Behavioural and biochemical effects of chronic reduction of cerebral noradrenaline receptor stimulation.

Mice were given various 7-day treatments designed to reduce cerebral noradrenergic function. Following these treatments, alterations in the sensitivity of limbic forebrain adenylate cyclase to noradrenaline (NA), and in the locomotor response of the mice to dopaminergic and noradrenergic agonists were studied. An enhanced response of the NA-sensitive adenylate cyclase to 1-NA(10-5 M), in comparison to control mice, was demonstrated after treatments producing a chronic reduction in stimulation of alpha-adrenergic receptors (phenoxybenzamine 10 mg/kg per day), beta-adrenergic receptors (propranolol, 0.05% diet), all noradrenergic receptors (reserpine 5 mg/kg, followed by FLA-63, 25 mg/kg per day), and dopaminergic as well as noradrenergic receptors (chlorpromazine, 5 mg/kg per day). Sensitivity of the NA-stimulated adenylate cyclase was not altered by chronic treatment with FLA-63 alone as a 0.05% diet. However, none of the chronic treatments except chlorpromazine administration increased the locomotor activity recorded for 2 h following apomorphine (1 mg/kg, s.c.) and none of the treatments altered the locomotor activity recorded in the 2 h following administration of the alpha-adrenergic agonist clonidine (1mg/kg, i.p.), or a combination of apomorphine (1 mg/kg, s.c.) plus clonidine (1 mg/kg, i.p.) The results support the hypothesis that noradrenergic stimulation plays a role secondary to that of dopamine in the production of locomotor activity.

Monoamine and GABA metabolism and the anticonvulsant action of di-n-propylacetate and ethanolamine-O-sulphate.

The time course of changes in behaviour, seizure response and cerebral monoamine and gamma-aminobutyric acid (GABA) metabolism has been studied in relation to the anticonvulsant actions of di-n-propylacetic acid (DPA) and ethanolamine-O-sulphate (EOS) on sound-induced seizures in DBA/2 mice. Changes in cerebral monoamine metabolism after EOS (75 or 150 mug, intracerebroventricularly) were not related to its anticonvulsant action. The primary effect was GABA-transaminase inhibition (by 50-70%) leading to a 2-4 fold increase in cerebral GABA concentration. Increases in brain GABA concentration (maximally 36%), 5-hydroxyindoleacetic acid (5HIAA, maximally 134%) and homovanillic acid (HVA, maximally 183%) were seen after DPA (400-600 mg/kg, i.p.). The time course of the increases in HVA and 5HIAA did not correlate with the anticonvulsant effect. Elimination of these increases by the use of inhibitors of monoamine synthesis (alpha-methyl-p-tyrosine and p-chlorophenyl-alanine) did not alter the anticonvulsant effect of DPA. Experiments using probenecid suggested that the increases in 5HIAA and HVA after DPA result from inhibition of their active transport out of the brain.

Picrotoxin convulsions and GABA metabolism after injection of anticonvulsants in chicks.

Two clinically effective anticonvulsants, phenobarbitone and diazepam, protected 5-day old chicks against picrotoxin convulsions without reducing brain GABA-transaminase activity or raising brain GABA concentration. Ethanolamine-O-sulphate and amino-oxyacetic acid, in doses which inhibited GABA-transminase by at least 63% and approximately doubled brain GABA concentration, did not significantly affect the ED50 for picrotoxin convulsions. The ED50 for picrotoxin convulsions was significantly raised by di-n-propylacetate (800 mg/kg) which inhibited GABA transaminase activity by 6% and elevated brain GABA concentration by 26%.

Effects of compound 48/80, a histamine-releasing agent, on accumulation and release of cyclic AMP in various regions of rat brain in vitro.

The effect of compound 48/80 in various rat brain regions - by means of incubating brain sclices with compound 48/80 - on cyclic AMP accumulation and release of the nucleotide into the incubation medium was studied. In all regions tested, accumulation of cyclic AMP occurred within at least 10 min. In the cortex, brain stem and cerebellar regions these increases of cyclic AMP could be blocked by propranolol, a beta-adrenergic antagonist. Diphenhydramin, an antihistaminic agent, was without effect in these regions, but could partially block the compound 48/80-induced rise of cyclic AMP in the hypothalamus. Propranolol had in this region only a moderate blocking effect. Release of cyclic AMP, induced by compound 48/80, occurred in all regions tested and could not be effectively blocked by propranolol or diphenhydramin.

Effects of anticonvulsant drugs on the cerebral enzymes metabolizing GABA.

The effect of anticonvulsant drugs on the activity of enzymes responsible for the further metabolism of GABA has been studied in mouse brain homogenates. Slight inhibition (5 to 20%) of GABA-T activity was seen with chlordiazepoxide (0.1 mM), ethosuximide (0.1 mM) and di-n-propylacetate (0.1 mM). No anticonvulsant drug (even at a concentration of 10 mM) produced inhibition comparable to that seen with amino-oxyacetic acid (65% at 0.01 mM). Succinic semialdehyde dehydrogenase activity was inhibited by 10 to 20% at low concentrations (0.01 to 0.1 mM) of diazepam, carbamazepine, beclamide, acetazolamide, and di-n-propylacetate, and by 40% or more at high concentrations (2.5 to 10.0 mM) of diazepam, phenobarbital, carbamazepine, beclamide, and di-n-propylacetate. Interference with the further metabolism of GABA may contribute to the antiepileptic action of drugs or to the acute neurological toxicity of anticonvulsant agents.