GABA-mediated Transmission Research Articles

Effect of the Benzodiazepine Derivative, Diazepam, on the Clonidine-Stimulated Human Growth Hormone Secretion

gamma-Aminobutyric acid (GABA) has both stimulatory and inhibitory effect on human GH secretion. We previously reported that the benzodiazepine derivative diazepam, which exerts its main pharmacological effect by facilitating GABA-mediated transmission, is able to reduce the GH response to L-dopa and apomorphine. To establish whether diazepam affects the alpha-adrenergic regulation of GH secretion, the GH response to clonidine (an alpha-agonist) was investigated in seven volunteers after placebo and diazepam premedications. After placebo pretreatment, clonidine (0.15 mg iv infused over 20 min) significantly stimulated GH secretion: the mean serum GH level rose from a basal level of 4.7 +/- 1.1 (+/- SEM) ng/ml to a maximum of 10.8 +/- 1.6 ng/ml (P less than 0.025). After 3 days of diazepam treatment, a similar GH response to clonidine was observed; the mean serum GH level rose from a basal value of 2.3 +/- 0.3 ng/ml to a maximum of 9.4 +/- 1.3 ng/ml. It is concluded that the inhibitory effect of diazepam on human GH secretion is mediated via inhibition of dopaminergic transmission, whereas the alpha-adrenergic control of GH release is not affected. Since diazepam potentiates GABAergic transmission, its effect may reflect the role of endogenous GABA in human GH secretion.

Convulsant and anticonvulsant effects of opioids: Relationship to GABA-mediated transmission

The convulsant benzodiazepine Ro 5-3663, bicuculline and picrotoxin induced electroencephalographie (EEG) and behavioural convulsions. In rabbits, the EEG modifications consisted, with increasing doses, of three different patterns: slow waves in the optic lead, spike- and wave-complexes in the sensorimotor cortex, and grand-mal generalized seizures. These EEG effects were terminated by administration of diazepam (1 mg/kg) and morphine (0.25–1.0 mg/kg). Naloxone, in doses of 5–10 mg/kg, potentiated the effects of the three convulsant drugs. This potentiating phenomenon was also antagonized by the administration of diazepam and morphine. In membrane preparations, obtained from rat cortex, deprived of endogenous modulators of [ 3H]GABA binding, naloxone but not morphine, was able to inhibit [ 3H]GABA binding to its specific recognition sites. These data agree with previous findings indicating a GABA-antagonistic effect of naloxone, and support the hypothesis that the anticonvulsant effect of morphine might be, at least in part, due to an increase in GABAergic activity at the synaptic level.

Development of GABA neurons in dissociated cell culture of rat cerebral cortex

Cortical neurons dissociated from newborn rat brain were maintained on supporting glial monolayers in the presence of the mitotic inhibitor, FUdR. The ability of this type of primary culture (NG) to synthesize, store, metabolize, accumulate and release GABA was compared to that of neuron-free glial monolayers (G) cultured under the same conditions. While NG cultures synthesized and stored GABA, there was little GABA, or GABA-synthesizing activity (GAD) in G cultures. In contrast, appreciable activities of the GABA catabolizing enzyme, GABA-T, were present in both cultures. Furthermore, accumulation of GABA by high affinity uptake and K +-stimulated release of GABA were associated exclusively with the neurons. Morphological differentiation, GABA metabolism, uptake and release increased with increasing time in culture. The present evidence suggests that the NG preparation may represent a good model system to study GABA-mediated transmission in culture.

Behavioral and biochemical analysis of gaba-mediated inhibition in the early chick embryo

Exogenous γ-aminobutyric acid (GABA) decreased spontaneous motility in 4-, 6-, 7-, 9-, and 13-day chick embryos; the younger embryos were more sensitive. Neither the positional isomers of GABA, α-aminobutyric acid (AABA) and β-aminobutyric acid, nor the principle GABA catabolite, succinic acid, decreased motility in 4-day embryos. Several semi-rigid GABA analogues decreased motility in 4-day embryos with a potency that paralleled their effectiveness in displacing [ 3H]GABA in ligand-binding studies. The effects of AABA and GABA on hind-limb motility were quantitatively similar in thoracic spinal and sham-operated 7-day embryos. Bicuculline and picrotoxin elicited absolute motility increases at 6, 7 and 9 days of incubation. Picrotoxin and two bicyclophosphate GABA antagonists elicited relative motility increases while bicuculline elicited an absolute motility increase at 4 days. The two bicyclophosphates increased motility with a potency that paralleled their electrophysiological effectiveness. L-Glutamic acid decar☐ylase (GAD) activity was detected in the embryonic lumbar spinal cord at all ages examined (3–7 days) using a new radiometric cation-exchange method. γ-Aminobutyric acid transaminase (GABA-T) activity was detected in the lumbar spinal cord at the earliest age examined (day 5). Both GAD and GABA-T activity were detected at earlier ages than previously reported. GABA receptors, and the enzymes necessary for the synthesis and degradation of GABA, all appear to be present at (or before) the onset of spontaneous motility. GABA-mediated transmission appears to be present at 6 days and perhaps as early as 4 days.