thesis
GABA shunt enzymes and the relationship with morphine abstinence
- Publication date
- 14 September 1977
- Publisher
- 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.