Ro 15-4513: partial inverse agonism at the BZR and interaction with ethanol.

The imidazobenzodiazepinone derivative Ro 15-4513 has the activity profile of a partial inverse (low efficacy) agonist at the benzodiazepine receptor (BZR). It reverses central nervous depressant effects of diazepam, and, in part, of phenobarbitone and ethanol in mice, rats and cats in behavioural, electrophysiological, and neurochemical paradigms. The interaction of Ro 15-4513 with barbiturates and ethanol is due to its inverse agonistic (negative allosteric modulatory) property at the BZR, as it was reversed by the selective BZR blocker flumazenil (Ro 15-1788). In the present experiment situations, other BZR partial inverse agonists in subconvulsant or overt convulsant doses were less effective against ethanol effects than Ro 15-4513. Possible mechanisms for this differential activity of BZR inverse agonists are discussed.

L-cycloserine: behavioural and biochemical effects after single and repeated administration to mice, rats and cats.

L-Cycloserine dose-dependently inhibited the activity of gamma-aminobutyric acid (GABA)-transaminase (GABA-T) and elevated the level of GABA in whole mouse brain with a peak effect 3-4 hr after a single intraperitoneal injection. At a dose (30 mg/kg) which elevated the level of GABA almost 4-fold, L-cycloserine moderately increased the content of alanine and slightly reduced that of aspartate, glutamate and glycine in the brain. L-Cycloserine (10-30 mg/kg, p.o. or i.p.) prevented tonic seizures induced by 3-mercaptopropionic acid (3-MPA) and audiogenic seizures in DBA/2 mice, without affecting those evoked by pentylenetetrazol, bicuculline and electroshock. Similarly small doses of L-cycloserine reduced the level of cGMP in the cerebellum of rats, prevented its elevation by 3-MPA and attenuated the hypothalamically-elicited rage reaction in cats. Larger doses of L-cycloserine (greater than 30-100 mg/kg) impaired the performance of mice in the rotarod, chimney and horizontal wire tests, and reduced spontaneous locomotor activity of rats. Upon repeated administration the inhibitory effect of L-cycloserine on the activity of GABA-T and on seizures elicited by 3-MPA in mice increased. In contrast, the depressant action of L-cycloserine on motor performance and locomotion declined in subchronically-treated mice and rats. The levels of amino acids in brain after repeated administration did not differ markedly from those in acutely-treated mice. It is suggested that small doses of L-cycloserine, probably by increasing GABAergic inhibition, reduce hyperexcitability in the brain in acute- and subchronically-treated animals. Larger doses of L-cycloserine, possibly by inducing multiple neurochemical changes, evoke central depressant effects which diminish during subchronic treatment.