·aminobutyric acid (GABA) might be of potential use in the treatment of many neurological or psychiatric disorders since it might correct a central GABA deficiency. Alternatively, as such diseases have not been correlated convincingly witb changes in tbe GABA-ergic system, inhibition of this rate-limiting step by specific drugs in clinical trials could be useful in demonstrating tbe existence of a GABA deficiency in tbese disturbances. The study of effects of drugs exerting a tberapeutic action in specific neurological or psychiatric disorders on the rate-limiting enzyme in GABA degradation might also be useful. Therefore, tbe primary object of tbis tbesis has been to find the rate-limiting step in GABA degradation. GABA is degraded by tbe consecutive action of two enzymes: GABA-transaminase and SSA-dehydrogenase. It is almost generally believed tbat GABA-transaminase is rate-limiting in GABA degradation. As a consequence, SSA-dehydrogenase has been almost completely ignored as a likely candidate for a regulatory function in tbe GABA ·shunt. Based on in vitro experiments it is suggested in this tbesis that SSA-dehydrogenase may have a regulatory function in the GABA shunt. To test this hypothesis in vivo it became of crucial importance to fmd a behavioural correlate of increased GABA-ergic activity in tbe rat. Such a behavioural correlate might be the increased locomotor activity and quasi-morphine abstinence behaviour observed after administration of di·n-propylacetate (DPA) to tbe rat. This drug is used in the treatment of petit mal epilepsy (SIMON & PENRY, 1975) and probably acts via inhibition of SSA-dehydrogenase (HARVEY et al, 1975; ANLEZARK et al., 1976). The special character of tbe behaviour observed after administration of DPA suggests tbat an increased GABA-ergic activity might be related to the well known morphine abstinence syndrome. Therefore, some studies have been conducted witb morphine to demonstrate this relationship. In addition, this DPA-induced abstinence behaviour has been studied pharmacologically to demonstrate its relationship witb an overactive GABA-ergic system in vivo.