1. The
drug HA-966 (1-hydroxy-3-amino-pyrrolidone-2), which chemically resembles the cyclic form of
GABA, has been studied for neuro-pharmacological properties and for effects on the
catecholamine content of the corpus striatum.2. The acute effects on spontaneous behaviour of rodents included flaccid
catalepsy and reversible tranquillization in doses which were 5% or less of the lethal dose. Long lasting depression of the CNS, followed by complete recovery, was produced in the cat and the dog. In the monkey
HA-966 caused periodical sleeping episodes.3. The exploratory behaviour and the
amphetamine-induced motor activity in mice were blocked by
HA-966. The toxicity of
amphetamine in aggregated mice was only moderately reduced, suggesting that
HA-966 differs from
neuroleptics.4.
Tremors induced by chemical agents (
nicotine,
zinc and
tremorine) were markedly inhibited by
HA-966. The
muscarinic effects of
tremorine were not reduced by
HA-966, indicating a selective central antitremor effect.5.
HA-966 elevated the threshold to
strychnine convulsions and abolished the ipsilateral flexor reflex, while not having motor endplate blocking properties. It is suggested that
HA-966 depresses central internuncial neurones.6. In rats and rabbits
HA-966 produced synchronous EEG and inhibited the sensory arousal in doses not causing sedation. In the monkey the
drug caused a periodical dissociation between ;sleep-EEG' and behaviour.7. In rat brain,
HA-966 selectively elevated the
dopamine content in the corpus striatum, while no changes in
noradrenaline and
5-hydroxytryptamine contents could be demonstrated. The effect was still present when
dopa synthesis was inhibited with alpha-methyl-p-tyrosine.8. Several effects of intravenously administered
HA-966 became manifest after an appreciable delay and in hepatectomized mice the effects were much reduced. It is postulated that
HA-966 is converted to a pharmacologically active metabolite.9. The results are discussed in the light of current views on
drug therapy in extrapyramidal conditions and a
GABA-related hypothesis as to the mode of action of
HA-966 is presented.