Anticonvulsant Effects of Bretazenil (Ro 16-6028) During Ontogenesis

Anticonvulsant action of a new benzodiaze-pine, bretazenil (Ro 16–6028), was studied in 240 rats in five age groups: age 7, 12, 18, 25 and 90 days. Motor seizures induced by metrazol (pentamethylenetetrazol, PTZ, 100 mg/kg subcutaneously (s.c.) except for 18-day-old rats which received a dose of 90 mg/kg) served as a model. Animals were pretreated with Ro 16–6028 in doses of 0.001–0.1 mg/kg intraperitoneally (i.p.) 10 min before metrazol. Both types of metrazol-induced seizures, minimal (mMS, predominantly clonic with preserved righting ability) and major (MMS, generalized tonic-clonic), were suppressed by Ro 16–6028 in a dose-dependent manner. Major seizures were always more sensitive to Ro 16–6028 than were minimal seizures. The youngest rats exhibited maximal effects of Ro 16–6028 against major seizures. On the other hand, this drug increased the incidence of minimal seizures in 7- and 12-day-old rats, i.e., in age groups in which this type of seizure is rare under control conditions.     

Effects of Vigabatrin (γ-vinyl GAB A) on Neuro transmission-Related Amino Acids and on GAB A nd Benzodiazepine Receptor Binding in Rats

The effect of 12-day intraperitoneal i.p. administration of vigabatrin (GVG, gamma-vinyl GABA) to rats on the neurotransmission-related amino acids in various brain regions (cortex, hippocampus, cerebellum, and spinal cord), cisternal fluid (CSF) and blood was studied. Results showed that GVG administration increased the levels of GABA in cortical and subcortical regions of the brain and CSF without affecting GABA and benzodiazepine receptors in the cortex. In addition, a dose-dependent decrease was noted in the concentration of glutamate in the hippocampus and in the concentrations of aspartate and glutamine in the cortex, hippocampus, and cerebellum. The changes in the levels of amino acids in the brain, except for that of GABA, were not reflected in the CSF, however, and the levels of amino acids in discrete brain regions did not show any correlation with those in the serum or in the CSF. The results suggest that GVG administration might suppress development and spread of seizures not only by elevating the level of the inhibitory amino acid GABA, but also by decreasing the levels of excitatory amino acids in the brain.     

Effects of Dextromethorphan, a Nonopioid Antitussive, on Development and Expression of Amygdaloid Kindled Seizures

The effects of dextromethorphan (DM), a nonopioid antitussive and a functional N-methyl-D-aspartate (NMDA) antagonist, on expression and development of amygdaloid kindled seizures were examined. The maximum anticonvulsant effect of DM (30 mg/kg) on fully kindled seizures appeared within 30 min of administration and lasted for at least 2 h. DM decreased, in a dose-dependent manner [10-70 mg/kg, intraperitoneally (i.p.)], the severity of kindled seizures 30 min after injection, but the estimated ED50 was 3 times higher than the previously reported value for maximal electroshock convulsions. Furthermore, the high dose (70 mg/kg), while suppressing kindled seizures, produced myoclonus which coincided with EEG spike activity in the amygdala and the cortex. When tested on the development of kindling, 30 mg/kg DM retarded the growth of afterdischarge in the amygdala and the cortex, but had no effect on the development of behavioral seizures. DM 60 mg/kg accelerated development of kindling and produced spontaneous seizures. These results indicate that DM, unlike other NMDA antagonists, has a narrow therapeutic window as an anticonvulsant on kindled seizures and that higher doses may potentiate the kindling process.     

Effects of valproate in a model nervous system (buccal ganglia of Helix pomatia): I. Antiepileptic actions.

Cellular actions of valproate (VPA) were studied using intracellular recordings of identified neuronal individuals in the buccal ganglia of Helix pomatia. Under nonepileptic conditions, VPA induced (a) a hyperpolarization, (b) slight changes in action potentials (AP), and (c) an increase in membrane resistance. Under epileptic conditions (i.e., during application of an epileptogenic drug), extracellular application of VPA decreased frequency of occurrence of epileptic depolarizations (early effect) and led to a decay in paroxysmal depolarizations (late effect). Intracellular injection of VPA could block epileptic activity in the treated neuron immediately. A metabolite of VPA (trans-2-en VPA) mainly lacked the late effect (decay in epileptic depolarizations) obtained with VPA. Results suggest that the early antiepileptic effect is exerted from the extracellular side of the neuronal membrane and that the late effect results from intracellular actions of VPA being delayed by slow access to an intracellular site.     

Effects of the imidazobenzodiazepine Ro 15-4513 on saccharin choice and acceptance, and on food intake, in the rat

The general aim of the present series of experiments was to investigate the effects of the imidazobenzodiazepine, Ro 15-4513, on ingestional behavior in the rat. The more specific aims were to test its effects on preference for sweet taste, to determine if it acts as a benzodiazepine-receptor inverse agonist, and if it selectively reduces sweetness preference. The results indicated that Ro 15-4513 (1.0-10 mg/kg, i.p.) abolished the preference for a 0.05% sodium saccharin solution in a two-choice test. Water intake in the same test was unaffected. Second, at 10 mg/kg, it suppressed saccharin ingestion in an acceptance test; this effect was completely reversed by the selective benzodiazepine antagonist, Ro 15-1788 (20 mg/kg). Third, Ro 15-4513 (1.0-10 mg/kg) reduced palatable food consumption in non-deprived rats, an effect which was also antagonized by Ro 15-1788. The results are consistent the bidirectional modulation of ingestional responses to palatable taste stimuli as a consequence of drug actions at benzodiazepine receptors. Furthermore, they emphasize that any reduction in consummatory responses produced by Ro 15-4513 is likely to reflect inverse agonist characteristics, as distinct from any putative ethanol antagonist property.     

Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease

Summary Behavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinson's disease.