Influence of a benzodiazepine, midazolam, and gamma-aminobutyric acid (GABA) on basal somatostatin secretion from cerebral and diencephalic neurons in dispersed cell culture.

To investigate the mechanisms of gamma-aminobutyric acid (GABA) and benzodiazepine-induced growth hormone (GH) release, we studied the effects of GABA and a water-soluble benzodiazepine, midazolam, on basal immunoreactive somatostatin secretion from fetal rat brain in dispersed cell culture. Both GABA and midazolam in concentrations of 10(-5) or 10(-6) M inhibited basal somatostatin secretion from either diencephalic or cerebral neurons in culture. Midazolam (10(-5) M) produced a 33.2 +/- 8.6% suppression (P = 0.004) and 10(-5) M GABA produced a 46.0 +/- 4.3% suppression (P = 0.0003) in the diencephalon cultures. When GABA and midazolam were used in combination over the 10(-5)-10(-9) M range, the drugs were shown to act independently (positive main effect, P less than 0.0001 for either drug by two-way analysis of variance); there was a simple additive effect with no statistically significant interaction between the two drugs over the 36 combinations tested. These results suggest that suppression of the GH inhibitory peptide, somatostatin, may be one of the mechanisms by which GABA and benzodiazepines stimulate GH secretion. Based on previous studies of GABA and benzodiazepine receptors, it appears likely that these drugs produce this inhibitory effect by interacting with unassociated lower affinity receptors which require micromolar concentrations of the drugs, and act through calcium-dependent pathways.